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WO2025262017A1 - Nutritional composition - Google Patents

Nutritional composition

Info

Publication number
WO2025262017A1
WO2025262017A1 PCT/EP2025/066846 EP2025066846W WO2025262017A1 WO 2025262017 A1 WO2025262017 A1 WO 2025262017A1 EP 2025066846 W EP2025066846 W EP 2025066846W WO 2025262017 A1 WO2025262017 A1 WO 2025262017A1
Authority
WO
WIPO (PCT)
Prior art keywords
cos
glucan
rhamnosus
nutritional composition
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/066846
Other languages
French (fr)
Inventor
Stéphane DUBOUX
Kieran James
Lisa Marcela LAMOTHE
Carine Blanchard
Cheong Kwet Choy KWONG CHUNG
Guénolée Eliane Marie PRIOULT
Murielle GRESSET
Delphine EGLI
Judith CRAMER
Florac DE BRUYN
Judith GAULOCHER
Danica Anja JAGGI-KUYPERS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Societe des Produits Nestle SA
Nestle SA
Original Assignee
Societe des Produits Nestle SA
Nestle SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Societe des Produits Nestle SA, Nestle SA filed Critical Societe des Produits Nestle SA
Publication of WO2025262017A1 publication Critical patent/WO2025262017A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135Bacteria or derivatives thereof, e.g. probiotics
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21Addition of substantially indigestible substances, e.g. dietary fibres
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • A61K35/741Probiotics
    • A61K35/744Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • A61K35/741Probiotics
    • A61K35/744Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745Bifidobacteria
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • A61K35/741Probiotics
    • A61K35/744Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747Lactobacilli, e.g. L. acidophilus or L. brevis
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20Bacteria; Culture media therefor
    • C12N1/205Bacterial isolates
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12RINDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00Microorganisms ; Processes using microorganisms
    • C12R2001/01Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225Lactobacillus

Definitions

  • Nutritional composition Field of the invention T he present invention relates to a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus modulating agent, or nutritional compositions comprising the combination.
  • the present invention also relates to uses of the combination, or of a nutritional composition comprising the combination.
  • P robiotics that is microbial organisms with a beneficial effect on the health or well- being of the host, can be used for the treatment or prevention of various diseases.
  • Lacticaseibacillus (formerly known as Lactobacillus) is a type of lactic acid bacteria which is used to ferment milk products and has been investigated for its health benefits for over 100 years.
  • Lacticaseibacillus rhamnosus (including the strain with ATCC Accession No. 53103 and strain CGMCC1.3724 (LPR)) has been shown to have several beneficial health effects including enhancing the immune response to vaccination, and the treatment or prevention of acute infectious diarrhea in children and adults, healthcare-associated- diarrhea, antibiotic-associated diarrhea, traveler's diarrhea, infant food allergies, dental caries, and acute respiratory infections (Segers, M.E. and Lebeer, S., 2014.
  • Bifidobacteria are one of the major genera of bacteria that make up the gastrointestinal tract microbiota in mammals. Bifidobacteria are among the first microbial colonizers of the intestines of newborns, and play key roles in the development of their physiology (Hidalgo-Cantabrana, C., et al., 2017. Microbiology spectrum, 5(3), pp.5-3). Moreover, alterations in composition and function of bifidobacteria have been associated with several gastrointestinal diseases, including inflammatory bowel disease, colorectal cancer, and irritable bowel syndrome (Tojo, R., et al., 2014. World journal of gastroenterology: WJG, 20(41), p.15163).
  • probiotics including L. rhamnosus and Bifidobacteria strains
  • probiotics have been proposed as therapeutic agents for gastrointestinal disorders.
  • existing solutions to enhancing the growth of L. rhamnosus have a number of drawbacks.
  • Probiotics need to be kept alive and be active at the site of action in order to exert their effects in the gastrointestinal tract and beyond (including the lungs), limiting their application.
  • Prebiotics generally require a dose of a few grams to deliver a benefit, which can make them less suitable for supplements since the capsule size typically limits ingredient dosage to below the gram range.
  • rhamnosus in the gastrointestinal tract of a subject.
  • Summary of the invention T he present inventors surprisingly found that a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent can advantageously be used in therapy because the combination showed increased growth of L. rhamnosus, increased growth of Bifidobacteria and increased production of short chain fatty acids (SCFA) in the gastrointestinal tract of the infant, young child and/or child.
  • SCFA short chain fatty acids
  • the inventors have unexpectedly found that the combination of L. rhamnosus and at least one further probiotic selected from the genus Lactobacillus, Streptococcus or Bifidobacterium enhances the growth of L.
  • L. rhamnosus in the gastrointestinal tract compared to the use of L. rhamnosus alone.
  • the inventors have found that a combination of L. rhamnosus and cello- oligosaccharides (COS) or of L. rhamnosus, cello-oligosaccharides (COS) and ⁇ -glucan synergistically enhances the growth of L. rhamnosus in the gastrointestinal tract and also increases the growth of Bifidobacteria and the levels of SCFAs stemming from the gastrointestinal tract.
  • COS cello- oligosaccharides
  • COS cello-oligosaccharides
  • ⁇ -glucan synergistically enhances the growth of L. rhamnosus in the gastrointestinal tract and also increases the growth of Bifidobacteria and the levels of SCFAs stemming from the gastrointestinal tract.
  • the present inventors have found that these specific combinations are particularly effective in increasing the growth and activity of L. r
  • the invention provides a way to increase the growth and activity of a probiotic (i.e., L. rhamnosus) with known health benefits.
  • a probiotic i.e., L. rhamnosus
  • the present invention provides a nutritional composition comprising Lacticaseibacillus rhamnosus and an L.
  • the composition comprises L. rhamnosus in an amount of 1 ⁇ 10 3 to 1.5 ⁇ 10 12 cfu/g of the composition (dry weight).
  • the L. rhamnosus has at least 99% Average Nucleotide Identity (ANI) to L. rhamnosus ATCC 53103 or to L. rhamnosus CGMCC1.3724 (LPR), preferably at least 99.9% ANI to L. rhamnosus ATCC 53103 or to L. rhamnosus CGMCC1.3724 (LPR).
  • ANI Average Nucleotide Identity
  • the L. rhamnosus ATCC 53103 is publicly available, and can be obtained commercially at the Belgian Coordinated Collection of Microorganisms under LMG 18243.
  • the L. rhamnosus is selected from L. rhamnosus ATCC 53103, L. rhamnosus LC705 (DSM 7061) and L. rhamnosus CGMCC1.3724 (LPR), preferably wherein the L. rhamnosus is LPR.
  • the L. rhamnosus-modulating agent is cello-oligosaccharides (COS).
  • COS cello-oligosaccharides
  • the rhamnosus-modulating agent is a combination of ⁇ - glucan and cello-oligosaccharides (COS).
  • the ⁇ -glucan and/or COS is derived from a plant, preferably a cereal.
  • the ⁇ -glucan and/or COS is derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt.
  • the ⁇ -glucan and/or COS is obtained from partial hydrolysis of a cereal comprising ⁇ -glucan and/or COS.
  • the COS are cellobiose or cellotriose.
  • the weight ratio of COS: ⁇ -glucan is from 10:90 to 90:10 dry weight, preferably from 25:75 to 75:25 dry weight.
  • the ⁇ -glucan is present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition.
  • the nutritional composition further comprises a probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus, Enterococcus, Bifidobacterium and Saccharomyces.
  • the L. rhamnosus-modulating agent comprises at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium.
  • the L. rhamnosus-modulating agent comprises at least one probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium.
  • the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461 (also known as CNCM I-2116), Lactobacillus johnsonii NCC 533 also known as Lactobacillus johnsonii CNCM I-1225 or Lactobacillus johnsonii LA1), Bifidobacterium animalis subsp. lactis NCC 2818 (also known as CNCM I-3446), Bifidobacterium longum subsp. longum NCC 2705 (also known as CNCM I-2618), Bifidobacterium longum subsp.
  • the composition according to the invention can comprise, in some embodiments, FOS (OF).
  • FOS FOS
  • An example of such FOS is the commercial ingredient ORAFTI® by Beneo GmbH (Mannheim, Germany).
  • the prebiotics of the composition of the invention comprise fructooligosaccharides (FOS) or/and galactooligosaccharides (GOS).
  • a combination of prebiotics may be used such as 90% GOS with 10% short chain fructooligosaccharides such as in the product by BENEO-Orafti sold under the trademark "Orafti® oligofructose (previously Raftilose®) or 10% inulin such as in the product sold by BENEO-Orafti under the trademark “Orafti® inulin” (previously Raftiline®).
  • the nutritional composition comprises inulin and oligofructose (FOS).
  • the nutritional composition comprises inulin and oligofructose (FOS) in a FOS:inulin ratio ranging from 95:5 to 30:70, preferably in a FOS:inulin ratio ranging from 90:10 to 50:50, such as 90:10, 80:20 or 70:30.
  • FOS oligofructose
  • the mixture of inulin and FOS can be purchased by Beneo GmbH (Mannheim, Germany) as Orafti® Synergy1.
  • the mixture of inulin and FOS is Prebio1 (70wt-% FOS, 30wt-% inulin), wherein a source of FOS is Orafti® P95 and a source of inulin is Orafti® GR, which can be both purchased by Beneo GmbH (Mannheim, Germany).
  • the nutritional composition is formulated for an infant, young child and/or child.
  • the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier or a supplement.
  • the present invention provides the nutritional composition of the invention for use as a medicament.
  • the present invention provides the nutritional composition of the invention for use in enhancing the immune response to infection or vaccination, for use in promoting and/or maintaining gut health, or for use in preventing and/or reducing the risk of developing an infection in an infant, young child or a child.
  • the present invention provides a method of enhancing the immune response to infection or vaccination, of promoting and/or maintaining gut health, or of preventing and/or reducing the risk of developing an infection in an infant, young child or a child, the method comprising administering the composition of the invention to the infant, young child or child.
  • the antibody response to infection or vaccination is enhanced in the infant, young child or child.
  • 150 to 450 mg/day of ⁇ -glucan and 150 to 450 mg/day of COS are administered to the infant, young child or child.
  • the infant, young child or child is non-responsive to treatment with ⁇ -glucan or with a combination of L. rhamnosus and ⁇ -glucan.
  • the present invention provides the use of the nutritional composition of the invention for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child.
  • the present invention provides a method of enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, the method comprising administering the composition of the invention to the infant, young child or child.
  • the present invention provides the use of the nutritional composition of the invention for enhancing the growth of Bifidobacteria in the gastrointestinal tract of an infant, young child or child.
  • the present invention provides a method of enhancing the growth of Bifidobacteria in the gastrointestinal tract of an infant, young child or child, the method comprising administering the composition of the invention to the infant, young child or child.
  • the present invention provides the use of the nutritional composition of the invention for increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child.
  • SCFA short chain fatty acid
  • the present invention provides a method of increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child, the method comprising administering the composition of the invention to the infant, young child or child.
  • SCFA short chain fatty acid
  • the at least one SCFA is acetate, propionate, butyrate or any combination thereof.
  • the at least one SCFA is butyrate and the infant, young child or child is non-responsive to treatment with ⁇ -glucan or with a combination of L. rhamnosus and ⁇ -glucan. I t was surprisingly found that when combined with COS or COS/ ⁇ -glucan, L.
  • L. rhamnosus CGMCC1.3724 (LPR) and was more efficient to increase the microbiome mediated butyrate production than the other strains of L. rhamnosus such as KY-3 (Umeki et. al., J Nutr Sci Vitaminol (Tokyo), 2004 Oct;50(5):330-4).
  • L. rhamnosus is CGMCC1.3724 (LPR) and the L. rhamnosus modulating agent is COS, preferably cellobiose.
  • L. rhamnosus is CGMCC1.3724 (LPR) and the L.
  • rhamnosus modulating agent is COS, preferably cellobiose, wherein 800 to 1500 mg/day of COS, for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS are administered to the infant, young child or child, preferably for increasing the microbiome mediated butyrate production, and thereby promoting the associated health benefits.
  • L. rhamnosus is CGMCC1.3724 (LPR) and the L. rhamnosus modulating agent is COS/ ⁇ -glucan, preferably cellobiose/ ⁇ -glucan.
  • L. rhamnosus is CGMCC1.3724 (LPR) and the L.
  • L. rhamnosus modulating agent is COS, preferably cellobiose, for increasing the microbiome mediated butyrate production.
  • L. rhamnosus is CGMCC1.3724 (LPR) and the L. rhamnosus modulating agent is COS/ ⁇ -glucan, preferably cellobiose/ ⁇ -glucan, for increasing the microbiome mediated butyrate production.
  • the present invention provides the use of at least one probiotic for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, wherein the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium.
  • the at least one probiotic is of the genus Lactobacillus, Streptococcus and/or Bifidobacterium. In some embodiments, the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof.
  • F igure 1 L.
  • rhamnosus NCC 4007 (LPR, CGMCC1.3724) biomass levels upon 48h growth on different cello-oligosaccharides (bi-tri-tetra- & polymer). ***p-value ⁇ 0.001 upon ANOVA and multiple testing against the no carbohydrate control.
  • F igure 2 L. rhamnosus NCC 4007 growth attributes after 24h incubation on glucose or cellobiose as sole carbon source.
  • F igure 3 Effect of a range of cellobiose & oat ⁇ -glucan mixes (0:100; 25:75, 50:50, 75:25, 100:0) at two different dosage levels (200 mg and 600 mg/day) on LPR levels in a set of 6 toddler fecal fermentations.
  • F igure 4 Effect of LPR and a mix of cellobiose & oat ⁇ -glucan (25:75; 600 mg/day) addition on the levels of Bifidobacteriaceae in a set of 6 toddler fecal fermentations.
  • Figure 5 Effect of a mix of LPR and cellobiose:oat ⁇ -glucan (25:75; 600 mg/day) on the levels of B.
  • Figure 6 Effect of a mix of LPR and cellobiose:oat ⁇ -glucan (25:75) on the levels of microbiota derived short chain fatty acids produced in a set of 6 toddler fecal fermentations. Two different daily equivalent doses of cellobiose: ⁇ -glucan are depicted (200 mg and 600 mg equivalent per day, respectively).
  • F igure 7 Effect of a mix of LPR and cellobiose:oat ⁇ -glucan (25:75, 600 mg daily equivalent) on the levels of microbiota derived acetate, propionate and butyrate produced in a set of 6 toddler fecal fermentations.
  • Figure 8 Effect of a range of cellobiose & oat ⁇ -glucan mixes (25:75, 50:50, 75:25) at a concentration of 200 mg/day on LPR mediated SCFA production in a set of 6 toddler fecal fermentations.
  • Figure 9 Effect of a range of cellobiose & oat ⁇ -glucan mixes (25:75, 50:50, 75:25) at a concentration of 600 mg/day on LPR mediated SCFA production in a set of 6 toddler fecal fermentations.
  • F igure 10 Effect of oat ⁇ -glucan (600 mg/day) on the levels of SCFA produced by the microbiota in a set of 6 toddler fecal fermentation.
  • F igure 11 Operation Taxonomic Units (OTU) levels differentiating high (responders) to low (non-responders) butyrate producing donors, upon administration of oat ⁇ -glucan (600 mg/day).
  • OFTU Operation Taxonomic Units
  • F igure 12 Effect of a range of cellobiose & oat ⁇ -glucan mixes (0:100, 25:75, 50:50, 75:25, 100:0) at a concentration of 600 mg/day on LPR mediated SCFA production in high (responders) and low (non-responders) butyrate producing donors.
  • Figure 13 Experimental set up. Three-week-old mice were purchased and fed with low fiber diet (LFD).
  • mice were left under low fiber diet only (group 1: control) or received 100mM of each short chain fatty acids (SCFA) acetate, butyrate and propionate in the drinking water (group 2: positive control) or received with a mix of 30 mg ⁇ -glucan and 10 mg cello oligosaccharides (mouse adapted dose calculated from 600mg/day of cellobiose & oat ⁇ -glucan mix at 25:75) in the drinking water together with 1x109 cfu of Lactobacillus rhamnosus (LPR) via gavage (group 4: synbiotic) or gavaged with only 1x109 cfu of LPR (group 3: probiotic).
  • SCFA short chain fatty acids
  • Nutritional supplementation with SCFA, probiotic or synbiotic were carried out for the duration of the experiment. Three weeks after the nutritional supplementation, animals were infected with 100 PFU with influenza (Mouse adapted strain PR8). Antibody responses were measured in the serum. F igure 14: Synbiotic supplementation significantly increases levels of total immunoglobulin in the serum. Changes in (A) absolute amount of immunoglobulin G (IgG) and (B) fold change in IgG in the serum between d21 and d0 post infection. Each dot represents a single animal with 9-10 animals per group with bars indicating the mean antibody response with error bars showing standard error of the mean. Unpaired t test was used to calculate differences between groups.
  • IgG immunoglobulin G
  • B fold change in IgG in the serum between d21 and d0 post infection.
  • Regression line is drawn to demonstrate the inverse relationship between antibody levels pre-infection and clinical score at peak of the infection.
  • F igure 17 Average L. rhamnosus plate counts at 24 hours for each arm of the study.
  • the dotted line indicates the level upon inoculation (1.2 ⁇ 0.2x10e 7 cfu/mL).
  • Statistical differences between treatments and the blank, as tested via a repeated measures ANOVA are indicated with * (0.01 ⁇ adjusted p-value ⁇ 0.05), ** (0.001 ⁇ adjusted p-value ⁇ 0.01) or *** (adjusted p-value ⁇ 0.001).
  • F igure 20 Effect of a range of cellobiose concentrations (from 200 to 800 mg per day) on LPR levels in a set of 6 toddler fecal fermentations. Statistical differences to the control arm (LPR only) are represented (*p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; ****p>0.0001). Detailed description of the invention Definitions
  • the term “infant” means a child under the age of 12 months.
  • the expression “young child” means a child aged between one and less than three years, also called toddler.
  • the expression “child” means a child between three and nine years of age.
  • the expression “child” means a child between three and five years of age.
  • the expression “nutritional composition” means a composition which nourishes a subject. This nutritional composition is usually to be taken orally or parenterally, and it usually includes a lipid or fat source and a protein source. A carbohydrate source may also be included.
  • the nutritional composition of the invention is a synthetic nutritional composition.
  • the combination or composition of the present invention is a “synthetic combination” or “synthetic nutritional composition”.
  • the expression “synthetic combination” or “synthetic nutritional composition” means a mixture obtained by chemical and/or biological means, which can be chemically identical to the mixture naturally occurring in mammalian milks (i.e. the synthetic combination or synthetic composition is not breast milk).
  • infant formula refers to a foodstuff intended for particular nutritional use by infants during the first months of life and satisfying by itself the nutritional requirements of this category of person (Article 2(c) of the European Commission Directive 91/321/EEC 2006/141/EC of 22 December 2006 on infant formulae and follow-on formulae). It also refers to a nutritional composition intended for infants and as defined in Codex Alimentarius (Codex STAN 72-1981) and Infant Specialities (incl. Food for Special Medical Purpose).
  • infant formula encompasses both “starter infant formula” and “follow-up formula” or “follow-on formula”. A “follow-up formula” or “follow-on formula” is given from the 6th month onwards.
  • the expression “baby food” means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.
  • infant cereal composition means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.
  • growing-up milk (or GUM) refers to a milk-based drink generally with added vitamins and minerals, that is intended for young children or children.
  • fortifier refers to liquid or solid nutritional compositions suitable for fortifying or mixing with human milk, infant formula, growing-up milk or human breast milk fortified with other nutrients.
  • the fortifier of the present invention can be administered after dissolution in human breast milk, in infant formula, in growing-up milk or in human breast milk fortified with other nutrients or otherwise it can be administered as a stand-alone composition.
  • the milk fortifier of the present invention can be also identified as being a “supplement”.
  • the milk fortifier of the present invention is a supplement.
  • the expression “weaning period” means the period during which the mother's milk is substituted by other food in the diet of an infant or young child.
  • the expressions “days/weeks/months/years of life” and “days/weeks/months/years after birth” can be used interchangeably.
  • the “mother’s milk” should be understood as the breast milk or the colostrum of the mother.
  • An “oligosaccharide” is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides).
  • T he term “galacto-oligosaccharides” refers to a type of non-digestible fiber with prebiotic activity.
  • GOS are formed via enzymatic conversion of lactose. GOS generally comprise a chain of galactose units that arise through consecutive transgalactosylation reactions, with a terminal glucose unit, although a terminal galactose unit may be present instead. The degree of polymerization of GOS typically ranges from 2 to 8 monomeric units.
  • oligofructose (abbreviated OF) and “fructo-oligosaccharides” (abbreviated FOS) refer to fructose oligomers (i.e. a fructose oligosaccharide) having a degree of polymerization of from 2 to 10, for example a degree of polymerization of from 2 to 8.
  • Oligofructose can also be referred as Fructo-Oligo-Saccharides (abbreviated FOS) or short-chain Fructo-Oligo- Saccharides (abbreviated scFOS).
  • oligofructose OF
  • fructose-oligosaccharide(s) FOS
  • Fructo-Oligo-saccharide Fructo-Oligo-saccharide
  • scFOS short-chain-fructo-oligosaccharide
  • the Inulin being polymers of long chains are specifically excluded from the present definition of OF.
  • Oligofructose is distinguishable from Inulin by its degree of polymerization (Inulin having longer chains).
  • Inulin is a form of fructan oligosaccharides, composed of fructose units linked by beta(2-1) bonds, typically with an N-terminal alpha(1-2) linked glucose, and chain lengths up to 60 units.
  • HMO human milk oligosaccharide(s). These carbohydrates are highly resistant to enzymatic hydrolysis, indicating that they may display essential functions not directly related to their caloric value. It has especially been illustrated that they play a vital role in the early development of infants and young children, such as the maturation of the immune system. Many different kinds of HMOs are found in the human milk.
  • Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose and/or N-acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in human milk - over 130 such structures have been identified so far. Almost all of them have a lactose moiety at their reducing end while sialic acid and/or fucose (when present) occupy terminal positions at the non-reducing ends.
  • the HMOs can be acidic (e.g. charged sialic acid containing oligosaccharide) or neutral (e.g. fucosylated oligosaccharide).
  • the combination or nutritional composition of the present invention can be in solid form (e.g. powder) or in liquid form.
  • the amount of the various ingredients e.g. the oligosaccharides
  • prebiotic means non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and/or the activity of healthy bacteria such as bifidobacteria in the colon of humans (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr.1995;125:1401-12).
  • probiotic means microbial cell preparations or components of microbial cells with a beneficial effect on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al. “Probiotics: how should they be defined” Trends Food Sci. Technol.1999:10 107-10).
  • the microbial cells are generally bacteria or yeasts.
  • the term “cfu” should be understood as colony-forming unit.
  • Treating means to address a medical condition or disease with the objective of improving or stabilising an outcome in the person being treated or addressing an underlying nutritional need. Treating, therefore, includes the dietary or nutritional management of the medical condition or disease by addressing nutritional needs of the person being treated. Treating includes the elimination, reduction or amelioration of symptoms associated with the medical condition or disease.
  • Preventing means to diminish the risk of onset or recurrence of a medical condition or disease. Both primary and secondary prevention are thus contemplated.
  • Primary prevention means preventing a medical condition or disease before it occurs
  • secondary prevention means preventing additional attacks of a medical condition or disease after the first attack has occurred.
  • Preventing therefore, includes the dietary or nutritional prophylaxis of the medical condition or disease by addressing nutritional needs of the person being treated. Preventing includes eliminating or minimising the risk of developing a medical condition or disease and reducing the risk of developing symptoms associated with the medical condition or disease.
  • the term "effective amount” preferably means an amount of the combination or composition that provides the active agents in a sufficient amount to render a desired treatment or prevention outcome in a subject. An effective amount can be administered in one or more doses to the subject to achieve the desired treatment or prevention outcome. All percentages are by weight unless otherwise stated.
  • composition of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise depending on the needs. It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims.
  • the present invention provides a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent.
  • the combination is in the form of a composition, such as a nutritional composition.
  • the composition may comprise the combination in any therapeutically effective amount.
  • the present invention provides a nutritional composition comprising or consisting of the combination according to the invention.
  • Lacticaseibacillus rhamnosus (formerly known as “Lactobacillus rhamnosus” and formerly considered a subspecies of Lacticaseibacillus casei) is a gram-positive, anaerobic, rod-shaped bacterium of the Lacticaseibacillus genus which can be found in the gastrointestinal tract of humans.
  • Any suitable L. rhamnosus strain may be used in the present invention.
  • any L. rhamnosus strain which is known to have a probiotic effect may be used in the present invention.
  • Such L. rhamnosus strains will be well known to the skilled person.
  • rhamnosus may be selected from: L. rhamnosus ATCC 53103 (also known as “L. rhamnosus GG” or “L. rhamnosus DSM 33156), L. rhamnosus LC705 (also known as “L. rhamnosus DSM 7061”) and L. rhamnosus CGMCC1.3724 (LPR).
  • L. rhamnosus is LPR.
  • L. rhamnosus CGMCC1.3724 (LPR) was deposited with the Chinese Culture Collection in October 2004 according to the Budapest Treaty under the reference CGMCC 1.3724. L.
  • rhamnosus GG (ATCC 53103, DSM 33156) is publicly available, and can be obtained commercially at the Belgian Coordinated Collection of Microorganisms under LMG 18243. T he L. rhamnosus may be a L. rhamnosus having at least 99% (suitably, at least 99.9%) Average Nucleotide Identity (ANI) to any L. rhamnosus known to the skilled person.
  • ANI Average Nucleotide Identity
  • the term “Average nucleotide identity (ANI)” refers to a distance- based approach to delineate species based on pair-wise comparisons of their genome sequences.
  • ANI is an in silico approach for phylogenetic definition of a species and has become the gold standard for species delineation (Goris et al., 2007, Int. J. Syst. Evol. Microbiol.57: 81-91; Kim et al., 2014, Int. J. Syst. Evol. Micr.64: 346-351; Richter et al., 2009, P Natl Acad Sci USA 106: 19126-19131; and Chan et al., 2012, Bmc. Microbiol.12).
  • the ANI of the shared genes between two strains is known to be a robust means to compare genetic relatedness among strains.
  • Strains with ANI values of at least about 96% can be considered to belong to the same species (Konstantinidis and Tiedje, 2005, Proc Natl Acad Sci USA, 102(7):2567-72; and Goris et al., 2007, Int Syst Evol Microbiol. 57(Pt 1):81-91), while ANI values of at least about 99% indicate that the bacterial genomes belong to the same strain.
  • the ANI between two bacterial genomes is calculated from pair-wise comparisons of all sequences shared between any two strains and can be determined, for example, using any of a number of publicly available ANI tools, including but not limited to OrthoANI with usearch (Yoon et al., 2017, Antonie van Leeuwenhoek 110:1281-1286); ANI Calculator, JSpecies (Richter and Rossello-Mora, 2009, Proc Natl Acad Sci USA 106:19126- 19131); and JSpeciesWS (Richter et al., 2016, Bioinformatics 32:929-931). Other methods for determining the ANI of two genomes are known in the art (Konstantinidis, K. T.
  • the L. rhamnosus has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to L. rhamnosus ATCC 53103, L. rhamnosus LC705 and/or to LPR. In some preferred embodiments, the L.
  • the rhamnosus has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to LPR.
  • the L. rhamnosus has at least 99.9% ANI to LPR.
  • the composition comprises L. rhamnosus in an amount of 1 ⁇ 10 3 to 1.5 ⁇ 10 12 cfu/g of the composition (dry weight). V arious health effects of Lacticaseibacillus rhamnosus as a probiotic are well documented (see e.g. Segers, M.E. and Lebeer, S., 2014.
  • the nutritional composition according to the invention may contain from 10 3 to 10 12 cfu of L. rhamnosus, more preferably between 107 and 1012 cfu such as between 108 and 1010 cfu of L. rhamnosus per g of composition on a dry weight basis.
  • L. rhamnosus is administered to the subject in an amount of at least about 10 6 cfu/day, at least about 10 7 cfu/day, or at least about 108 cfu/day.
  • rhamnosus is administered to the subject in an amount of about 10 12 cfu/day or less, about 10 11 cfu/day or less, or about 10 10 cfu/day or less.
  • the probiotics e.g. L. rhamnosus
  • the probiotics are viable.
  • Probiotic components and metabolites can also be added.
  • L. rhamnosus-modulating agent As used herein, the term “Lactocaseibacillus rhamnosus-modulating agent” or “L. rhamnosus-modulating agent” may refer to any agent which modulates the abundance of L. rhamnosus in the gastrointestinal tract of a subject. Preferably, the L. rhamnosus-modulating agent increases the abundance of L.
  • the L. rhamnosus-modulating agent is in the form of a probiotic, prebiotic, and/or synbiotic (i.e. synergistic relationship between probiotics and prebiotics).
  • the microbiota-modulating agent of the present invention comprises or consists of a probiotic, prebiotic, and/or synbiotic.
  • prebiotic may refer to a non-digestible component that benefits the subject by selectively stimulating the favourable growth and/or activity of one or more bacterial taxa (see e.g. Gibson, G.R., et al., 2017).
  • Exemplary prebiotics include fibres, for example oligosaccharides, such as human milk oligosaccharides (HMOs).
  • the L. rhamnosus-modulating agent may increase the abundance of L. rhamnosus in the gastrointestinal tract of the subject.
  • the L. rhamnosus-modulating agent may increase the relative abundance of L. rhamnosus in the gastrointestinal tract of the subject.
  • the “abundance” of a bacterial taxa in the gut of a subject may be determined by any suitable method (see e.g. Tang, Q., et al., 2020. Frontiers in cellular and infection microbiology, 10, p.151).
  • the abundance of bacterial taxa may be obtained from or obtainable from fecal samples.
  • the abundance may be a relative abundance and/or absolute abundance.
  • the abundance is a relative abundance, for example, the abundance may be calculated relative to total bacterial abundance in the gut of the subject.
  • the abundance of L. rhamnosus in the gastrointestinal tract of the subject may be measured as described herein (see Example 4 and/or Example 6). T he inventors have surprisingly found that cello-oligosaccharides (COS) or a combination of cello-oligosaccharides (COS) and ⁇ -glucan is capable of increasing the abundance of L. rhamnosus in the gastrointestinal tract of the subject.
  • a probiotic which is a lactic acid bacterium (for example, a probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus and/or Streptococcus) and/or is a Bifidobacterium is capable of increasing the abundance of L. rhamnosus in the gastrointestinal tract of the subject.
  • the L. rhamnosus-modulating agent is cello-oligosaccharides (COS).
  • COS cello-oligosaccharides
  • the present invention provides a nutritional composition comprising L. rhamnosus and cello-oligosaccharides (COS).
  • the L. rhamnosus is cello-oligosaccharides
  • the rhamnosus-modulating agent comprises or consists of a combination of cello-oligosaccharides (COS) and ⁇ -glucan.
  • the L. rhamnosus- modulating agent is a combination of COS and ⁇ -glucan.
  • the present invention provides a nutritional composition comprising L. rhamnosus and a combination of cello-oligosaccharides (COS) and ⁇ -glucan.
  • the L. rhamnosus-modulating agent comprises or consists of at least one probiotic which is a lactic acid bacterium and/or Bifidobacterium.
  • the rhamnosus-modulating agent comprises or consists of at least one probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium.
  • the L. rhamnosus-modulating agent is at least one probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium.
  • the present invention provides a nutritional composition comprising L. rhamnosus and at least one probiotic which is a lactic acid bacterium and/or Bifidobacterium.
  • COS Cello-oligosaccharides are linear oligosaccharides comprising oligomers of 2, 3, 4, 5 or 6 ⁇ -1,4-linked D-glucose units, termed cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose, respectively.
  • COS are soluble dietary fibers.
  • COS may be isolated from source materials (e.g. plant sources), synthesised (e.g. by enzymatic synthesis) or obtained by full or partial hydrolysis of source materials (e.g. plant sources).
  • the term “derived from” means isolated from or obtained by full or partial hydrolysis of the source material.
  • COS are derived from a plant.
  • the plant comprises COS.
  • COS are derived from a cereal.
  • the cereal comprises COS.
  • the COS are derived from a plant, such as a cereal.
  • the COS are isolated from a plant, such as a cereal.
  • the COS are derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt.
  • COS are derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt.
  • the COS are derived from oat or barley.
  • the COS are derived from oat.
  • the COS are derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt.
  • the COS are obtained from full or partial hydrolysis of a cereal fraction comprising COS.
  • the COS are obtained from partial hydrolysis of a ⁇ - glucan cereal fraction.
  • the COS are obtained from partial hydrolysis of a ⁇ -glucan cereal fraction.
  • the cereal is selected from barley, oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt.
  • the cereal is barley or oat.
  • the cereal is oat.
  • the COS comprise at least two of cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose. In some embodiments, the COS comprise cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose. In some embodiments, the COS comprise cellobiose, cellotriose or a combination thereof. In one embodiment, the COS are cellotriose. In a preferred embodiment, the COS are cellobiose.
  • the COS are present in an amount ranging from 1.20 to 2.50 g/100g dry weight of composition, such as from 1.30 to 2.50 g/100g dry weight of composition.
  • the COS are present in an amount from at least 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40 or 2.45 g/100g dry weight of composition.
  • the COS are present in an amount from less than 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45 or 2.50 g/100g dry weight of composition.
  • the COS are present in an amount ranging from 1.80 to 2.10 g/100g dry weight of composition, such as 2.05 g/100g dry weight of composition.
  • the nutritional composition may be intended for administration twice daily.
  • the nutritional composition may be formulated to provide two servings per day.
  • Combination of COS and ⁇ -glucan ⁇ -glucans are ⁇ -d-glucose polysaccharides which naturally occur in the cell walls of certain plants (such as cereals), bacteria, and fungi.
  • ⁇ -glucans are soluble dietary fibers.
  • ⁇ - glucan comprises linear chains of glucose residues which are linked by ⁇ -(1–4) and ⁇ -(1–3) glycosidic bonds.
  • ⁇ -glucan may be isolated from source materials (e.g. plant sources), synthesised (e.g. by enzymatic synthesis) or obtained by full or partial hydrolysis of source materials (e.g. plant sources).
  • the term “derived from” means isolated from or obtained by full or partial hydrolysis of the source material.
  • the ⁇ -glucan and/or COS is derived from a plant.
  • the plant comprises ⁇ -glucan and/or COS.
  • the ⁇ -glucan and/or COS is derived from a cereal.
  • the cereal comprises ⁇ -glucan and/or COS.
  • the ⁇ -glucan and COS are derived from a plant, such as a cereal.
  • the ⁇ -glucan and/or COS are isolated from a plant, such as a cereal.
  • the ⁇ -glucan and/or COS is derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some embodiments, the ⁇ -glucan and/or COS is derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some preferred embodiments, the ⁇ -glucan and/or COS is derived from oat or barley. Preferably, the ⁇ - glucan and/or COS is derived from oat.
  • the ⁇ -glucan and COS are derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt.
  • the ⁇ -glucan and/or COS is obtained from full or partial hydrolysis of a cereal fraction comprising ⁇ -glucan and/or COS.
  • the cereal comprises ⁇ -glucan.
  • the cereal is a ⁇ -glucan cereal fraction. Cereal fractions and methods to prepare such cereal fractions are well known in the art.
  • the ⁇ -glucan and/or COS is obtained from partial hydrolysis of a ⁇ -glucan cereal fraction.
  • the ⁇ - glucan and COS are obtained from partial hydrolysis of a ⁇ -glucan cereal fraction.
  • the cereal is selected from barley, oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt.
  • the cereal is barley or oat.
  • the cereal is oat.
  • ⁇ -glucan obtained from cereal sources, and in particular from oat or barley is advantageous since these sources provide ⁇ -glucan comprising glucose residues which are linked by both ⁇ -(1–4) and ⁇ -(1–3) glycosidic bonds.
  • ⁇ -glucan obtained from other plant sources such as apple provides ⁇ -glucan containing glucose residues which are only linked by ⁇ -(1–4) glycosidic bonds.
  • the provision of ⁇ -glucan comprising glucose residues which are linked by both ⁇ -(1–4) and ⁇ -(1–3) glycosidic bonds is beneficial since it has been shown that some predominant commensal species (e.g.
  • ⁇ -glucan is cereal ⁇ -glucan, preferably oat ⁇ -glucan.
  • ⁇ -glucan is cereal ⁇ -glucan, preferably oat ⁇ -glucan, comprising glucose residues which are linked by both ⁇ -(1–4) and ⁇ -(1–3) glycosidic bonds.
  • ⁇ -glucan is cereal ⁇ -glucan, preferably oat ⁇ -glucan, having a linear (1,3;1,4) ⁇ -glucan structure (Clinical and Physiological Perspectives of ⁇ -Glucans: The Past, Present, and Future, Khawaja Bengal Imran Bashir and Jae-Suk Choi, Int. J. Mol. Sci. 2017, 18(9), 1906; https://doi.org/10.3390/ijms18091906).
  • any method known in the art can be used for full or partial hydrolysis of a source material, e.g. a cereal fraction.
  • a source material e.g. a cereal fraction.
  • the methods described in WO2022/253662 A1 can be used. It is within the capabilities of the skilled person to perform sufficient hydrolysis of the source material in order to obtain the desired weight ratio of COS: ⁇ -glucan as described herein.
  • a weight ratio of COS: ⁇ -glucan of 25:75 corresponds to 25% hydrolysis of a ⁇ -glucan cereal fraction
  • a weight ratio of COS: ⁇ -glucan of 75:25 corresponds to 75% hydrolysis of a ⁇ -glucan cereal fraction, and so on.
  • 25% hydrolysis of a ⁇ -glucan cereal fraction refers to a ⁇ -glucan cereal fraction that is partially hydrolysed such that the ⁇ -glucan content is 25% hydrolysed.
  • the ⁇ -glucan has an average molecular weight range of from 20 to 500 kDa, preferably from 50 to 250 kDa.
  • the ⁇ -glucan has an average molecular weight range of from 25 to 450 kDa, from 30 to 400 kDa, from 40 to 350 kDa, from 50 to 250 kDa, from 60 to 200 kDa, or from 70 to 150 kDa.
  • a ny suitable method for measuring the average molecular weight known in the art may be used e.g.
  • the COS comprise at least two of cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose.
  • the COS comprise cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose.
  • the COS comprise cellobiose, cellotriose or a combination thereof.
  • the COS are cellotriose.
  • the COS are cellobiose.
  • the weight ratio of COS: ⁇ -glucan is from 10:90 to 90:10 dry weight of composition, preferably from 25:75 to 75:25 dry weight of composition.
  • the weight ratio of COS: ⁇ -glucan is 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25; 80:20 or 85:15 dry weight of composition.
  • the weight ratio of COS: ⁇ -glucan is 25:75, 50:50 or 75:25 dry weight of composition.
  • the weight ratio of COS: ⁇ -glucan is 25:75 dry weight of composition.
  • the ⁇ -glucan is present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition.
  • the ⁇ - glucan is present in an amount from at least 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.80 g/100g dry weight of composition and/or the COS are present in an amount from at least 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.80 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount from less than 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80 or 0.85 g/100g dry weight of composition and/or the COS are present in an amount from less than 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80 or 0.85 g/100g dry weight of composition.
  • the nutritional composition may be provided in a serving size of 31g total dry weight.
  • COS e.g cellobiose
  • COS is present in an amount ranging from 0.20 to 12.10 g/100g dry weight of composition, such as 0.20 to 1.61 g/100g dry weight of composition or 1.29 to 1.61 g/100g dry weight of composition.
  • COS e.g cellobiose
  • COS preferably cellobiose
  • COS is present in an amount ranging from 0.20 to 12.10 g/100g dry weight of composition, more preferably from 1.29 to 12.10 g/100g dry weight of composition, even more preferably from 1.29 to 1.61 g/100g dry weight of composition.
  • COS e.g cellobiose
  • the ⁇ -glucan is present in an amount ranging from 0.10 to 0.40 g/100g, preferably ranging from 0.2 to 0.3 g/100g dry weight of composition.
  • COS e.g cellobiose
  • the ⁇ -glucan is present in an amount of 0.24 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount ranging from 0.5 to 1.0 g/100g, preferably ranging from 0.7 to 0.8 g/100g dry weight of composition
  • COS e.g cellobiose
  • the ⁇ -glucan is present in an amount ranging from 0.10 to 0.40 g/100g, preferably ranging from 0.2 to 0.3 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of 0.73 g/100g dry weight of composition, and COS (e.g cellobiose) is present in an amount of 0.24 g/100g dry weight of composition.
  • COS e.g cellobiose
  • the ⁇ -glucan is present in an amount ranging from 0.20 to 0.80 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.20 to 0.80 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount ranging from 0.70 to 0.80 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.20 to 0.30 g/100g dry weight of composition. In some embodiments of the composition, the ⁇ -glucan is present in an amount of about 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79 or 0.80 g/100g dry weight of composition and/or the COS are present in an amount of about 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29 or 0.30 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.75 g/100g dry weight of composition and/or the COS are present in an amount of about 0.24 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount ranging from 0.45 to 0.55 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.45 to 0.55 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54 or 0.55 g/100g dry weight of composition and/or the COS are present in an amount of about 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54 or 0.55 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.50 g/100g dry weight of composition and/or the COS are present in an amount of about 0.50 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount ranging from 0.20 to 0.30 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.70 to 0.80 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29 or 0.30 g/100g dry weight of composition and/or the COS are present in an amount of about 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79 or 0.80 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.24 g/100g dry weight of composition and/or the COS are present in an amount of about 0.75 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount ranging from 0.15 to 0.27 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.58 to 0.70 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26 or 0.27 g/100g dry weight of composition and/or the COS are present in an amount of about 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69 or 0.70 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.21 g/100g dry weight of composition and/or the COS are present in an amount of about 0.63 g/100g dry weight of composition.
  • the nutritional composition may be provided in a serving size of 36g total dry weight.
  • the ⁇ -glucan is present in an amount ranging from 0.15 to 0.70 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.70 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount ranging from 0.37 to 0.47 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.37 to 0.47 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46 or 0.47 g/100g dry weight of composition and/or the COS are present in an amount of about 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46 or 0.47 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.42 g/100g dry weight of composition and/or the COS are present in an amount of about 0.42 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount ranging from 0.58 to 0.70 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.27 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69 or 0.70 g/100g dry weight of composition and/or the COS are present in an amount of about 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26 or 0.27 g/100g dry weight of composition.
  • the ⁇ -glucan is present in an amount of about 0.63 g/100g dry weight of composition and/or the COS are present in an amount of about 0.21 g/100g dry weight of composition.
  • the nutritional composition may be intended for administration twice daily.
  • the nutritional composition may be formulated to provide two servings per day.
  • ß-glucan Molecular Weight determination The average molecular weight (MW) of ⁇ -glucan may be determined by Size Exclusion Chromatography (SEC) with a specific post-column labelling and a fluorescence detection (FLD) based on a calibration curve established with known MW of commercial ß- glucans as described below.
  • rhamnosus modulating agent which decreases the pH of the gastrointestinal tract closer to this optimal pH range for L. rhamnosus growth would be expected to increase the abundance of L. rhamnosus within the gastrointestinal tract.
  • certain probiotic bacterial strains such as lactic acid bacteria or bacteria of the Bifidobacterium genus, would be expected to decrease the pH of the gastrointestinal tract closer to the optimal pH range for L. rhamnosus growth.
  • the enhanced acidification induced by metabolic activity of certain secondary probiotic strains, creates a more acidic environment, closer to the median of the optimal pH range for L. rhamnosus growth, and thus may allow L. rhamnosus to proliferate more successfully.
  • This enhanced acidification is most likely mediated by increased organic acid production by the secondary strains successfully catabolising particular metabolites (such as longer-chain FOS molecules and/or inulin), where L. rhamnosus cannot.
  • this synergistic effect of the secondary probiotic is not necessarily dependent on the specific prebiotics used (e.g., a combination of FOS and inulin), since any prebiotic that allows these secondary probiotic strains to mediate enhanced L. rhamnosus growth via increased acidification could induce this effect. Indeed, this may be especially true for more catabolically accessible prebiotics, such as fructo- oligosaccharides (FOS), inulin, galacto-oligosaccharides (GOS), HMOs (in particular for B.
  • FOS fructo- oligosaccharides
  • GOS galacto-oligosaccharides
  • HMOs in particular for B.
  • the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium.
  • the at least one probiotic is a lactic acid bacterium.
  • the lactic acid bacteria are an order of gram-positive, acid-tolerant, either rod- shaped (bacilli) or spherical (cocci) bacteria that share common metabolic and physiological characteristics.
  • the L. rhamnosus-modulating agent comprises at least one probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium.
  • the at least one probiotic is selected from Lacticaseibacillus paracasei, Lactobacillus johnsonii, Bifidobacterium animalis (such as Bifidobacterium animalis subsp.
  • L acticaseibacillus paracasei (formerly known as “Lactobacillus paracasei” and formerly considered a subspecies of Lacticaseibacillus casei) is a gram-positive, is a gram- positive, homofermentative species of lactic acid bacteria of the Lacticaseibacillus genus which can be found in the gastrointestinal tract of humans.
  • Lactobacillus johnsonii is a bacterium of the Lactobacillus genus which can be found in the gastrointestinal tract of humans.
  • Bifidobacterium animalis is a bacterium of the Bifidobacterium genus which can be found in the large intestines of most mammals, including humans.
  • Bifidobacterium animalis and Bifidobacterium lactis were previously described as two distinct species. Presently, both are considered B. animalis with the subspecies Bifidobacterium animalis subsp. animalis and Bifidobacterium animalis subsp. lactis (Masco, L., et al., 2004.
  • B ifidobacterium longum is a bacterium of the Bifidobacterium genus which is present in the human gastrointestinal tract.
  • B. infantis, B. longum, and B. suis three previously distinct species of Bifidobacterium, B. infantis, B. longum, and B. suis, were unified into a single species named B. longum with the biotypes infantis, longum, and suis, respectively (Sakata, S., et al., 2002. International journal of systematic and evolutionary microbiology, 52(6), pp.1945-1951).
  • S treptococcus thermophilus is a bacterium of the Streptococcus genus and is a gram- positive bacterium, and a fermentative facultative anaerobe. Streptococcus thermophilus can be found in the gastrointestinal tract of humans. Any suitable Lacticaseibacillus paracasei, Lactobacillus johnsonii, Bifidobacterium animalis (such as Bifidobacterium animalis subsp. lactis), Bifidobacterium longum (such as Bifidobacterium longum subsp. longum or Bifidobacterium longum subsp. infantis) and/or Streptococcus thermophilus strain may be used in the present invention.
  • Lacticaseibacillus paracasei Lactobacillus johnsonii
  • Bifidobacterium animalis such as Bifidobacterium animalis subsp. lactis
  • Bifidobacterium longum such as Bifidobacterium longum subsp. longum or Bifidobacterium longum subsp.
  • Streptococcus thermophilus may be a strain having at least 99% (suitably, at least 99.9%) ANI to any Lacticaseibacillus paracasei, Lactobacillus johnsonii, Bifidobacterium animalis (such as Bifidobacterium animalis subsp. lactis), Bifidobacterium longum (such as Bifidobacterium longum subsp. longum or Bifidobacterium longum subsp. infantis) and/or Streptococcus thermophilus strain, respectively, known to the skilled person.
  • Bifidobacterium animalis such as Bifidobacterium animalis subsp. lactis
  • Bifidobacterium longum such as Bifidobacterium longum subsp. longum or Bifidobacterium longum subsp. infantis
  • Streptococcus thermophilus strain respectively, known to the skilled person.
  • the Bifidobacterium longum subsp longum strain may be selected from Bifidobacterium longum subsp longum strain CNCM I-2169, Bifidobacterium longum subsp longum strain CNCM I-2171, Bifidobacterium longum subsp longum strain ATCC 15708, Bifidobacterium longum subsp longum strain DSM 20097, Bifidobacterium longum subsp longum strain NCIMB 8809, Bifidobacterium longum subsp longum strain CNCM I-2618 (NCC 2705), Bifidobacterium longum subsp longum strain CNCM I-2170, Bifidobacterium longum subsp longum strain ATCC 15707, or a combination thereof, in particular B.
  • the Lacticaseibacillus paracasei has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Lacticaseibacillus paracasei NCC 2461 (also known as Lacticaseibacillus paracasei CNCM I-2116 or Lacticaseibacillus paracasei ST11).
  • the Lacticaseibacillus paracasei has at least 99.9% ANI to Lacticaseibacillus paracasei NCC 2461.
  • Lactobacillus johnsonii has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Lactobacillus johnsonii NCC 533 (also known as Lactobacillus johnsonii CNCM I-1225 or Lactobacillus johnsonii LA1).
  • the Lactobacillus johnsonii has at least 99.9% ANI to Lactobacillus johnsonii NCC 533.
  • Lactobacillus johnsonii NCC 533 was deposited with the Institute Pasteur according to the Budapest Treaty on 30th June 1992 receiving the deposit no. CNCM I-1225.
  • the Bifidobacterium animalis subsp. lactis has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Bifidobacterium animalis subsp.
  • lactis NCC 2818 also known as Bifidobacterium animalis subsp. lactis CNCM I-3446 or Bifidobacterium animalis subsp. lactis BL818).
  • the Bifidobacterium animalis subsp. lactis has at least 99.9% ANI to Bifidobacterium animalis subsp. lactis NCC 2818.
  • Bifidobacterium animalis subsp. lactis NCC 2818 was deposited with the Institute Pasteur according to the Budapest Treaty on 7th June 2005 receiving the deposit no. CNCM I-3446. S
  • longum has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Bifidobacterium longum subsp. longum NCC 2705 (also known as Bifidobacterium longum subsp. longum CNCM I-2618).
  • the Bifidobacterium longum subsp. longum has at least 99.9% ANI to Bifidobacterium longum subsp. longum NCC 2705.
  • the Bifidobacterium longum subsp. infantis has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Bifidobacterium longum subsp. infantis LMG 11588 (also known as Bifidobacterium longum subsp. infantis NCC3039).
  • infantis has at least 99.9% ANI to Bifidobacterium longum subsp. infantis LMG 11588.
  • B ifidobacterium longum subsp. infantis LMG 11588 is sold by the Belgian Coordinated Collections of Microorganisms (BCCM) under the LMG accession number LMG 11588.
  • the Streptococcus thermophilus has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Streptococcus thermophilus NCC 2496 (also known as Streptococcus thermophilus CNCM I-3915 or Streptococcus thermophilus ST496).
  • the Streptococcus thermophilus has at least 99.9% ANI to Streptococcus thermophilus NCC 2496.
  • the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof.
  • the at least one probiotic is Lacticaseibacillus paracasei NCC 2461. In one embodiment, the at least one probiotic is Lactobacillus johnsonii NCC 533. In one embodiment, the at least one probiotic is Bifidobacterium animalis subsp. lactis NCC 2818. In one embodiment, the at least one probiotic is Bifidobacterium longum subsp. longum NCC 2705. In one embodiment, the at least one probiotic is Bifidobacterium longum subsp. infantis LMG 11588. In one embodiment, the at least one probiotic is Streptococcus thermophilus NCC 2496.
  • the composition comprises the at least one probiotic in an amount of 1 ⁇ 10 3 to 1.5 ⁇ 10 12 cfu/g of the composition (dry weight).
  • the nutritional composition according to the invention may contain from 10 3 to 10 12 cfu of the at least one probiotic, more preferably between 107 and 1012 cfu such as between 108 and 1010 cfu of the at least one probiotic per g of composition on a dry weight basis.
  • the at least one probiotic is administered to the subject in an amount of at least about 106 cfu/day, at least about 107 cfu/day, or at least about 108 cfu/day.
  • the at least one probiotic is administered to the subject in an amount of about 1012 cfu/day or less, about 10 11 cfu/day or less, or about 10 10 cfu/day or less.
  • the at least one probiotic is viable.
  • the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp.
  • the at least one probiotic is Lacticaseibacillus paracasei NCC 2461. In one embodiment, the at least one probiotic is Lactobacillus johnsonii NCC 533. In one embodiment, the at least one probiotic is Bifidobacterium animalis subsp. lactis NCC 2818. In one embodiment, the at least one probiotic is Bifidobacterium longum subsp. longum NCC 2705. In one embodiment, the at least one probiotic is Bifidobacterium longum subsp. infantis LMG 11588.
  • the at least one probiotic is Streptococcus thermophilus NCC 2496.
  • the L. rhamnosus-modulating agent is not L. rhamnosus.
  • the nutritional composition further comprises prebiotics.
  • the prebiotics may be those which are more catabolically accessible, such as FOS, inulin, GOS, HMOs (in particular for B. infantis), BMOs, pectins, arabinan/arabinoxylan, resistant starch, or any combination thereof.
  • the nutritional composition further comprises inulin and oligofructose. Use to enhance the growth of L.
  • the present invention provides the use of the combination or nutritional composition of the invention for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child.
  • the present invention provides a method of enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, the method comprising administering the combination or composition of the invention to the infant, young child or child.
  • the present invention provides the use of at least one probiotic for enhancing the growth of L.
  • the use is therapeutic. In some embodiments, the use is non- therapeutic.
  • Use as a bifidogenic factor As described above, the combinations and compositions of the invention have surprisingly been found to enhance growth of Bifidobacteria, indicating a surprising bifidogenic effect. In one aspect, the present invention provides use of the combinations and compositions of the invention as a bifidogenic factor.
  • a “bifidogenic factor” is an agent or composition that specifically enhances the growth of bifidobacteria in the gastrointestinal tract of humans.
  • the use of the combinations and compositions of the invention as a bifidogenic factor enhances the growth of Bifidobacteria in the gastrointestinal tract of a subject.
  • the present invention provides the combinations and compositions of the invention for use in enhancing the growth of Bifidobacteria in the gastrointestinal tract of a subject.
  • the present invention provides a method of enhancing the growth of Bifidobacteria in the gastrointestinal tract of a subject comprising administering a combination or composition of the invention to the subject.
  • the combinations and compositions of the invention enhance the growth of one or more bifidobacteria which are usually abundant in the gastrointestinal tract of humans (see e.g. Turroni, F., et al., 2009. The ISME journal, 3(6), pp.745-751 and Turroni, F., et al., 2012. PloS one, 7(5), p.e36957).
  • the combinations and compositions of the invention may enhance the growth of one or more bifidobacterial phylogenetic groups selected from the B.
  • the combinations and compositions of the invention may enhance the growth of one or more bifidobacterial species selected from: B. longum, B. animalis, B. adolescentis, B. bifidum, B. catenulatum, B. pseudocatenulatum, B. breve, B. pseudolongum, B. gallicum, B. angulatum, and B. faecal (see e.g., Rivière, A., et al., 2016. Frontiers in microbiology, 7, p.979).
  • the combinations and compositions of the invention may enhance the growth of B.
  • the use is therapeutic. In some embodiments, the use is non- therapeutic.
  • Methods of treating or preventing infection or disease L . rhamnosus (including the strain with ATCC Accession No. 53103 and strain CGMCC1.3724 (LPR)) has been shown to have several beneficial health effects including enhancing the immune response to vaccination (Davidson et al., 2011, Eur J Clin Nutr.
  • SCFAs have been shown to promote host antibody responses (Kim et al., 2016, Cell Host & Microbe, 20(2): 202-214), protect against respiratory syncytial virus infection (Antunes et al., 2019, Nat Commun 10: 3273), enhance antimicrobial function of macrophages (and thereby boost the host defence against infections) (Schulthess et al., 2019, Immunity, 50(2): 432-445; and Machado et al., 2022, Front.
  • B ifidobacterium is one of the main genera of commensal bacteria present in the human gastrointestinal tracts and its presence has been related to health benefits in several studies (Hidalgo-Cantabrana, C., et al., 2017. Microbiology spectrum, 5(3), pp.5-3).
  • the use of the combination or composition of the invention, which enhances the growth of L. rhamnosus and/or Bifidobacteria and/or increases the levels of SCFA in the gastrointestinal tract of the subject would be expected to have the same effects as the administration of the probiotics or SCFAs discussed above.
  • the present invention provides the combination or nutritional composition of the invention for use as a medicament.
  • the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament.
  • the combination or nutritional composition of the invention may prevent or treat an infection or a disease by enhancing the growth of L. rhamnosus in the gastrointestinal tract of the subject.
  • T he combination or nutritional composition of the invention may prevent or treat an infection or a disease by enhancing the growth of Bifidobacteria in the gastrointestinal tract of the subject.
  • T he combination or nutritional composition of the invention may prevent or treat an infection or a disease by increasing the levels of SCFA in the gastrointestinal tract and systemic levels of SCFA of the subject.
  • the increased systemic levels of SCFA in the subject facilitates the exertion of the effects of the combination or nutritional composition of the invention beyond the gastrointestinal tract (e.g., in the lungs).
  • the combination or composition of the invention may be used to treat or prevent disorders associated with decreased numbers of Bifidobacteria in the gut (see e.g., Rivière, A., et al., 2016. Frontiers in microbiology, 7, p.979).
  • the invention provides the combination or composition of the invention for use in treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut.
  • the invention provides for use of the combination or composition of the invention for the manufacture of a medicament for treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut.
  • the invention provides a method of treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut in a subject, comprising administering the combination or composition of the invention to the subject.
  • the disorder associated with decreased numbers of Bifidobacteria in the gut in a subject may be selected from: a gastrointestinal disease, obesity, an allergic disease, and regressive autism. U se of L.
  • the present invention provides the combination or nutritional composition of the invention for use in enhancing the immune response to infection or vaccination in an infant, young child or child.
  • the antibody response to infection or vaccination is enhanced in the infant, young child or child.
  • the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament for enhancing the immune response to infection or vaccination in an infant, young child or child in an infant, young child or child.
  • the present invention provides a method of enhancing the immune response to infection or vaccination in an infant, young child or a child, the method comprising administering the composition of the invention to the infant, young child or child.
  • the antibody response to infection or vaccination is enhanced in the infant, young child or child.
  • the immune response to infection is enhanced.
  • the immune response to vaccination is enhanced. T he use of L. rhamnosus as a probiotic has been shown to be effective for the treatment or prevention of various infections.
  • L. rhamnosus as a probiotic has been shown to reduce the incidence of respiratory tract infections, including rhinovirus infections, in preterm infants (Luoto et al., 2014, J Allergy Clin Immunol, 133(2):405-13) and to reduce the number of days with symptoms of respiratory tract infections in children attending day care (Kumpu et al., 2013, J Med Virol, 85(9):1632-8).
  • rhamnosus as a probiotic has been shown to significantly reduce the risk of healthcare-associated infections, including gastrointestinal infections, respiratory tract infections, vomiting episodes, diarrheal episodes, episodes of gastrointestinal infections that lasted >2 days, and episodes of respiratory tract infections that lasted >3 days in hospitalised children (Hojsak et al., 2010, Pediatrics 125 (5): e1171–e1177).
  • a meta-analysis of the effect of L. rhamnosus as a probiotic on the prevention of healthcare-associated diarrhoea in children concluded that this probiotic can reduce the overall incidence of healthcare-associated diarrhoea in children (Szajewska et al., 2011, Aliment Pharmacol Ther, 34: 1079–1087).
  • the present invention provides the combination or nutritional composition of the invention for use in preventing and/or reducing the risk of developing an infection in an infant, young child or child.
  • the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament for preventing and/or reducing the risk of developing an infection in an infant, young child or child in an infant, young child or child.
  • the invention provides a method of preventing and/or reducing the risk of developing an infection in an infant, young child or a child, the method comprising administering the composition of the invention to the infant, young child or child.
  • the term “preventing and/or reducing the risk of developing an infection” includes preventing and/or reducing the risk of infection, delaying or preventing the onset of symptoms of infection and/or reducing the number or severity of symptoms of the infection.
  • the infection may be selected from respiratory tract infections (such as rhinovirus infections, respiratory syncytial virus infections, influenza virus infections), gastrointestinal tract infections (including candida infections, healthcare-associated infections and healthcare-associated diarrhea).
  • the composition of the invention may be administered once daily.
  • the composition of the invention is administered in multiple servings, for example in two servings (also known as “unit doses”) per day.
  • unit doses or “servings” it is particularly useful to define the amount of oligosaccharides and probiotics in terms of the daily dose to be administered to the infant, or young child or child.
  • the uses or methods are therapeutic.
  • the uses or methods are non-therapeutic. I n some embodiments, a total amount ranging from 800 to 7500 mg COS/day administered to the infant, young child or child corresponds to 1290 to 12100 mg/100 g dry weight of composition.
  • a total amount ranging from 100 to 1500 mg/day (suitably, 250 to 1500 mg/day, or 800 to 1400 mg/day, or 800 to 1350 mg/day) of COS are administered to the infant, young child or child.
  • a total amount ranging from 800 to 1500 mg/day, for example 800 to 1250 mg/day, or 1000 to 1500 mg/day of COS are administered to the infant, young child or child.
  • the maximum dose of COS (e.g., cellobiose) and/or ⁇ -glucan well tolerated by infant, young child and children is preferably a up to 7500 mg per day.
  • I n some embodiments 800 to 7500 mg COS/day are administered to the infant, young child or child.
  • a total amount of at least 800 mg/day of COS e.g., cellobiose
  • COS e.g., cellobiose
  • about 100 mg/day (suitably, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day, 550 mg/day, 600 mg /day, 650 mg/day, 700 mg/day, 750 mg/day, 800 mg/day, 850 mg/day, 900 mg/day, 950 mg/day, 1000 mg/day, 1050 mg/day, 1100 mg/day, 1150 mg/day, 1200 mg/day, 1250 mg/day, 1300 mg/day, 1350 mg/day, 1400 mg/day, 1450 mg/day or 1500 mg/day) of COS (e.g.
  • cellobiose are administered to the infant, young child or child.
  • about 800 mg/day to 1250 mg/day of COS are administered to the infant, young child or child.
  • a total amount ranging from 100 to 1000 mg/day (suitably, 150-800 mg/day or 200 to 600 mg/day) of ⁇ -glucan and COS (e.g. cellobiose) combined are administered to the infant, young child or child.
  • a total amount ranging from 200 to 600 mg/day of ⁇ -glucan and COS combined are administered to the infant, young child or child.
  • an amount 450 mg/day of ⁇ -glucan and an amount 150 mg/day of COS (preferably cellobiose) combined are administered to the infant, young child or child.
  • an amount 150 mg/day of ⁇ -glucan and an amount 450 mg/day of COS (preferably cellobiose) combined are administered to the infant, young child or child.
  • an amount ranging from 50 to 950 mg/day of ⁇ -glucan and an amount ranging from 50 to 950 mg/day of COS are administered to the infant, young child or child.
  • an amount ranging from 100 to 800 mg/day of ⁇ -glucan and an amount ranging from 100 to 800 mg/day of COS are administered to the infant, young child or child.
  • an amount ranging from 150 to 450 mg/day of ⁇ - glucan and an amount ranging from 150 to 450 mg/day of COS are administered to the infant, young child or child.
  • about 50 mg/day (suitably, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day, 550 mg/day, 600 mg /day, 650 mg/day, 700 mg/day, 750 mg/day, 800 mg/day, 850 mg/day, 900 mg/day or 950 mg/day) of ⁇ -glucan and about 50 mg/day (suitably, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day, 550 mg/day, 600 mg /day, 650 mg/day, 700 mg/day, 750 mg/day,
  • about 150 mg/day of ⁇ -glucan and about 450 mg/day of COS are administered to the infant, young child or child.
  • about 300 mg/day of ⁇ - glucan and about 300 mg/day of COS are administered to the infant, young child or child.
  • about 450 mg/day of ⁇ -glucan and about 150 mg/day of COS are administered to the infant, young child or child.
  • about 50 mg/day of ⁇ - glucan and about 150 mg/day of COS are administered to the infant, young child or child.
  • about 100 mg/day of ⁇ -glucan and about 100 mg/day of COS are administered to the infant, young child or child.
  • about 150 mg/day of ⁇ - glucan and about 50 mg/day of COS are administered to the infant, young child or child.
  • the infant, young child or child is non-responsive to treatment with ⁇ -glucan or with a combination of L. rhamnosus and ⁇ -glucan.
  • non-responsive to treatment with ⁇ -glucan or with a combination of L. rhamnosus and ⁇ -glucan refers to an infant, young child or a child who does not respond to the oral administration of ⁇ -glucan or ⁇ -glucan in combination with L. rhamnosus.
  • an infant, young child or a child who is non-responsive to treatment with ⁇ -glucan or with a combination of L. rhamnosus and ⁇ -glucan does not show increased levels of butyrate in the gastrotintestinal tract when ⁇ -glucan or ⁇ -glucan in combination with L. rhamnosus is administered compared to no administration of ⁇ -glucan or ⁇ -glucan in combination with L. rhamnosus.
  • an infant, young child or a child who is non- responsive to treatment with ⁇ -glucan or with a combination of L. rhamnosus and ⁇ -glucan is characterized by the presence of lower levels of Faecalibacterium spp.
  • an infant, young child or a child may be identified as responsive or non-responsive to treatment ⁇ -glucan or ⁇ -glucan in combination with L. rhamnosus based upon the levels of Faecalibacterium spp. and Parabacteroides distasonis in fecal samples.
  • rhamnosus and ⁇ -glucan shows increased levels of butyrate in the gastrointestinal tract when ⁇ -glucan or ⁇ -glucan in combination with L. rhamnosus is administered compared to no administration of ⁇ -glucan or ⁇ -glucan in combination with L. rhamnosus.
  • an infant, young child or a child who is responsive to treatment with ⁇ -glucan or with a combination of L. rhamnosus and ⁇ -glucan is characterized by the presence of higher levels of Faecalibacterium spp.
  • OTUs Operational Taxonomic Units
  • the species level OTUs and butyrate levels in the gastrointestinal tract may be determined by any suitable methods known in the art. For example, species level OTUs and butyrate levels in the gastrointestinal tract may be measured using the methods described herein (see Example 4).
  • the present invention provides the use of the nutritional composition of the invention for increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child.
  • SCFA short chain fatty acid
  • the present invention provides a method of increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child, the method comprising administering the composition of the invention to the infant, young child or child.
  • the at least one SCFA is acetate, propionate, butyrate, or any combination thereof.
  • the at least one SCFA is acetate.
  • the at least one SCFA is propionate.
  • the at least one SCFA is butyrate. In a most preferred embodiment, the at least one SCFA is butyrate. In some embodiments, the at least one SCFA is butyrate and the infant, young child or child is non-responsive to treatment with ⁇ -glucan or with a combination of Lactobacillus rhamnosus and ⁇ -glucan.
  • the combination or nutritional composition of the invention may be administered by any suitable method known to the skilled person. For example, the combination or nutritional composition of the invention may be administered by oral and/or enteral administration. In some embodiments, the combination or nutritional composition of the invention is orally administered.
  • HCAD Healthcare-associated-diarrhea
  • Acute respiratory infections Acute respiratory infections (ARIs) are classified as upper respiratory tract infections (URIs) or lower respiratory tract infections (LRIs). Acute upper respiratory tract infections are common, especially among children, and include rhinitis, pharyngitis, tonsillitis, and laryngitis.
  • Acute lower respiratory infections include pneumonia (infection of the lung alveoli), as well as infections affecting the airways such as acute bronchitis and bronchiolitis, influenza and whooping cough.
  • Acute respiratory infections are responsible for 4.25 million deaths worldwide, with the great majority of deaths from respiratory infections being caused by LRIs - predominantly pneumonia.
  • L. rhamnosus has been shown to treat or prevent acute respiratory infections (Kumpu et al., 2013, J Med Virol, 85(9):1632-8) such as rhinovirus infections (Luoto et al., 2014, J Allergy Clin Immunol, 133(2):405-13).
  • SCFAs have been shown to protect against respiratory syncytial virus infection (Antunes et al., 2019, Nat Commun 10: 3273), protect against influenza virus infection or enhance the immune response to influenza virus (Trompette et al., 2018, Immunity, 48(5): 992-1005; and Moriyama and Ichinoe, 2019, PNAS, 116(8): 3118-3125), and protect against respiratory syncytial virus (RSV)–bronchiolitis (Lynch et al., 2018, J Exp Med., 215(2): 537– 557).
  • Rhinovirus infections Rhinovirus infections are the predominant cause of the common cold. Most rhinovirus infections are mild, but they can sometimes lead to bronchiolitis and pneumonia.
  • Influenza virus infections Influenza is an acute respiratory infection caused by influenza viruses which circulate in all parts of the world. These viruses are easily transmitted from person to person. In a typical year, 5–15% of the population contracts influenza. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin from one to four days after exposure to the virus (typically two days) and last for about 2–8 days. In healthy individuals, influenza is typically self-limiting and rarely fatal, but it can be deadly in high-risk groups, including young children, the elderly, and people with chronic health conditions. There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year.
  • I nfluenza infection may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection.
  • Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.
  • Respiratory syncytial virus (RSV) infections RSV is a common respiratory virus that usually causes mild, cold-like symptoms. Most people recover in a week or two. RSV can also cause more severe infections such as bronchiolitis, an inflammation of the small airways in the lung, and pneumonia, an infection of the lungs. RSV is so common that most children have been infected with the virus by age 2.
  • Fungal infections Fungal infections that are not life-threatening, such as skin, nail, or vaginal yeast infections, are common. Some infections can be more serious. Fungal infections are more prevalent in individuals with a weakened immune system. C olonization by Candida species is reported to be the most important predictor of the development of invasive fungal disease in preterm neonates, and the enteric reservoir is a major site of colonization. It has been evidenced that orally administered L. rhamnosus significantly reduces the incidence and the intensity of enteric colonization by Candida species among very low birth weight neonates (Manzoni et al., 2006, Clin Infect Dis, 42(12):1735-42). Methods of promoting and/or maintaining gastrointestinal health As described above, the use of probiotics, including L.
  • the present invention provides the combination or nutritional composition of the invention for use in promoting and/or maintaining gastrointestinal health in an infant, young child or child.
  • the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament for promoting and/or maintaining gastrointestinal health in an infant, young child or child.
  • the present invention provides a method of promoting and/or maintaining gastrointestinal health in an infant, young child or a child, the method comprising administering the combination or composition of the invention to the infant, young child or child.
  • the invention provides the use of the combination or composition of the invention for promoting and/or maintaining gastrointestinal health.
  • the combination or composition of the invention may promote and/or maintain gastrointestinal health by enhancing the growth of L. rhamnosus or Bifidobacteria, or by increasing the levels of SCFA, in the gastrointestinal tract of the subject.
  • Methods of treating and/or preventing a gastrointestinal disease includes treating and/or preventing a gastrointestinal disease.
  • the invention provides the combination or composition of the invention for use in treating and/or preventing a gastrointestinal disease.
  • the invention provides for use of the combination or composition of the invention for the manufacture of a medicament for treating and/or preventing a gastrointestinal disease.
  • the invention provides a method of treating and/or preventing a gastrointestinal disease in a subject, comprising administering the combination or composition of the invention to the subject.
  • a “gastrointestinal disease” also known as “GI disease” or “GI illness” may refer to diseases involving the gastrointestinal tract, which includes the oesophagus, stomach, small intestine, large intestine and rectum.
  • the gastrointestinal disease is a gastric disease or an intestinal disease.
  • the gastrointestinal disease is a gastric disease.
  • a “gastric disease” may refer to diseases affecting the stomach.
  • the gastrointestinal disease is an intestinal disease.
  • an “intestinal disease” may refer to diseases affecting the small intestine (including the duodenum, jejunum, and ileum) or large intestine (including the cecum, colon, and rectum).
  • the gastrointestinal disease is selected from: healthcare- associated diarrhea, antibiotic-associated diarrhea, Helicobacter pylori infection, an inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, infectious diarrhea, and necrotizing enterocolitis.
  • the methods are therapeutic.
  • the methods are non-therapeutic.
  • Antibiotic-associated diarrhea A common complication of antibiotic use is the development of gastrointestinal disease. This complication ranges from mild diarrhea to pseudomembranous colitis.
  • Antibiotic-associated diarrhea typically occurs in 5–35% of patients taking antibiotics and varies depending upon the specific type of antibiotic, the health of the host and exposure to pathogens.
  • the pathogenesis of antibiotic-associated diarrhea may be mediated through the disruption of the normal microbiota resulting in pathogen overgrowth or metabolic imbalances (McFarland, L.V., 2008. Future Microbiology, 3(5), p.563).
  • a probiotic mixture which contains several Bifidobacteria strains, among which are B. breve, B. infantis, and B. longum, displayed an ability to reduce the incidence of antibiotic- associated diarrhea (Selinger, C.P., et al., 2013. Journal of Hospital Infection, 84(2), pp.159- 165).
  • H elicobacter pylori is a gram-negative microaerophilic bacterium that infects the epithelial lining of the stomach.
  • Helicobacter pylori is the main cause of chronic gastritis and the principal etiological agent for gastric cancer and peptic ulcer disease.
  • a recent global systematic review estimated that more than half the world’s population is infected with Helicobacter pylori (Hooi, J.K., et al., 2017. Gastroenterology, 153(2), pp.420-429).
  • a Helicobacter pylori eradication rate of 32.5% has been reported in adults after 10 days of administration of a probiotic mixture which contains several Bifidobacteria strains, among which are B. breve, B. infantis, and B. longum (Boltin, D., 2016. Best Practice & Research Clinical Gastroenterology, 30(1), pp.99-109). Moreover, such a probiotic mixture has be shown to accelerate gastric ulcer healing (Dharmani, P., et al., 2013. PLoS One, 8(3), p.e58671). Inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine.
  • IBD Inflammatory bowel disease
  • IBDs include Crohn’s disease (CD), ulcerative colitis (UC), and pouchitis.
  • CD Crohn’s disease
  • UC ulcerative colitis
  • pouchitis Is has been suggested that dysbiosis (that is, abnormal microbiota composition) and decreased complexity of the gut microbial ecosystem are common features in patients with IBD (see Manichanh, C., et al., 2012. Nature reviews Gastroenterology & hepatology, 9(10), pp.599-608).
  • I n IBD a probiotic mixture which contains several Bifidobacteria strains, among which are B. breve, B. infantis, and B. longum, was able to reduce the UC symptoms in adults (Tursi, A., et al., 2010.
  • IBD Irritable bowel syndrome
  • IBS Irritable bowel syndrome
  • Infectious diarrhea is inflammation of the gastrointestinal tract caused by an infection.
  • Gastroenteritis is usually caused by viruses (e.g. rotavirus, norovirus, adenovirus, astrovirus, and coronavirus), however, bacteria (e.g. C. jeuni, E. coli, Salmonella, Shigella, C. difficile, and S. aureus), parasites (e.g. Giardia lamblia), and fungus can also cause gastroenteritis.
  • viruses e.g. rotavirus, norovirus, adenovirus, astrovirus, and coronavirus
  • bacteria e.g. C. jeuni, E. coli, Salmonella, Shigella, C. difficile, and S. aureus
  • parasites e.g. Giardia lamblia
  • fungus can also cause gastroenteritis.
  • Necrotizing enterocolitis is an intestinal disease that affects premature infants. It has been shown that probiotic supplementation with Bifidobacteria can reduce both the incidence and severity of NEC in a premature neonatal population (Bin-Nun, A., et al., 2005. The Journal of pediatrics, 147(2), pp.192-196).
  • the invention provides the combination or composition of the invention for use in treating and/or preventing lactose intolerance, infectious diarrhea, or necrotizing enterocolitis.
  • the invention provides for use of the combination or composition of the invention for the manufacture of a medicament for treating and/or preventing lactose intolerance, infectious diarrhea, or necrotizing enterocolitis.
  • the invention provides a method of treating and/or preventing lactose intolerance, infectious diarrhea, or necrotizing enterocolitis in a subject, comprising administering the combination or composition of the invention to the subject. Subject In some embodiments of the methods and uses of the invention, the combination or composition is administered to an infant.
  • the combination or composition is administered to a young child. In some embodiments of the methods and uses of the invention, the combination or composition is administered to a child. In a further embodiment, the infant has an age ranging from 0 months to 12 months, for example 9 or 6 months. I n some embodiments, the young child has an age ranging from one year to three years, for example 2 years. I n some embodiments, the child has an age ranging from three years to nine years, for example from three years to seven years. In some preferred embodiments, the child has an age ranging from three years to five years, for example four years. Some specific populations of infants, young children and children are particularly in need of compositions of the invention.
  • Such infants, young children and children are for example preterm infants, low birth weight infant, and/or growth-retarded infants, young children or children. Indeed such subjects are often experiencing adverse medical conditions and require significantly more frequent medical intervention than term infants and infants having experienced normal development.
  • T he nutritional composition according to the invention is for use in infants, young children and/or children.
  • the infants, young children and/or children may be born term or preterm.
  • the nutritional composition of the invention is for use in infants, young children and/or children that were born preterm, having a low birth weight and/or born small for gestational age (SGA).
  • the nutritional composition of the invention is for use in preterm infants, infants having a low birth weight and/or infants born small for gestational age (SGA).
  • the nutritional composition of the present invention may also be used in an infant, young child or child that was born by C-section or that was vaginally delivered.
  • the composition according to the invention can be for use before and/or during the weaning period.
  • the nutritional composition can be administered (or given or fed) at an age and for a period that depends on the needs.
  • the nutritional composition can be for example given immediately after birth of the infants.
  • composition of the invention can also be given during the first week of life of the infant, or during the first 2 weeks of life, or during the first 3 weeks of life, or during the first month of life, or during the first 2 months of life, or during the first 3 months of life, or during the first 4 months of life, or during the first 6 months of life, or during the first 8 months of life, or during the first 10 months of life, or during the first year of life, or during the first two years of life or even more.
  • the nutritional composition is given (or administered) to an infant within the first 4, 6 or 12 months of birth of said infant.
  • the nutritional composition of the invention is given few days (e.g.1, 2, 3, 5, 10, 15, 20%), or few weeks (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10%), or few months (e.g.1 , 2, 3, 4, 5, 6, 7, 8, 9, 10...) after birth. This may be especially the case when the infant is premature, but not necessarily.
  • the composition of the invention is given to the infant or young child as a supplementary composition to the mother’s milk.
  • the infant or young child receives the mother’s milk during at least the first 2 weeks, first 1, 2, 4, or 6 months.
  • the nutritional composition of the invention is given to the infant or young child after such period of mother’s nutrition, or is given together with such period of mother’s milk nutrition.
  • the composition is given to the infant or young child as the sole or primary nutritional composition during at least one period of time, e.g., after the1st, 2nd or 4th month of life, during at least 1, 2, 4 or 6 months.
  • the subject may have or may be at risk of a low abundance of L. rhamnosus in their gastrointestinal tract.
  • the subject may have or may be at risk of a low abundance of Bifidobacteria in their gastrointestinal tract.
  • the abundance of L. rhamnoosus or Bifidobacteria in the gastrointestinal tract may be determined by any method known to the skilled person (e.g., any method described in Tang, Q., et al., 2020.
  • a gastrointestinal tract sample may be obtained from or obtainable from fecal samples, endoscopy samples (e.g., biopsy samples, luminal brush samples, laser capture microdissection samples), aspirated intestinal fluid samples, surgery samples, or by in vivo models or intelligent capsule.
  • a gastrointestinal tract sample may be obtained from or obtainable from fecal samples. Fecal samples are naturally collected, non-invasive and can be sampled repeatedly. T he abundance of L.
  • rhamnoosus or Bifidobacteria may be determined from the samples by any suitable method.
  • the abundance of L. rhamnoosus or Bifidobacteria may be obtained by or obtainable from the samples by sequencing methods (e.g., next-generation sequencing (NGS) methods), PCR-based methods, semi-quantitative detection methods, cycling temperature capillary electrophoresis, immunological-based methods, cell-based methods, or any combination thereof.
  • NGS next-generation sequencing
  • the subject may have or may be at risk of a disorder associated with decreased numbers of L. rhamnosus or Bifidobacteria in the gut. Such disorders are described by Rivière, A., et al., 2016.
  • the subject may have or may be at risk of a gastrointestinal disease.
  • gastrointestinal diseases are described in more detail in the section entitled “Methods of treating and/or preventing a gastrointestinal disease”.
  • the subject may have or may be at risk of an antibiotic-associated diarrhea.
  • the subject may have or may be at risk of a Helicobacter pylori infection.
  • the subject may have or may be at risk of an IBD.
  • the subject may have or may be at risk of IBS.
  • the subject may have or may be at risk of lactose intolerance, infectious diarrhea, or necrotizing enterocolitis.
  • Other ingredients may also comprise other types of oligosaccharide(s) (i.e., other than COS and ⁇ -glucan mentioned above) and/or a fiber(s) and/or a precursor(s) thereof.
  • the other oligosaccharide and/or fiber and/or precursor thereof may be selected from the list comprising human milk oligosaccharides (HMOs), fructo-oligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose and any combination thereof.
  • the nutritional composition or the growing-up milk can also contain at least one BMO (bovine milk oligosaccharide).
  • BMOs bovine milk oligosaccharide
  • HMOs which may be included in the combination or nutritional composition according to the present invention may be selected from the group consisting of 2-FL (2- fucosyllactose), 3-FL (3- fucosyllactose), Lacto-difucotetraose (LDFT)), lacto-N- fucopentaose (e.g.
  • lacto-N-fucopentaose I lacto-N-fucopentaose II, lacto-N- fucopentaose III, lacto-N- fucopentaose V)
  • lacto-N-fucohexaose lacto-N-difucohexaose I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose I, difucosyllacto-N-neohexaose II, para-lacto-N-neohexaose (para-LNnH), LNT (lacto-N-tetraose), LNnT (lacto-N-neotetraose), lacto-N-hexaose, lacto- N-neohexaose, para-lacto
  • the combination or nutritional composition according to the invention comprises at least one additional HMO. In other embodiments, the combination or nutritional composition according to the present invention is devoid of any further HMOs.
  • the nutritional composition of the present invention can further comprise at least one further probiotic (or probiotic strain), such as at least one further probiotic bacterial strain.
  • the probiotic microorganisms most commonly used are principally bacteria and yeasts of the following genera: Lactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.
  • the probiotic is a probiotic bacterial strain.
  • Suitable probiotic bacterial strains include Lactobacillus paracasei CNCM I-2116, Lactobacillus johnsonii CNCM I-1225, Streptococcus salivarius DSM 13084 sold by BLIS Technologies Limited of New Zealand under the designation KI2, Bifidobacterium lactis CNCM 1-3446 sold inter alia by the Christian Hansen company of Denmark under the trademark Bb 12, Bifidobacterium breve sold by Danisco under the trademark Bb-03, Bifidobacterium breve sold by Morinaga under the trade mark M-16V, Bifidobacterium infantis sold by Procter & GambIe Co.
  • the nutritional composition according to the invention may contain from 10 3 to 10 12 cfu of the at least one further probiotic strain, more preferably between 10 7 and 10 12 cfu such as between 10 8 and 10x 10 cfu of probiotic strain per g of composition on a dry weight basis.
  • the probiotics are viable.
  • the nutritional composition according to the invention can be for example an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier such as a human milk fortifier, or a supplement.
  • the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first 4 or 6 months of age.
  • the nutritional composition of the invention is an infant formula.
  • the nutritional composition of the present invention is a fortifier.
  • the fortifier can be a breast milk fortifier (e.g., a human milk fortifier) or a formula fortifier such as an infant formula fortifier or a follow-on/follow-up formula fortifier.
  • the nutritional composition is a supplement, it can be provided in the form of unit doses.
  • the nutritional composition is a supplement, it may comprise 2’-FL and no other additional nutrient on top of the excipients necessary to obtain a stable nutritional composition.
  • the nutritional composition of the present invention can be in solid (e.g., powder), liquid or gelatinous form.
  • the nutritional composition is a supplement, wherein the supplement is in powder form and provided in a sachet, preferably a sachet with 0.1 to 20 g per sachet, for example 1 to 10 g per sachet, or in the form of a syrup, preferably a syrup with a total solid concentration of 5 to 75 g/100 mL (5 to 75% (w/v)).
  • the supplement when it is in powder form, it may comprise a carrier. It is however preferred that the supplement is devoid of a carrier.
  • the components are preferably dissolved or suspended in water acidified with citrate.
  • the nutritional composition according to the invention generally contains a protein source.
  • the protein can be in an amount of from 1.6 to 3 g per 100 kcal. In some embodiments, especially when the composition is intended for premature infants, the protein amount can be between 2.4 and 4 g/100kcal or more than 3.6 g/100kcal. In some other embodiments the protein amount can be below 2.0 g per 100 kcal, e.g., between 1.8 to 2 g/100 kcal, or in an amount below 1.8 g per 100 kcal. Protein sources based on whey, casein and mixtures thereof may be used as well as protein sources based on soy.
  • the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha- lactalbumin and beta-lactoglobulin in any desired proportions.
  • the protein source is whey predominant (i.e., more than 50% of proteins are coming from whey proteins, such as 60% or 70%).
  • the proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins.
  • intact is meant that the main part of the proteins are intact, i.e.
  • the molecular structure is not altered, for example at least 80% of the proteins are not altered, such as at least 85% of the proteins are not altered, preferably at least 90% of the proteins are not altered, even more preferably at least 95% of the proteins are not altered, such as at least 98% of the proteins are not altered. In a particular embodiment, 100% of the proteins are not altered.
  • the term “hydrolysed” means in the context of the present invention a protein which has been hydrolysed or broken down into its component amino acids.
  • the proteins may be either fully or partially hydrolysed. It may be desirable to supply partially hydrolysed proteins (degree of hydrolysis between 2 and 20%), for example for infants or young children believed to be at risk of developing cow’s milk allergy.
  • whey protein hydrolysates may be prepared by enzymatically hydrolysing the whey fraction in one or more steps. If the whey fraction used as the starting material is substantially lactose free, it is found that the protein suffers much less lysine blockage during the hydrolysis process. This enables the extent of lysine blockage to be reduced from about 15% by weight of total lysine to less than about 10% by weight of lysine; for example about 7% by weight of lysine which greatly improves the nutritional quality of the protein source.
  • At least 70% of the proteins are hydrolysed, preferably at least 80% of the proteins are hydrolysed, such as at least 85% of the proteins are hydrolysed, even more preferably at least 90% of the proteins are hydrolysed, such as at least 95% of the proteins are hydrolysed, particularly at least 98% of the proteins are hydrolysed.
  • 100% of the proteins are hydrolysed.
  • the proteins of the nutritional composition are hydrolyzed, fully hydrolyzed or partially hydrolyzed.
  • the degree of hydrolysis (DH) of the protein can be between 8 and 40, or between 20 and 60 or between 20 and 80 or more than 10, 20, 40, 60, 80 or 90.
  • the protein component can alternatively be replaced by a mixture or synthetic amino acid, for example for preterm or low birth weight infants.
  • the nutritional composition or the growing-up milk according to the invention is a hypoallergenic composition.
  • the composition according to the invention is a hypoallergenic nutritional composition or growing-up milk.
  • the nutritional composition according to the present invention generally contains a carbohydrate source. This is particularly preferable in the case where the nutritional composition of the invention is an infant formula. In this case, any carbohydrate source conventionally found in infant formulae such as lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof may be used although one of the preferred sources of carbohydrates is lactose.
  • the nutritional composition according to the present invention generally contains a source of lipids. This is particularly relevant if the nutritional composition of the invention is an infant formula.
  • the lipid source may be any lipid or fat which is suitable for use in infant formulae.
  • Some suitable fat sources include palm oil, structured triglyceride oil, high oleic sunflower oil and high oleic safflower oil, medium-chain-triglyceride oil.
  • the essential fatty acids linoleic and ⁇ -linolenic acid may also be added, as well small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils.
  • the fat source may have a ratio of n-6 to n-3 fatty acids of about 5:1 to about 15:1; for example about 8:1 to about 10:1.
  • the nutritional composition of the invention may also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals.
  • Examples of minerals, vitamins and other nutrients optionally present in the composition of the invention include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended population.
  • the nutritional composition of the invention may contain emulsifiers and stabilisers such as soy, lecithin, citric acid esters of mono- and diglycerides, and the like.
  • the nutritional composition of the invention may also contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, and the like.
  • the nutritional composition of the invention may also contain carotenoid(s). In some particular embodiments of the invention, the nutritional composition of the invention does not comprise any carotenoid.
  • the nutritional composition according to the invention may be prepared in any suitable manner. A composition will now be described by way of example.
  • a formula such as an infant formula may be prepared by blending together the protein source, the carbohydrate source and the fat source in appropriate proportions. If used, the emulsifiers may be included at this point. The vitamins and minerals may be added at this point but they are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The temperature of the water is conveniently in the range between about 50°C and about 80°C to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture.
  • the fucosylated oligosaccharide(s) and the N-acetylated oligosaccharide(s) may be added at this stage, especially if the final product is to have a liquid form. If the final product is to be a powder, they may likewise be added at this stage if desired.
  • the liquid mixture is then homogenised, for example in two stages.
  • the liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range between about 80°C and about 150°C for a duration between about 5 seconds and about 5 minutes, for example. This may be carried out by means of steam injection, an autoclave or a heat exchanger, for example a plate heat exchanger.
  • the liquid mixture may be cooled to between about 60°C and about 85°C for example by flash cooling.
  • the liquid mixture may then be again homogenised, for example in two stages between about 10 MPa and about 30 MPa in the first stage and between about 2 MPa and about 10 MPa in the second stage.
  • the homogenised mixture may then be further cooled to add any heat sensitive components, such as vitamins and mineraIs.
  • the pH and solids content of the homogenised mixture are conveniently adjusted at this point.
  • the homogenised mixture is transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder.
  • the powder should have a moisture content of less than about 5% by weight.
  • the oligosaccharide(s) may also or alternatively be added at this stage by dry-mixing or by blending them in a syrup form of crystals, along with the probiotic strain(s), and the mixture is spray-dried or freeze-dried.
  • the homogenised mixture may be sterilised then aseptically filled into suitable containers or may be first filled into the containers and then retorted.
  • the composition of the invention may be a supplement.
  • the supplement may be in the form of tablets, capsules, pastilles or a liquid for example.
  • the supplement may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents and gel forming agents.
  • protective hydrocolloids such as gums, proteins, modified starches
  • binders film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aid
  • the supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatine of any origin, vegetable gums, lignin-sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.
  • the supplement may contain an organic or inorganic carrier material suitable for oral or parenteral administration as well as vitamins, minerals trace elements and other micronutrients in accordance with the recommendations of Government bodies such as the USRDA.
  • a nutritional composition comprising Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent, wherein the L. rhamnosus-modulating agent is preferably selected from the list consisting of: a combination of FOS and inulin, cello-oligosaccharides (COS), a combination of ⁇ -glucan and COS, at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium, and any combination thereof.
  • the nutritional composition of para 1 wherein the composition comprises L.
  • rhamnosus in an amount of 1 ⁇ 103 to 1.5 ⁇ 1012 cfu/g of the composition (dry weight).
  • 3. The nutritional composition of para 1 or para 2, wherein the L. rhamnosus has at least 99% Average Nucleotide Identity (ANI) to L. rhamnosus CGMCC1.3724 (LPR), preferably at least 99.9% ANI to L. rhamnosus CGMCC1.3724 (LPR).
  • ANI Average Nucleotide Identity
  • LPR Average Nucleotide Identity
  • LPR Average Nucleotide Identity
  • LPR Average Nucleotide Identity
  • CGMCC1.3724 LPR
  • 4 The nutritional composition of any one of the preceding paras, wherein the L. rhamnosus comprises or consists of selected from L. rhamnosus LC705 (DSM 7061) and L. rhamnosus CGMCC1.3724 (LPR), preferably wherein the L.
  • rhamnosus is CGMCC1.3724 (LPR). 5. The nutritional composition of any one of the preceding paras, wherein the L. rhamnosus-modulating agent is cello-oligosaccharides (COS), preferably cellobiose and/or cellotriose, more preferably cellobiose. 6. The nutritional composition of para 5, wherein the COS are derived from a plant, preferably a cereal. 7. The nutritional composition of para 5 or para 6, wherein the COS are derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. 8.
  • COS cello-oligosaccharides
  • the nutritional composition further comprises a probiotic of the genus Lactobacillus, Streptococcus, Enterococcus, Bifidobacterium and Saccharomyces. 17.
  • the at least one probiotic is of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium.
  • the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp.
  • lactis NCC 2818 Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof.
  • 20 The nutritional composition according to any one of paras 17 to 19, wherein the nutritional composition further comprises inulin and oligofructose.
  • 21 The nutritional composition according to any one of the preceding paras, wherein the nutritional composition is formulated for an infant, young child and/or child. 22.
  • the nutritional composition according to any one of the preceding paras wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow- up infant formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier or a supplement.
  • the nutritional composition according to any one of the preceding paras for use as a medicament.
  • the nutritional composition according to any one of paras 1 to 22 for use in enhancing the immune response to infection or vaccination, for use in promoting and/or maintaining gut health, or for use in preventing and/or reducing the risk of developing an infection in an infant, young child or child.
  • any one of paras 1 to 22 for enhancing the growth of Bifidobacteria in the gastrointestinal tract of an infant, young child or child.
  • 30. Use of the nutritional composition according to any one of paras 1 to 22 for increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child.
  • 31. The use according to para 30, wherein the at least one SCFA is acetate, propionate, butyrate or any combination thereof.
  • 32. The use according to para 30 or para 31, wherein the at least one SCFA is butyrate and wherein the infant, young child or child is non-responsive to treatment with ⁇ -glucan or with a combination of L. rhamnosus and ⁇ -glucan. 33.
  • At least one probiotic for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, wherein the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium, optionally wherein the at least one probiotic is of the genus Lactobacillus, Streptococcus and/or Bifidobacterium.
  • the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp.
  • mice were fed a low- fiber diet (KLIBA NAFAG diet 2122, Kliba Nafag AG, Kaiseraugst, Switzerland) at arrival and throughout the duration of the experiment.
  • KLIBA NAFAG diet 2122, Kliba Nafag AG, Kaiseraugst, Switzerland One-week post-arrival, mice received sodium acetate, sodium propionate, and sodium butyrate (Sigma-Aldrich, St. Louis, MO) in the drinking water at a final concentration of 100 mM each.
  • Mice were monitored weekly prior to influenza infection to ensure that the SCFA mix was well-tolerated by the animals.
  • Probiotic L rhamnosus (1x109 cfu per mouse) was diluted in sterile PBS and given by gavage every other day until the end of experiment in 200 ⁇ l final volume.
  • the synbiotic group received the probiotic as above along with a prebiotic blend diluted in the drinking water and changed every other day until the end of experiment (mouse adapted dose calculated from 600mg/day of cellobiose & oat b-glucan mix at 25:75 ratio equivalent to 30 mg oat ⁇ -glucan and 10 mg Cello-oligosaccharide per mouse per day).
  • adult (7-week-old) female mice were anesthetized with a mixture of ketamine and xylazine (Dr. E.
  • Ex vivo fecal fermentation study This study was conducted with Cryptobiotix SA, using their proprietary ex-vivo human Gastro Intestinal Tract (GIT) replica model and microbiota colonic incubations.
  • NIDO milk matrices were pre-digested, and then spiked with Prebio1, LPR and one of six additional probiotic strains. These various combinations were then added to a replica colonic incubation, containing the ex-vivo faecal microbiota of 1–2-year-old toddlers.
  • Nine arms were used in the study. These consisted of: 1. Blank (ex vivo microbiota and NIDO milk matrix) 2. Prebio1 3. Lacticaseibacillus rhamnosus LPR 4. Prebio1 & LPR 5.
  • Prebio1 & LPR & Lacticaseibacillus paracasei ST11 6.
  • Prebio1 & LPR & Lactobacillus johnsonii LA1 7.
  • Prebio1 & LPR & Bifidobacterium animalis subsp. lactis BL818 8.
  • Prebio1 & LPR & Bifidobacterium longum subsp. infantis NCC3039 9.
  • Prebio1 (70% FOS, 30% inulin) was dosed at a final concentration of 3g/L (0.82 g/L inulin, 1.94 g/L FOS).
  • the NIDO milk matrix as dosed at a concentration of 17.35 g/L.
  • All probiotics, including (LPR) were dosed at a concentration of 1.5x10 7 cfu/mL.
  • Colonic incubations were carried out for 24-hours, with sampling at 0 and 24 hours for: ⁇ pH ⁇ LPR plate counts ⁇ 16S rRNA sequencing and flow cytometry 16S rRNA sequencing was performed using Illumina sequencing, paired with flow cytometry to facilitate absolute quantification.
  • Example 1 An example of the composition of an infant formula according to the present invention is given in the below table 1. This composition is given by way of illustration only.
  • Table 1 Composition of the infant formula of Example 1 N utrients per 100kcal per litre Energy (kcal) 100 670 Protein (g) 1.83 12.3 Fat (g) 5.3 35.7 Linoleic acid (g) 0.79 5.3 ⁇ -Linolenic acid (mg) 101 675 Lactose (g) 11.2 74.7 Minerals (g) 0.37 2.5 Na (mg) 23 150 K (mg) 89 590 Cl (mg) 64 430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 7 50 Mn ( ⁇ g) 8 50 Se ( ⁇ g) 2 13 Vitamin A ( ⁇ g RE) 105 700 Vitamin D ( ⁇ g) 1.5 10 Vitamin E (mg TE) 0.8 5.4 Vitamin K1 ( ⁇ g) 8 54 Vitamin C (mg) 10 67 Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1.0 Niacin (mg) 1 6.7 Vitamin B6 (mg) 0.075 0.50 Folic acid
  • Lacticaseibacillus rhamnosus LPR (cfu) 1.2x108 9.3x108
  • Example 2 Lacticaseibacillus rhamnosus LPR (CGMCC1.3724) was retrieved from the Nestle Culture Collection (NCC; Nestlé Research, Lausanne, Switzerland). The strain was grown in a modified de Man, de Rogosa & Sharpe medium lacking carbohydrates (MRS-C) previously described by Duboux et al. (Duboux, S., et al., Sci Rep, 2021. 11(1): p. 7236).
  • MRS-C was supplemented with 0.5% of different carbohydrates (glucose, cellobiose, cellotriose, cellotetratose, polygalacturonic acid (Sigma-Aldrich Chemie GmbH, Buchs, Switzerland) using filter sterilized (0.22 ⁇ m) stock solutions prepared at 100 g/L in water.
  • the strain was then cultured in a microbiorector system (BioLector; m2p-labs GmbH, Baesweiler, Germany) in anaerobiosis for 48h. Growth was recorded using the integrated biomass measurement system and is depicted in Error! Reference source not found.. Results demonstrated that L.
  • rhamnosus LPR was able to grow on different cello- oligosaccharides (COS), cellobiose and cellotriose respectively, at levels which appeared higher than glucose. The strain was however not able to grow on COS displaying higher degrees of polymerization (DP), i.e. cellotretraose and polygalacturonic acid.
  • COS cello- oligosaccharides
  • DP degrees of polymerization
  • Example 3 To evaluate synbiotic growth, L. rhamnosus LPR was further co-supplemented with glucose and cellobiose, in a controlled fermentation system (Prodigest, Gent, Belgium). Both sugars were supplemented from filter sterilized stock solutions, which were then supplemented at 1% (final concentration) to sterile sugar-depleted nutritional medium (nutritional medium representative for the colonic environment).
  • rhamnosus LPR is modified when grown on cellobiose. On that substrate (and compared to glucose), lower levels of lactate and higher levels of acetate are produced by the strain (Error! Reference source not found.).
  • LPR levels were assessed using LAMVAB agar (acidified MES containing vancomycin), microbiota composition was assessed by shotgun metagenomics sequencing and the resulting Short Chain Fatty Acids (SCFA, acetate, propionate, butyrate and valerate) produced by the microbiota were assessed in each combination.
  • SCFA Short Chain Fatty Acids
  • Results demonstrated that cellobiose was able to promote the growth of LPR, but only when sufficiently high levels were concomitantly added (equivalent dose of 800 mg per day) (Figure 20). Levels below 800 mg daily equivalent were not sufficient to increase the levels of LPR.
  • cellobiose and ⁇ -glucan were administered as a mix, they promoted the levels of LPR after 24h of fermentation.
  • rhamnosus LPR highlighting the possible microbiome diversity found in the set of toddlers’ fecal samples tested.
  • donors 1 and 5 were shown to produce higher levels of butyrate (7.3 and 12.8 mM, respectively) (Figure 10).
  • OTUs Operational Taxonomic Units
  • the fecal samples producing higher levels of butyrate were characterized by the presence of higher levels of Faecalibacterium spp. and Parabacteroides distasonis (Figure 11).
  • Parabacteroides distasonis has been proposed, depending on the context, to promote digestive health and to exert protective effects against certain diseases, like diabetes or inflammatory bowel disease (Ezeji et al., 2021, Gut Microbes, 13: 1922241). It produces as metabolic outputs hydrogen, carbon dioxide, formic acid, acetic acid, carboxylic acid and succinic acid, the latter being proposed as an inflammatory regulation signal (Ezeji et al., 2021, Gut Microbes, 13: 1922241).
  • the combination of cellobiose, ⁇ -glucan and LPR also provided a marked bifidogenic effect and increase in SCFA levels, independent of both the dose of cellobiose and ⁇ -glucan and the ratio of COS: ⁇ -glucan.
  • the data suggest that a selective mix of cellobiose/beta-glucan together with LPR may augment SCFA levels, and in particular butyrate levels, within the gastrointestinal tract of all toddlers independent of their Faecalibacterium spp. and Parabacteroides distasonis levels. Enhancing butyrate levels in the gastrointestinal tract is relevant for health benefits as butyrate can promote protective immune responses within the intestine and beyond (including the lungs).
  • Example 5 A preclinical experiment was set up (Figure 13) to evaluate whether addition of LPR together with a mix of cellobiose: ⁇ -glucan (25:75, representing a 25% hydrolysed oat) increases endogenous antibody production and its impact on protection against flu infection. This mix was shown to increase short chain fatty acids (Figure 6B) known to promote antibody responses.
  • Example 6 An ex-vivo fecal fermentation study was performed using the SIFR® technology (Cryptobiotix, Ghent, Belgium) as described herein above, modifications as described hereafter. Prior to colonic fermentation simulation, food digestion simulation INFOGEST 2.0 method was used (see Brodkorb, A., Egger, L., Alminger, M. et al., INFOGEST static in vitro simulation of gastrointestinal food digestion. Nat Protoc 14, 991–1014 (2019).
  • this second probiotic strain which is also capable of utilising at least some components of Prebio1
  • the findings of this work may enable the generation of new combinations of probiotics for compositions.
  • the finding that addition of a second probiotic strain further enhances LPR survival and engraftment in an ex-vivo toddler gut microbiota model, and therefore the beneficial effects of LPR to the host, enables improved health benefits.
  • a nutritional composition comprising Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent, wherein the L. rhamnosus-modulating agent is preferably selected from the list consisting of: a combination of FOS and inulin, cello-oligosaccharides (COS), a combination of ⁇ -glucan and COS, at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium, and any combination thereof.
  • the L. rhamnosus has at least 99% Average Nucleotide Identity (ANI) to L. rhamnosus CGMCC1.3724 (LPR) or wherein the L.
  • rhamnosus is LPR.
  • the L. rhamnosus- modulating agent comprises or consists of cello-oligosaccharides (COS), preferably cellobiose and/or cellotriose, more preferably cellobiose; preferably wherein the L. rhamnosus- modulating agent is present in an amount ranging from 0.20 to 12.10 g/100g dry weight of composition, more preferably from 1.29 to 12.10 g/100g dry weight of composition, even more preferably from 1.29 to 1.61 g/100g dry weight of nutritional composition.
  • COS cello-oligosaccharides
  • the L. rhamnosus- modulating agent is present in an amount ranging from 0.20 to 12.10 g/100g dry weight of composition, more preferably from 1.29 to 12.10 g/100g dry weight of composition, even more preferably from 1.29 to 1.61 g/100g dry weight of nutritional composition.
  • rhamnosus-modulating agent comprises or consists of a combination of ⁇ -glucan and cello- oligosaccharides (COS), wherein the cello-oligosaccharides (COS) is preferably cellobiose and/or cellotriose, more preferably cellobiose. 5.
  • COS cello-oligosaccharides
  • the L. rhamnosus-modulating agent comprises at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium, optionally wherein the at least one probiotic is of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium. 10.
  • the nutritional composition according to claim 9 or claim 10 wherein the nutritional composition further comprises inulin and oligofructose. 12.
  • the nutritional composition according to any one of the preceding claims wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier or a supplement. 13.
  • the nutritional composition according to any one of the preceding claims formulated to provide one, two, three or more servings per day, preferably one or two servings per day, more preferably two servings per day, comprising 800 to 1500 mg/day of COS, for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS, COS being preferably cellobiose and/or cellotriose, COS being more preferably cellobiose. 14.
  • the nutritional composition according to any one of the preceding claims for use as a medicament.
  • the nutritional composition according to any one of claims 1 to 14 for use in enhancing the immune response to infection or vaccination, for use in promoting and/or maintaining gut health, or for use in preventing and/or reducing the risk of developing an infection in an infant, young child or child.
  • SCFA short chain fatty acid
  • At least one probiotic for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, wherein the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium, optionally wherein the at least one probiotic is of the genus Lactobacillus, Streptococcus and/or Bifidobacterium.
  • the present invention relates to a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus modulating agent, or nutritional compositions comprising the combination.
  • the present invention also relates to uses of the combination, or of a nutritional composition comprising the combination.

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Abstract

The present invention relates to a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus modulating agent, or nutritional compositions comprising the combination. The present invention also relates to uses of the combination, or of a nutritional composition comprising the combination.

Description

Nutritional composition Field of the invention The present invention relates to a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus modulating agent, or nutritional compositions comprising the combination. The present invention also relates to uses of the combination, or of a nutritional composition comprising the combination. Background of the invention Probiotics, that is microbial organisms with a beneficial effect on the health or well- being of the host, can be used for the treatment or prevention of various diseases. Lacticaseibacillus (formerly known as Lactobacillus) is a type of lactic acid bacteria which is used to ferment milk products and has been investigated for its health benefits for over 100 years. The species Lacticaseibacillus rhamnosus (including the strain with ATCC Accession No. 53103 and strain CGMCC1.3724 (LPR)) has been shown to have several beneficial health effects including enhancing the immune response to vaccination, and the treatment or prevention of acute infectious diarrhea in children and adults, healthcare-associated- diarrhea, antibiotic-associated diarrhea, traveler's diarrhea, infant food allergies, dental caries, and acute respiratory infections (Segers, M.E. and Lebeer, S., 2014. Microbial cell factories, 13(1), pp.1-16; Davidson et al., 2011, Eur J Clin Nutr.65(4):501-7; Luoto et al., 2014, J Allergy Clin Immunol, 133(2):405-13; Manzoni et al., 2006, Clin Infect Dis, 42(12):1735-42; Szajewska et al., 2011, Aliment Pharmacol Ther, 34: 1079–1087; Hojsak et al., 2010, Pediatrics 125 (5): e1171–e1177; and Kumpu et al., 2013, J Med Virol, 85(9):1632-8;). Bifidobacteria are one of the major genera of bacteria that make up the gastrointestinal tract microbiota in mammals. Bifidobacteria are among the first microbial colonizers of the intestines of newborns, and play key roles in the development of their physiology (Hidalgo-Cantabrana, C., et al., 2017. Microbiology spectrum, 5(3), pp.5-3). Moreover, alterations in composition and function of bifidobacteria have been associated with several gastrointestinal diseases, including inflammatory bowel disease, colorectal cancer, and irritable bowel syndrome (Tojo, R., et al., 2014. World journal of gastroenterology: WJG, 20(41), p.15163). The use of probiotics, including L. rhamnosus and Bifidobacteria strains, in preventive medicine to maintain a healthy intestinal function is well documented and such probiotics have been proposed as therapeutic agents for gastrointestinal disorders. However, existing solutions to enhancing the growth of L. rhamnosus have a number of drawbacks. Probiotics need to be kept alive and be active at the site of action in order to exert their effects in the gastrointestinal tract and beyond (including the lungs), limiting their application. Prebiotics generally require a dose of a few grams to deliver a benefit, which can make them less suitable for supplements since the capsule size typically limits ingredient dosage to below the gram range. Thus, there is a demand for alternative agents and compositions which can enhance the growth of L. rhamnosus in the gastrointestinal tract of a subject. Summary of the invention The present inventors surprisingly found that a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent can advantageously be used in therapy because the combination showed increased growth of L. rhamnosus, increased growth of Bifidobacteria and increased production of short chain fatty acids (SCFA) in the gastrointestinal tract of the infant, young child and/or child. In particular, the inventors have unexpectedly found that the combination of L. rhamnosus and at least one further probiotic selected from the genus Lactobacillus, Streptococcus or Bifidobacterium enhances the growth of L. rhamnosus in the gastrointestinal tract compared to the use of L. rhamnosus alone. Surprisingly, the inventors have found that a combination of L. rhamnosus and cello- oligosaccharides (COS) or of L. rhamnosus, cello-oligosaccharides (COS) and β-glucan synergistically enhances the growth of L. rhamnosus in the gastrointestinal tract and also increases the growth of Bifidobacteria and the levels of SCFAs stemming from the gastrointestinal tract. In other words, the present inventors have found that these specific combinations are particularly effective in increasing the growth and activity of L. rhamnosus in the gastrointestinal tract of the infant, young child and/or child. Thus, the invention provides a way to increase the growth and activity of a probiotic (i.e., L. rhamnosus) with known health benefits. The impact of at least one further probiotic selected from the genus Lactobacillus, Streptococcus or Bifidobacterium or of cello-oligosaccharides (COS) or of the combination of cello-oligosaccharides (COS) and β-glucan on the growth of L. rhamnosus in the gastrointestinal tract was not previously, especially for L. rhamnosus CGMCC1.3724 (LPR). Accordingly, in a first aspect, the present invention provides a nutritional composition comprising Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent. In some embodiments, the composition comprises L. rhamnosus in an amount of 1×103 to 1.5×1012 cfu/g of the composition (dry weight). In some embodiments, the L. rhamnosus has at least 99% Average Nucleotide Identity (ANI) to L. rhamnosus ATCC 53103 or to L. rhamnosus CGMCC1.3724 (LPR), preferably at least 99.9% ANI to L. rhamnosus ATCC 53103 or to L. rhamnosus CGMCC1.3724 (LPR). L. rhamnosus ATCC 53103 is publicly available, and can be obtained commercially at the Belgian Coordinated Collection of Microorganisms under LMG 18243. In some embodiments, the L. rhamnosus is selected from L. rhamnosus ATCC 53103, L. rhamnosus LC705 (DSM 7061) and L. rhamnosus CGMCC1.3724 (LPR), preferably wherein the L. rhamnosus is LPR. In some embodiments, the L. rhamnosus-modulating agent is cello-oligosaccharides (COS). In some embodiments, the L. rhamnosus-modulating agent is a combination of β- glucan and cello-oligosaccharides (COS). In some embodiments, the β-glucan and/or COS is derived from a plant, preferably a cereal. In some embodiments, the β-glucan and/or COS is derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some embodiments, the β-glucan and/or COS is obtained from partial hydrolysis of a cereal comprising β-glucan and/or COS. In some embodiments, the COS are cellobiose or cellotriose. In some embodiments, the weight ratio of COS:β-glucan is from 10:90 to 90:10 dry weight, preferably from 25:75 to 75:25 dry weight. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition. In some embodiments, the nutritional composition further comprises a probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus, Enterococcus, Bifidobacterium and Saccharomyces. In some embodiments, the L. rhamnosus-modulating agent comprises at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium. In some embodiments, the L. rhamnosus-modulating agent comprises at least one probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium. In some embodiments, the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461 (also known as CNCM I-2116), Lactobacillus johnsonii NCC 533 also known as Lactobacillus johnsonii CNCM I-1225 or Lactobacillus johnsonii LA1), Bifidobacterium animalis subsp. lactis NCC 2818 (also known as CNCM I-3446), Bifidobacterium longum subsp. longum NCC 2705 (also known as CNCM I-2618), Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496 (also known as CNCM I-3915), and any combination thereof. The composition according to the invention can comprise, in some embodiments, FOS (OF). An example of such FOS is the commercial ingredient ORAFTI® by Beneo GmbH (Mannheim, Germany). ln some embodiments the prebiotics of the composition of the invention, comprise fructooligosaccharides (FOS) or/and galactooligosaccharides (GOS). A combination of prebiotics may be used such as 90% GOS with 10% short chain fructooligosaccharides such as in the product by BENEO-Orafti sold under the trademark "Orafti® oligofructose (previously Raftilose®) or 10% inulin such as in the product sold by BENEO-Orafti under the trademark "Orafti® inulin” (previously Raftiline®). In some embodiments, the nutritional composition comprises inulin and oligofructose (FOS). In some embodiments, the nutritional composition comprises inulin and oligofructose (FOS) in a FOS:inulin ratio ranging from 95:5 to 30:70, preferably in a FOS:inulin ratio ranging from 90:10 to 50:50, such as 90:10, 80:20 or 70:30. In some embodiments, the mixture of inulin and FOS can be purchased by Beneo GmbH (Mannheim, Germany) as Orafti® Synergy1. In some embodiments, the mixture of inulin and FOS is Prebio1 (70wt-% FOS, 30wt-% inulin), wherein a source of FOS is Orafti® P95 and a source of inulin is Orafti® GR, which can be both purchased by Beneo GmbH (Mannheim, Germany). In some embodiments, the nutritional composition is formulated for an infant, young child and/or child. In some embodiments, the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier or a supplement. In a further aspect, the present invention provides the nutritional composition of the invention for use as a medicament. In a further aspect, the present invention provides the nutritional composition of the invention for use in enhancing the immune response to infection or vaccination, for use in promoting and/or maintaining gut health, or for use in preventing and/or reducing the risk of developing an infection in an infant, young child or a child. In a further aspect, the present invention provides a method of enhancing the immune response to infection or vaccination, of promoting and/or maintaining gut health, or of preventing and/or reducing the risk of developing an infection in an infant, young child or a child, the method comprising administering the composition of the invention to the infant, young child or child. In some embodiments, the antibody response to infection or vaccination is enhanced in the infant, young child or child. In some embodiments, 150 to 450 mg/day of β-glucan and 150 to 450 mg/day of COS are administered to the infant, young child or child. In some embodiments, the infant, young child or child is non-responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan. In a further aspect, the present invention provides the use of the nutritional composition of the invention for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child. In a further aspect, the present invention provides a method of enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, the method comprising administering the composition of the invention to the infant, young child or child. In a further aspect, the present invention provides the use of the nutritional composition of the invention for enhancing the growth of Bifidobacteria in the gastrointestinal tract of an infant, young child or child. In a further aspect, the present invention provides a method of enhancing the growth of Bifidobacteria in the gastrointestinal tract of an infant, young child or child, the method comprising administering the composition of the invention to the infant, young child or child. In a further aspect, the present invention provides the use of the nutritional composition of the invention for increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child. In a further aspect, the present invention provides a method of increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child, the method comprising administering the composition of the invention to the infant, young child or child. In some embodiments, the at least one SCFA is acetate, propionate, butyrate or any combination thereof. In some embodiments, the at least one SCFA is butyrate and the infant, young child or child is non-responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan. It was surprisingly found that when combined with COS or COS/ β-glucan, L. rhamnosus CGMCC1.3724 (LPR) and was more efficient to increase the microbiome mediated butyrate production than the other strains of L. rhamnosus such as KY-3 (Umeki et. al., J Nutr Sci Vitaminol (Tokyo), 2004 Oct;50(5):330-4). In some preferred embodiments, L. rhamnosus is CGMCC1.3724 (LPR) and the L. rhamnosus modulating agent is COS, preferably cellobiose. In some preferred embodiments, L. rhamnosus is CGMCC1.3724 (LPR) and the L. rhamnosus modulating agent is COS, preferably cellobiose, wherein 800 to 1500 mg/day of COS, for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS are administered to the infant, young child or child, preferably for increasing the microbiome mediated butyrate production, and thereby promoting the associated health benefits. In some preferred embodiments, L. rhamnosus is CGMCC1.3724 (LPR) and the L. rhamnosus modulating agent is COS/ β-glucan, preferably cellobiose/ β-glucan. In some preferred embodiments, L. rhamnosus is CGMCC1.3724 (LPR) and the L. rhamnosus modulating agent is COS, preferably cellobiose, for increasing the microbiome mediated butyrate production. In some preferred embodiments, L. rhamnosus is CGMCC1.3724 (LPR) and the L. rhamnosus modulating agent is COS/ β-glucan, preferably cellobiose/ β-glucan, for increasing the microbiome mediated butyrate production. In a further aspect, the present invention provides the use of at least one probiotic for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, wherein the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium. In some embodiments, the at least one probiotic is of the genus Lactobacillus, Streptococcus and/or Bifidobacterium. In some embodiments, the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof. Brief description of the figures Figure 1: L. rhamnosus NCC 4007 (LPR, CGMCC1.3724) biomass levels upon 48h growth on different cello-oligosaccharides (bi-tri-tetra- & polymer). ***p-value<0.001 upon ANOVA and multiple testing against the no carbohydrate control. Figure 2: L. rhamnosus NCC 4007 growth attributes after 24h incubation on glucose or cellobiose as sole carbon source. A) Viable (grey) and non-viable (black) assessed by flow cytometry B) acetate and lactate levels produced. Figure 3: Effect of a range of cellobiose & oat β-glucan mixes (0:100; 25:75, 50:50, 75:25, 100:0) at two different dosage levels (200 mg and 600 mg/day) on LPR levels in a set of 6 toddler fecal fermentations. Figure 4: Effect of LPR and a mix of cellobiose & oat β-glucan (25:75; 600 mg/day) addition on the levels of Bifidobacteriaceae in a set of 6 toddler fecal fermentations. Figure 5: Effect of a mix of LPR and cellobiose:oat β-glucan (25:75; 600 mg/day) on the levels of B. longum, B. pseudocatenulatum, B. catenulatum in a set of 6 toddler fecal fermentations. Figure 6: Effect of a mix of LPR and cellobiose:oat β-glucan (25:75) on the levels of microbiota derived short chain fatty acids produced in a set of 6 toddler fecal fermentations. Two different daily equivalent doses of cellobiose:β-glucan are depicted (200 mg and 600 mg equivalent per day, respectively). Figure 7: Effect of a mix of LPR and cellobiose:oat β-glucan (25:75, 600 mg daily equivalent) on the levels of microbiota derived acetate, propionate and butyrate produced in a set of 6 toddler fecal fermentations. Figure 8: Effect of a range of cellobiose & oat β-glucan mixes (25:75, 50:50, 75:25) at a concentration of 200 mg/day on LPR mediated SCFA production in a set of 6 toddler fecal fermentations. Figure 9: Effect of a range of cellobiose & oat β-glucan mixes (25:75, 50:50, 75:25) at a concentration of 600 mg/day on LPR mediated SCFA production in a set of 6 toddler fecal fermentations. Figure 10: Effect of oat β-glucan (600 mg/day) on the levels of SCFA produced by the microbiota in a set of 6 toddler fecal fermentation. Figure 11: Operation Taxonomic Units (OTU) levels differentiating high (responders) to low (non-responders) butyrate producing donors, upon administration of oat β-glucan (600 mg/day). Figure 12: Effect of a range of cellobiose & oat β-glucan mixes (0:100, 25:75, 50:50, 75:25, 100:0) at a concentration of 600 mg/day on LPR mediated SCFA production in high (responders) and low (non-responders) butyrate producing donors. Figure 13: Experimental set up. Three-week-old mice were purchased and fed with low fiber diet (LFD). One week after acclimatization in the animal facility, mice were left under low fiber diet only (group 1: control) or received 100mM of each short chain fatty acids (SCFA) acetate, butyrate and propionate in the drinking water (group 2: positive control) or received with a mix of 30 mg β-glucan and 10 mg cello oligosaccharides (mouse adapted dose calculated from 600mg/day of cellobiose & oat β-glucan mix at 25:75) in the drinking water together with 1x109 cfu of Lactobacillus rhamnosus (LPR) via gavage (group 4: synbiotic) or gavaged with only 1x109 cfu of LPR (group 3: probiotic). Nutritional supplementation with SCFA, probiotic or synbiotic were carried out for the duration of the experiment. Three weeks after the nutritional supplementation, animals were infected with 100 PFU with influenza (Mouse adapted strain PR8). Antibody responses were measured in the serum. Figure 14: Synbiotic supplementation significantly increases levels of total immunoglobulin in the serum. Changes in (A) absolute amount of immunoglobulin G (IgG) and (B) fold change in IgG in the serum between d21 and d0 post infection. Each dot represents a single animal with 9-10 animals per group with bars indicating the mean antibody response with error bars showing standard error of the mean. Unpaired t test was used to calculate differences between groups. *p value<0.05, **p value<0.005 and ***p value<0.0005. Figure 15 Synbiotic supplementation reduces severity of flu infection. (A) Clinical score, (B) body temperature and (C) changes in body weight (compared to d0 post infection) were measured for each animal with each dot showing the mean with error bars indicating the standard error the mean. Each symbol shows the difference between 2 specific groups with the number of symbols highlighting the level of significance between the indicated groups. *,# or & p value <0.05, **,##, && p value <0.005 and *** p value <0.0005. Figure 16: Total levels of immunoglobulin G at d0 post infection correlates inversely with peak disease score (day 9 post infection). Each dot represents a single animal with pooled results from a single experiment with n=9-10 mice/group being shown. Regression line is drawn to demonstrate the inverse relationship between antibody levels pre-infection and clinical score at peak of the infection. Figure 17: Average L. rhamnosus plate counts at 24 hours for each arm of the study. The dotted line indicates the level upon inoculation (1.2 ± 0.2x10e7 cfu/mL). Statistical differences between treatments and the blank, as tested via a repeated measures ANOVA, are indicated with * (0.01 < adjusted p-value < 0.05), ** (0.001 < adjusted p-value < 0.01) or *** (adjusted p-value < 0.001). Differences due to additional supplementation of ST11, LA1, BL818, LMG 11588 and ST496 are indicated by $ (0.01 < adjusted p-value < 0.05), $$ (0.001 < adjusted p-value < 0.01) and $$$ (adjusted p-value < 0.001). Figure 18: Average LPR levels at 24 hours in each arm of the study, calculated by multiplying the relative proportion of LPR form the 16S data by the overall cell numbers quantified by flow cytometry. Statistical differences between treatments and the blank, as tested via a repeated measures ANOVA, are indicated with * (0.01 < adjusted p-value < 0.05), ** (0.001 < adjusted p-value < 0.01) or *** (adjusted p-value < 0.001). Differences due to additional supplementation of ST11, LA1, BL818, LMG 11588 and ST496 are indicated by $ (0.01 < adjusted p-value < 0.05), $$ (0.001 < adjusted p-value < 0.01) and $$$ (adjusted p- value < 0.001). Figure 19: Average pH for each arm of the study at 24 hours. Statistical differences between treatments and the blank, as tested via a repeated-measures ANOVA, are indicated with * (0.01 < adjusted p-value < 0.05), ** (0.001 < adjusted p-value < 0.01) or *** (adjusted p-value < 0.001). Differences due to additional supplementation of ST11, LA1, BL818, LMG 11588 and ST496 are indicated by $ (0.01 < adjusted p-value < 0.05), $$ (0.001 < adjusted p- value < 0.01) and $$$ (adjusted p-value < 0.001). Figure 20: Effect of a range of cellobiose concentrations (from 200 to 800 mg per day) on LPR levels in a set of 6 toddler fecal fermentations. Statistical differences to the control arm (LPR only) are represented (*p<0.05; **p<0.01; ***p<0.001; ****p>0.0001). Detailed description of the invention Definitions The term “infant” means a child under the age of 12 months. The expression “young child” means a child aged between one and less than three years, also called toddler. The expression “child” means a child between three and nine years of age. Preferably, the expression “child” means a child between three and five years of age. The expression “nutritional composition” means a composition which nourishes a subject. This nutritional composition is usually to be taken orally or parenterally, and it usually includes a lipid or fat source and a protein source. A carbohydrate source may also be included. In one embodiment, the nutritional composition of the invention is a synthetic nutritional composition. In a particular embodiment, the combination or composition of the present invention is a “synthetic combination” or “synthetic nutritional composition”. The expression “synthetic combination” or “synthetic nutritional composition” means a mixture obtained by chemical and/or biological means, which can be chemically identical to the mixture naturally occurring in mammalian milks (i.e. the synthetic combination or synthetic composition is not breast milk). The expression "infant formula" as used herein refers to a foodstuff intended for particular nutritional use by infants during the first months of life and satisfying by itself the nutritional requirements of this category of person (Article 2(c) of the European Commission Directive 91/321/EEC 2006/141/EC of 22 December 2006 on infant formulae and follow-on formulae). It also refers to a nutritional composition intended for infants and as defined in Codex Alimentarius (Codex STAN 72-1981) and Infant Specialities (incl. Food for Special Medical Purpose). The expression "infant formula" encompasses both “starter infant formula” and “follow-up formula” or “follow-on formula”. A “follow-up formula” or “follow-on formula” is given from the 6th month onwards. It constitutes the principal liquid element in the progressively diversified diet of this category of person. The expression “baby food” means a foodstuff intended for particular nutritional use by infants or young children during the first years of life. The expression “infant cereal composition” means a foodstuff intended for particular nutritional use by infants or young children during the first years of life. The expression “growing-up milk” (or GUM) refers to a milk-based drink generally with added vitamins and minerals, that is intended for young children or children. The term “fortifier” refers to liquid or solid nutritional compositions suitable for fortifying or mixing with human milk, infant formula, growing-up milk or human breast milk fortified with other nutrients. Accordingly, the fortifier of the present invention can be administered after dissolution in human breast milk, in infant formula, in growing-up milk or in human breast milk fortified with other nutrients or otherwise it can be administered as a stand-alone composition. When administered as a stand-alone composition, the milk fortifier of the present invention can be also identified as being a “supplement”. In one embodiment, the milk fortifier of the present invention is a supplement. The expression “weaning period” means the period during which the mother's milk is substituted by other food in the diet of an infant or young child. The expressions “days/weeks/months/years of life” and “days/weeks/months/years after birth” can be used interchangeably. The “mother’s milk” should be understood as the breast milk or the colostrum of the mother. An “oligosaccharide” is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides). The term “galacto-oligosaccharides” refers to a type of non-digestible fiber with prebiotic activity. GOS are formed via enzymatic conversion of lactose. GOS generally comprise a chain of galactose units that arise through consecutive transgalactosylation reactions, with a terminal glucose unit, although a terminal galactose unit may be present instead. The degree of polymerization of GOS typically ranges from 2 to 8 monomeric units. The terms "oligofructose" (abbreviated OF) and “fructo-oligosaccharides” (abbreviated FOS) refer to fructose oligomers (i.e. a fructose oligosaccharide) having a degree of polymerization of from 2 to 10, for example a degree of polymerization of from 2 to 8. Oligofructose can also be referred as Fructo-Oligo-Saccharides (abbreviated FOS) or short-chain Fructo-Oligo- Saccharides (abbreviated scFOS). In the present document the terms oligofructose (OF), fructose-oligosaccharide(s) (FOS), Fructo-Oligo-saccharide (FOS), short-chain-fructo-oligosaccharide (scFOS) have the same meaning and can be used interchangeably. The Inulin, being polymers of long chains are specifically excluded from the present definition of OF. Oligofructose is distinguishable from Inulin by its degree of polymerization (Inulin having longer chains). Inulin is a form of fructan oligosaccharides, composed of fructose units linked by beta(2-1) bonds, typically with an N-terminal alpha(1-2) linked glucose, and chain lengths up to 60 units. FOS / scFOS / Oligofructose is typically commercially available, for example under the commercial name ORAFTI Oligofructose by Beneo GmbH (Mannheim, Germany) (for example ingredient Orafti® P95). The term “HMO” or “HMOs” refers to human milk oligosaccharide(s). These carbohydrates are highly resistant to enzymatic hydrolysis, indicating that they may display essential functions not directly related to their caloric value. It has especially been illustrated that they play a vital role in the early development of infants and young children, such as the maturation of the immune system. Many different kinds of HMOs are found in the human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose and/or N-acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in human milk - over 130 such structures have been identified so far. Almost all of them have a lactose moiety at their reducing end while sialic acid and/or fucose (when present) occupy terminal positions at the non-reducing ends. The HMOs can be acidic (e.g. charged sialic acid containing oligosaccharide) or neutral (e.g. fucosylated oligosaccharide). The combination or nutritional composition of the present invention can be in solid form (e.g. powder) or in liquid form. The amount of the various ingredients (e.g. the oligosaccharides) can be expressed in g/100g of composition on a dry weight basis when it is in a solid form, e.g. a powder, or as a concentration in g/L of the composition when it refers to a liquid form (this latter also encompasses liquid composition that may be obtained from a powder after reconstitution in a liquid such as milk, water…, e.g. a reconstituted infant formula or a follow-on/follow-up formula or a growing-up milk or an infant cereal product or any other formulation designed for infant nutrition). The term “prebiotic” means non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and/or the activity of healthy bacteria such as bifidobacteria in the colon of humans (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr.1995;125:1401-12). The term “probiotic” means microbial cell preparations or components of microbial cells with a beneficial effect on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al. “Probiotics: how should they be defined” Trends Food Sci. Technol.1999:10 107-10). The microbial cells are generally bacteria or yeasts. The term “cfu” should be understood as colony-forming unit. "Treating" means to address a medical condition or disease with the objective of improving or stabilising an outcome in the person being treated or addressing an underlying nutritional need. Treating, therefore, includes the dietary or nutritional management of the medical condition or disease by addressing nutritional needs of the person being treated. Treating includes the elimination, reduction or amelioration of symptoms associated with the medical condition or disease. "Preventing" means to diminish the risk of onset or recurrence of a medical condition or disease. Both primary and secondary prevention are thus contemplated. “Primary prevention” means preventing a medical condition or disease before it occurs, and “secondary prevention” means preventing additional attacks of a medical condition or disease after the first attack has occurred. Preventing, therefore, includes the dietary or nutritional prophylaxis of the medical condition or disease by addressing nutritional needs of the person being treated. Preventing includes eliminating or minimising the risk of developing a medical condition or disease and reducing the risk of developing symptoms associated with the medical condition or disease. The term "effective amount" preferably means an amount of the combination or composition that provides the active agents in a sufficient amount to render a desired treatment or prevention outcome in a subject. An effective amount can be administered in one or more doses to the subject to achieve the desired treatment or prevention outcome. All percentages are by weight unless otherwise stated. In addition, in the context of the invention, the terms “comprising” or “comprises” do not exclude other possible elements. The composition of the present invention, including the many embodiments described herein, can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise depending on the needs. It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims. Combinations In one aspect the present invention provides a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent. Suitably, the combination is in the form of a composition, such as a nutritional composition. The composition may comprise the combination in any therapeutically effective amount. Accordingly, in a further aspect, the present invention provides a nutritional composition comprising or consisting of the combination according to the invention. Lacticaseibacillus rhamnosus Lacticaseibacillus rhamnosus (formerly known as “Lactobacillus rhamnosus” and formerly considered a subspecies of Lacticaseibacillus casei) is a gram-positive, anaerobic, rod-shaped bacterium of the Lacticaseibacillus genus which can be found in the gastrointestinal tract of humans. Any suitable L. rhamnosus strain may be used in the present invention. For example, any L. rhamnosus strain which is known to have a probiotic effect may be used in the present invention. Such L. rhamnosus strains will be well known to the skilled person. Suitably, the L. rhamnosus may be selected from: L. rhamnosus ATCC 53103 (also known as “L. rhamnosus GG” or “L. rhamnosus DSM 33156), L. rhamnosus LC705 (also known as “L. rhamnosus DSM 7061”) and L. rhamnosus CGMCC1.3724 (LPR). Preferably, the L. rhamnosus is LPR. L. rhamnosus CGMCC1.3724 (LPR) was deposited with the Chinese Culture Collection in October 2004 according to the Budapest Treaty under the reference CGMCC 1.3724. L. rhamnosus GG (ATCC 53103, DSM 33156) is publicly available, and can be obtained commercially at the Belgian Coordinated Collection of Microorganisms under LMG 18243. The L. rhamnosus may be a L. rhamnosus having at least 99% (suitably, at least 99.9%) Average Nucleotide Identity (ANI) to any L. rhamnosus known to the skilled person. As used herein the term “Average nucleotide identity (ANI)” refers to a distance- based approach to delineate species based on pair-wise comparisons of their genome sequences. ANI is an in silico approach for phylogenetic definition of a species and has become the gold standard for species delineation (Goris et al., 2007, Int. J. Syst. Evol. Microbiol.57: 81-91; Kim et al., 2014, Int. J. Syst. Evol. Micr.64: 346-351; Richter et al., 2009, P Natl Acad Sci USA 106: 19126-19131; and Chan et al., 2012, Bmc. Microbiol.12). The ANI of the shared genes between two strains is known to be a robust means to compare genetic relatedness among strains. Strains with ANI values of at least about 96% can be considered to belong to the same species (Konstantinidis and Tiedje, 2005, Proc Natl Acad Sci USA, 102(7):2567-72; and Goris et al., 2007, Int Syst Evol Microbiol. 57(Pt 1):81-91), while ANI values of at least about 99% indicate that the bacterial genomes belong to the same strain. The ANI between two bacterial genomes is calculated from pair-wise comparisons of all sequences shared between any two strains and can be determined, for example, using any of a number of publicly available ANI tools, including but not limited to OrthoANI with usearch (Yoon et al., 2017, Antonie van Leeuwenhoek 110:1281-1286); ANI Calculator, JSpecies (Richter and Rossello-Mora, 2009, Proc Natl Acad Sci USA 106:19126- 19131); and JSpeciesWS (Richter et al., 2016, Bioinformatics 32:929-931). Other methods for determining the ANI of two genomes are known in the art (Konstantinidis, K. T. and Tiedje, 2005, J. M., Proc. Natl. Acad. Sci. U.S.A., 102: 2567-2572; and Varghese et al., 2015, Nucleic Acids Research, 43(14):6761-6771). Suitably, the L. rhamnosus has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to L. rhamnosus ATCC 53103, L. rhamnosus LC705 and/or to LPR. In some preferred embodiments, the L. rhamnosus has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to LPR. Preferably, the L. rhamnosus has at least 99.9% ANI to LPR. In some embodiments, the composition comprises L. rhamnosus in an amount of 1×103 to 1.5×1012 cfu/g of the composition (dry weight). Various health effects of Lacticaseibacillus rhamnosus as a probiotic are well documented (see e.g. Segers, M.E. and Lebeer, S., 2014. Microbial cell factories, 13(1), pp.1- 16). The nutritional composition according to the invention may contain from 103 to 1012 cfu of L. rhamnosus, more preferably between 107 and 1012 cfu such as between 108 and 1010 cfu of L. rhamnosus per g of composition on a dry weight basis. Suitably, L. rhamnosus is administered to the subject in an amount of at least about 106 cfu/day, at least about 107 cfu/day, or at least about 108 cfu/day. Suitably, L. rhamnosus is administered to the subject in an amount of about 1012 cfu/day or less, about 1011 cfu/day or less, or about 1010 cfu/day or less. In one embodiment the probiotics (e.g. L. rhamnosus) are viable. Probiotic components and metabolites can also be added. L. rhamnosus-modulating agent As used herein, the term “Lactocaseibacillus rhamnosus-modulating agent” or “L. rhamnosus-modulating agent” may refer to any agent which modulates the abundance of L. rhamnosus in the gastrointestinal tract of a subject. Preferably, the L. rhamnosus-modulating agent increases the abundance of L. rhamnosus in the gastrointestinal tract of a subject. Suitably, the L. rhamnosus-modulating agent is in the form of a probiotic, prebiotic, and/or synbiotic (i.e. synergistic relationship between probiotics and prebiotics). Suitably, the microbiota-modulating agent of the present invention comprises or consists of a probiotic, prebiotic, and/or synbiotic. As used herein, the term “prebiotic” may refer to a non-digestible component that benefits the subject by selectively stimulating the favourable growth and/or activity of one or more bacterial taxa (see e.g. Gibson, G.R., et al., 2017). Exemplary prebiotics include fibres, for example oligosaccharides, such as human milk oligosaccharides (HMOs). The L. rhamnosus-modulating agent may increase the abundance of L. rhamnosus in the gastrointestinal tract of the subject. Suitably, the L. rhamnosus-modulating agent may increase the relative abundance of L. rhamnosus in the gastrointestinal tract of the subject. The “abundance” of a bacterial taxa in the gut of a subject may be determined by any suitable method (see e.g. Tang, Q., et al., 2020. Frontiers in cellular and infection microbiology, 10, p.151). Suitably, the abundance of bacterial taxa may be obtained from or obtainable from fecal samples. The abundance may be a relative abundance and/or absolute abundance. Preferably, the abundance is a relative abundance, for example, the abundance may be calculated relative to total bacterial abundance in the gut of the subject. Suitably, the abundance of L. rhamnosus in the gastrointestinal tract of the subject may be measured as described herein (see Example 4 and/or Example 6). The inventors have surprisingly found that cello-oligosaccharides (COS) or a combination of cello-oligosaccharides (COS) and β-glucan is capable of increasing the abundance of L. rhamnosus in the gastrointestinal tract of the subject. The inventors have also surprisingly found that a probiotic which is a lactic acid bacterium (for example, a probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus and/or Streptococcus) and/or is a Bifidobacterium is capable of increasing the abundance of L. rhamnosus in the gastrointestinal tract of the subject. In some embodiments, the L. rhamnosus-modulating agent is cello-oligosaccharides (COS). Accordingly, in another aspect, the present invention provides a nutritional composition comprising L. rhamnosus and cello-oligosaccharides (COS). In some embodiments, the L. rhamnosus-modulating agent comprises or consists of a combination of cello-oligosaccharides (COS) and β-glucan. Suitably, the L. rhamnosus- modulating agent is a combination of COS and β-glucan. Accordingly, in another aspect, the present invention provides a nutritional composition comprising L. rhamnosus and a combination of cello-oligosaccharides (COS) and β-glucan. In some embodiments, the L. rhamnosus-modulating agent comprises or consists of at least one probiotic which is a lactic acid bacterium and/or Bifidobacterium. Suitably, the L. rhamnosus-modulating agent comprises or consists of at least one probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium. Suitably, the L. rhamnosus-modulating agent is at least one probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium. Accordingly, in another aspect, the present invention provides a nutritional composition comprising L. rhamnosus and at least one probiotic which is a lactic acid bacterium and/or Bifidobacterium. COS Cello-oligosaccharides (COS) are linear oligosaccharides comprising oligomers of 2, 3, 4, 5 or 6 β-1,4-linked D-glucose units, termed cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose, respectively. COS are soluble dietary fibers. COS may be isolated from source materials (e.g. plant sources), synthesised (e.g. by enzymatic synthesis) or obtained by full or partial hydrolysis of source materials (e.g. plant sources). As used herein, the term “derived from” means isolated from or obtained by full or partial hydrolysis of the source material. In some embodiments, COS are derived from a plant. Suitably, the plant comprises COS. Preferably, COS are derived from a cereal. Suitably, the cereal comprises COS. In some embodiments, the COS are derived from a plant, such as a cereal. In some embodiments, the COS are isolated from a plant, such as a cereal. In some embodiments, the COS are derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some embodiments, COS are derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some preferred embodiments, the COS are derived from oat or barley. Preferably, the COS are derived from oat. In some embodiments, the COS are derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some embodiments, the COS are obtained from full or partial hydrolysis of a cereal fraction comprising COS. Cereal fractions and methods to prepare such cereal fractions are well known in the art. In some preferred embodiments, the COS are obtained from partial hydrolysis of a β- glucan cereal fraction. In some particularly preferred embodiments, the COS are obtained from partial hydrolysis of a β-glucan cereal fraction. Suitably, the cereal is selected from barley, oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. Suitably, the cereal is barley or oat. Preferably, the cereal is oat. In some embodiments, the COS comprise at least two of cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose. In some embodiments, the COS comprise cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose. In some embodiments, the COS comprise cellobiose, cellotriose or a combination thereof. In one embodiment, the COS are cellotriose. In a preferred embodiment, the COS are cellobiose. In some embodiments of the composition, the COS are present in an amount ranging from 1.20 to 2.50 g/100g dry weight of composition, such as from 1.30 to 2.50 g/100g dry weight of composition. Suitably, the COS are present in an amount from at least 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40 or 2.45 g/100g dry weight of composition. Suitably, the COS are present in an amount from less than 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45 or 2.50 g/100g dry weight of composition. In some preferred embodiments of the composition, the COS are present in an amount ranging from 1.80 to 2.10 g/100g dry weight of composition, such as 2.05 g/100g dry weight of composition. Suitably, the nutritional composition may be intended for administration twice daily. Thus, the nutritional composition may be formulated to provide two servings per day. Combination of COS and β-glucan β-glucans are β-d-glucose polysaccharides which naturally occur in the cell walls of certain plants (such as cereals), bacteria, and fungi. β-glucans are soluble dietary fibers. β- glucan comprises linear chains of glucose residues which are linked by β-(1–4) and β-(1–3) glycosidic bonds. β-glucan may be isolated from source materials (e.g. plant sources), synthesised (e.g. by enzymatic synthesis) or obtained by full or partial hydrolysis of source materials (e.g. plant sources). As used herein, the term “derived from” means isolated from or obtained by full or partial hydrolysis of the source material. In some embodiments, the β-glucan and/or COS is derived from a plant. Suitably, the plant comprises β-glucan and/or COS. Preferably, the β-glucan and/or COS is derived from a cereal. Suitably, the cereal comprises β-glucan and/or COS. In some embodiments, the β-glucan and COS are derived from a plant, such as a cereal. In some embodiments, the β-glucan and/or COS are isolated from a plant, such as a cereal. In some embodiments, the β-glucan and/or COS is derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some embodiments, the β-glucan and/or COS is derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some preferred embodiments, the β-glucan and/or COS is derived from oat or barley. Preferably, the β- glucan and/or COS is derived from oat. In some embodiments, the β-glucan and COS are derived from a cereal selected from oat, barley, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. In some embodiments, the β-glucan and/or COS is obtained from full or partial hydrolysis of a cereal fraction comprising β-glucan and/or COS. Preferably, the cereal comprises β-glucan. Suitably, the cereal is a β-glucan cereal fraction. Cereal fractions and methods to prepare such cereal fractions are well known in the art. In some preferred embodiments, the β-glucan and/or COS is obtained from partial hydrolysis of a β-glucan cereal fraction. In some particularly preferred embodiments, the β- glucan and COS are obtained from partial hydrolysis of a β-glucan cereal fraction. Suitably, the cereal is selected from barley, oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. Suitably, the cereal is barley or oat. Preferably, the cereal is oat. β-glucan obtained from cereal sources, and in particular from oat or barley, is advantageous since these sources provide β-glucan comprising glucose residues which are linked by both β-(1–4) and β-(1–3) glycosidic bonds. By contrast, β-glucan obtained from other plant sources such as apple provides β-glucan containing glucose residues which are only linked by β-(1–4) glycosidic bonds. The provision of β-glucan comprising glucose residues which are linked by both β-(1–4) and β-(1–3) glycosidic bonds is beneficial since it has been shown that some predominant commensal species (e.g. Bacteroidetes) can utilise these mixed-linkage β-glucan structures and hydrolyze them in the gut. This liberates smaller oligosaccharides (e.g. cello-oligosaccharides) that L. rhamnosus can then use. Moreover, the presence of β-glucan comprising glucose residues which are linked by both β-(1–4) and β-(1– 3) glycosidic bonds provides substrates for a greater number of commensal bacterial strains than β-glucan containing glucose residues which are only linked by β-(1–4) glycosidic bonds. Hence in preferred embodiments, β-glucan is cereal β-glucan, preferably oat β-glucan. In preferred embodiments, β-glucan is cereal β-glucan, preferably oat β-glucan, comprising glucose residues which are linked by both β-(1–4) and β-(1–3) glycosidic bonds. In preferred embodiments, β-glucan is cereal β-glucan, preferably oat β-glucan, having a linear (1,3;1,4) β-glucan structure (Clinical and Physiological Perspectives of β-Glucans: The Past, Present, and Future, Khawaja Muhammad Imran Bashir and Jae-Suk Choi, Int. J. Mol. Sci. 2017, 18(9), 1906; https://doi.org/10.3390/ijms18091906). Any method known in the art can be used for full or partial hydrolysis of a source material, e.g. a cereal fraction. For example, the methods described in WO2022/253662 A1 can be used. It is within the capabilities of the skilled person to perform sufficient hydrolysis of the source material in order to obtain the desired weight ratio of COS:β-glucan as described herein. For example, the skilled person would understand that a weight ratio of COS:β-glucan of 25:75 corresponds to 25% hydrolysis of a β-glucan cereal fraction, that a weight ratio of COS:β-glucan of 75:25 corresponds to 75% hydrolysis of a β-glucan cereal fraction, and so on. Thus, 25% hydrolysis of a β-glucan cereal fraction refers to a β-glucan cereal fraction that is partially hydrolysed such that the β-glucan content is 25% hydrolysed. In some embodiments, the β-glucan has an average molecular weight range of from 20 to 500 kDa, preferably from 50 to 250 kDa. Suitably, the β-glucan has an average molecular weight range of from 25 to 450 kDa, from 30 to 400 kDa, from 40 to 350 kDa, from 50 to 250 kDa, from 60 to 200 kDa, or from 70 to 150 kDa. Any suitable method for measuring the average molecular weight known in the art may be used e.g. size exclusion chromatography and fluorescence detection. Suitably, the average molecular weight is determined using the method as disclosed herein. In some embodiments, the COS comprise at least two of cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose. In some embodiments, the COS comprise cellobiose, cellotriose, cellotetraose, cellopentose and cellohexose. In some embodiments, the COS comprise cellobiose, cellotriose or a combination thereof. In one embodiment, the COS are cellotriose. In a preferred embodiment, the COS are cellobiose. In some embodiments of the composition, the weight ratio of COS:β-glucan is from 10:90 to 90:10 dry weight of composition, preferably from 25:75 to 75:25 dry weight of composition. Suitably, the weight ratio of COS:β-glucan is 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25; 80:20 or 85:15 dry weight of composition. Suitably, the weight ratio of COS:β-glucan is 25:75, 50:50 or 75:25 dry weight of composition. Suitably, the weight ratio of COS:β-glucan is 25:75 dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition. Suitably, the β- glucan is present in an amount from at least 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.80 g/100g dry weight of composition and/or the COS are present in an amount from at least 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.80 g/100g dry weight of composition. Suitably, the β-glucan is present in an amount from less than 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80 or 0.85 g/100g dry weight of composition and/or the COS are present in an amount from less than 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80 or 0.85 g/100g dry weight of composition. Suitably, the nutritional composition may be provided in a serving size of 31g total dry weight. In some embodiments of the composition, COS (e.g cellobiose) is present in an amount ranging from 0.20 to 12.10 g/100g dry weight of composition, such as 0.20 to 1.61 g/100g dry weight of composition or 1.29 to 1.61 g/100g dry weight of composition. In some embodiments of the composition, COS (e.g cellobiose) is present in an amount ranging from 1.29 to 12.10 g/100g dry weight of composition, such as 1.29 to 1.61 g/100g dry weight of composition. In some embodiments of the composition, COS (preferably cellobiose) is present in an amount ranging from 0.20 to 12.10 g/100g dry weight of composition, more preferably from 1.29 to 12.10 g/100g dry weight of composition, even more preferably from 1.29 to 1.61 g/100g dry weight of composition. In some embodiments of the composition, COS (e.g cellobiose) is present in an amount ranging from 0.5 to 1.0 g/100g, preferably ranging from 0.7 to 0.8 g/100g dry weight of composition, and the β-glucan is present in an amount ranging from 0.10 to 0.40 g/100g, preferably ranging from 0.2 to 0.3 g/100g dry weight of composition. In some embodiments of the composition, COS (e.g cellobiose) is present in an amount of 0.73 g/100g dry weight of composition, and the β-glucan is present in an amount of 0.24 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.5 to 1.0 g/100g, preferably ranging from 0.7 to 0.8 g/100g dry weight of composition, and COS (e.g cellobiose) is present in an amount ranging from 0.10 to 0.40 g/100g, preferably ranging from 0.2 to 0.3 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount of 0.73 g/100g dry weight of composition, and COS (e.g cellobiose) is present in an amount of 0.24 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.20 to 0.80 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.20 to 0.80 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.70 to 0.80 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.20 to 0.30 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount of about 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79 or 0.80 g/100g dry weight of composition and/or the COS are present in an amount of about 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29 or 0.30 g/100g dry weight of composition. In a preferred embodiment of the composition, the β-glucan is present in an amount of about 0.75 g/100g dry weight of composition and/or the COS are present in an amount of about 0.24 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.45 to 0.55 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.45 to 0.55 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount of about 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54 or 0.55 g/100g dry weight of composition and/or the COS are present in an amount of about 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54 or 0.55 g/100g dry weight of composition. In a preferred embodiment of the composition, the β-glucan is present in an amount of about 0.50 g/100g dry weight of composition and/or the COS are present in an amount of about 0.50 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.20 to 0.30 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.70 to 0.80 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount of about 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29 or 0.30 g/100g dry weight of composition and/or the COS are present in an amount of about 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79 or 0.80 g/100g dry weight of composition. In a preferred embodiment of the composition, the β-glucan is present in an amount of about 0.24 g/100g dry weight of composition and/or the COS are present in an amount of about 0.75 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.15 to 0.27 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.58 to 0.70 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount of about 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26 or 0.27 g/100g dry weight of composition and/or the COS are present in an amount of about 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69 or 0.70 g/100g dry weight of composition. In a preferred embodiment of the composition, the β-glucan is present in an amount of about 0.21 g/100g dry weight of composition and/or the COS are present in an amount of about 0.63 g/100g dry weight of composition. Suitably, the nutritional composition may be provided in a serving size of 36g total dry weight. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.15 to 0.70 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.70 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.37 to 0.47 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.37 to 0.47 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount of about 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46 or 0.47 g/100g dry weight of composition and/or the COS are present in an amount of about 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46 or 0.47 g/100g dry weight of composition. In a preferred embodiment of the composition, the β-glucan is present in an amount of about 0.42 g/100g dry weight of composition and/or the COS are present in an amount of about 0.42 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount ranging from 0.58 to 0.70 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.27 g/100g dry weight of composition. In some embodiments of the composition, the β-glucan is present in an amount of about 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69 or 0.70 g/100g dry weight of composition and/or the COS are present in an amount of about 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26 or 0.27 g/100g dry weight of composition. In a preferred embodiment of the composition, the β-glucan is present in an amount of about 0.63 g/100g dry weight of composition and/or the COS are present in an amount of about 0.21 g/100g dry weight of composition. Suitably, the nutritional composition may be intended for administration twice daily. Thus, the nutritional composition may be formulated to provide two servings per day. ß-glucan Molecular Weight determination The average molecular weight (MW) of β-glucan may be determined by Size Exclusion Chromatography (SEC) with a specific post-column labelling and a fluorescence detection (FLD) based on a calibration curve established with known MW of commercial ß- glucans as described below. Reagents and Materials ^ Calibration: ß-glucans standards, MW 35’600- 650’000 Da (six standards) with known MW ^ Quality control: ß-glucan 229’000 and 391’000 Da with known MW Equipment and Instruments ^ UltiMate 3000 HPLC (autosampler, column compartment, pump, fluorescence detector) ^ Columns: Shodex SB 806-HQ, SB 804-HQ, OHPak SBG (precolumn). ^ Tee connexion for post-column addition ^ Syringes, filters 0,45 µm Standards preparation (calibration curve) ß-glucans are dispersed in Milli Q® water (1 mg/ mL), heated to achieve a complete dissolution. After cooling the solution is filtered on 0.45 µm and injected on the SEC system. Samples preparation Identical to the standards preparation with a centrifugation step prior to the 0.45 µm filtration to recover the soluble fraction. Instrument Parameters: ^ Eluent: 0.1 M NaNO3 + 0.002 % NaN3 (prepared in Milli Q® water) ^ Flow rate: 0.5 mL/ min ^ System temperature: 60° C. ^ ß-glucan specific fluorescent labelling (post column addition) ^ Injection: 100 µL Probiotic The optimal pH range for L. rhamnosus growth is known to be between 4.5 and 6.4. Without wishing to be bound by theory, a L. rhamnosus modulating agent which decreases the pH of the gastrointestinal tract closer to this optimal pH range for L. rhamnosus growth would be expected to increase the abundance of L. rhamnosus within the gastrointestinal tract. For example, certain probiotic bacterial strains, such as lactic acid bacteria or bacteria of the Bifidobacterium genus, would be expected to decrease the pH of the gastrointestinal tract closer to the optimal pH range for L. rhamnosus growth. As such, the enhanced acidification, induced by metabolic activity of certain secondary probiotic strains, creates a more acidic environment, closer to the median of the optimal pH range for L. rhamnosus growth, and thus may allow L. rhamnosus to proliferate more successfully. This enhanced acidification is most likely mediated by increased organic acid production by the secondary strains successfully catabolising particular metabolites (such as longer-chain FOS molecules and/or inulin), where L. rhamnosus cannot. Thus, this synergistic effect of the secondary probiotic is not necessarily dependent on the specific prebiotics used (e.g., a combination of FOS and inulin), since any prebiotic that allows these secondary probiotic strains to mediate enhanced L. rhamnosus growth via increased acidification could induce this effect. Indeed, this may be especially true for more catabolically accessible prebiotics, such as fructo- oligosaccharides (FOS), inulin, galacto-oligosaccharides (GOS), HMOs (in particular for B. infantis), bovine milk oligosaccharides (BMOs), pectins, arabinan/arabinoxylan, resistant starch, or any combination thereof. In some embodiments, the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium. In some embodiments, the at least one probiotic is a lactic acid bacterium. The lactic acid bacteria are an order of gram-positive, acid-tolerant, either rod- shaped (bacilli) or spherical (cocci) bacteria that share common metabolic and physiological characteristics. This large group of bacteria that is widespread in nature and commonly used as probiotics or in fermented dairy products, produce lactic acid as the major metabolic end product of carbohydrate fermentation, giving them the common name lactic acid bacteria (LAB). In some embodiments, the L. rhamnosus-modulating agent comprises at least one probiotic of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium. In some embodiments, the at least one probiotic is selected from Lacticaseibacillus paracasei, Lactobacillus johnsonii, Bifidobacterium animalis (such as Bifidobacterium animalis subsp. lactis), Bifidobacterium longum (such as Bifidobacterium longum subsp. longum or Bifidobacterium longum subsp. infantis), Streptococcus thermophilus, and any combination thereof. Lacticaseibacillus paracasei (formerly known as “Lactobacillus paracasei” and formerly considered a subspecies of Lacticaseibacillus casei) is a gram-positive, is a gram- positive, homofermentative species of lactic acid bacteria of the Lacticaseibacillus genus which can be found in the gastrointestinal tract of humans. Lactobacillus johnsonii is a bacterium of the Lactobacillus genus which can be found in the gastrointestinal tract of humans. Bifidobacterium animalis is a bacterium of the Bifidobacterium genus which can be found in the large intestines of most mammals, including humans. Bifidobacterium animalis and Bifidobacterium lactis were previously described as two distinct species. Presently, both are considered B. animalis with the subspecies Bifidobacterium animalis subsp. animalis and Bifidobacterium animalis subsp. lactis (Masco, L., et al., 2004. International Journal of Systematic and Evolutionary Microbiology, 54(4), pp.1137-1143). Bifidobacterium longum is a bacterium of the Bifidobacterium genus which is present in the human gastrointestinal tract. In 2002, three previously distinct species of Bifidobacterium, B. infantis, B. longum, and B. suis, were unified into a single species named B. longum with the biotypes infantis, longum, and suis, respectively (Sakata, S., et al., 2002. International journal of systematic and evolutionary microbiology, 52(6), pp.1945-1951). Streptococcus thermophilus is a bacterium of the Streptococcus genus and is a gram- positive bacterium, and a fermentative facultative anaerobe. Streptococcus thermophilus can be found in the gastrointestinal tract of humans. Any suitable Lacticaseibacillus paracasei, Lactobacillus johnsonii, Bifidobacterium animalis (such as Bifidobacterium animalis subsp. lactis), Bifidobacterium longum (such as Bifidobacterium longum subsp. longum or Bifidobacterium longum subsp. infantis) and/or Streptococcus thermophilus strain may be used in the present invention. Such strains will be well known to the skilled person. The Lacticaseibacillus paracasei, Lactobacillus johnsonii, Bifidobacterium animalis (such as Bifidobacterium animalis subsp. lactis), Bifidobacterium longum (such as Bifidobacterium longum subsp. longum or Bifidobacterium longum subsp. infantis) and/or Streptococcus thermophilus may be a strain having at least 99% (suitably, at least 99.9%) ANI to any Lacticaseibacillus paracasei, Lactobacillus johnsonii, Bifidobacterium animalis (such as Bifidobacterium animalis subsp. lactis), Bifidobacterium longum (such as Bifidobacterium longum subsp. longum or Bifidobacterium longum subsp. infantis) and/or Streptococcus thermophilus strain, respectively, known to the skilled person. In some preferred embodiments the Bifidobacterium longum subsp longum strain may be selected from Bifidobacterium longum subsp longum strain CNCM I-2169, Bifidobacterium longum subsp longum strain CNCM I-2171, Bifidobacterium longum subsp longum strain ATCC 15708, Bifidobacterium longum subsp longum strain DSM 20097, Bifidobacterium longum subsp longum strain NCIMB 8809, Bifidobacterium longum subsp longum strain CNCM I-2618 (NCC 2705), Bifidobacterium longum subsp longum strain CNCM I-2170, Bifidobacterium longum subsp longum strain ATCC 15707, or a combination thereof, in particular B. longum CNCM I-2618 (NCC 2705). Suitably, the Lacticaseibacillus paracasei has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Lacticaseibacillus paracasei NCC 2461 (also known as Lacticaseibacillus paracasei CNCM I-2116 or Lacticaseibacillus paracasei ST11). Preferably, the Lacticaseibacillus paracasei has at least 99.9% ANI to Lacticaseibacillus paracasei NCC 2461. Lacticaseibacillus paracasei NCC 2461 was deposited with the Institute Pasteur according to the Budapest Treaty on 12th January 1999 receiving the deposit no. CNCM I- 2116. Suitably, the Lactobacillus johnsonii has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Lactobacillus johnsonii NCC 533 (also known as Lactobacillus johnsonii CNCM I-1225 or Lactobacillus johnsonii LA1). Preferably, the Lactobacillus johnsonii has at least 99.9% ANI to Lactobacillus johnsonii NCC 533. Lactobacillus johnsonii NCC 533 was deposited with the Institute Pasteur according to the Budapest Treaty on 30th June 1992 receiving the deposit no. CNCM I-1225. Suitably, the Bifidobacterium animalis subsp. lactis has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Bifidobacterium animalis subsp. lactis NCC 2818 (also known as Bifidobacterium animalis subsp. lactis CNCM I-3446 or Bifidobacterium animalis subsp. lactis BL818). Preferably, the Bifidobacterium animalis subsp. lactis has at least 99.9% ANI to Bifidobacterium animalis subsp. lactis NCC 2818. Bifidobacterium animalis subsp. lactis NCC 2818 was deposited with the Institute Pasteur according to the Budapest Treaty on 7th June 2005 receiving the deposit no. CNCM I-3446. Suitably, the Bifidobacterium longum subsp. longum has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Bifidobacterium longum subsp. longum NCC 2705 (also known as Bifidobacterium longum subsp. longum CNCM I-2618). Preferably, the Bifidobacterium longum subsp. longum has at least 99.9% ANI to Bifidobacterium longum subsp. longum NCC 2705. B. longum NCC 2705 was deposited with the Institute Pasteur according to the Budapest Treaty on 29th January 2001 receiving the deposit no. CNCM I-2618. Suitably, the Bifidobacterium longum subsp. infantis has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Bifidobacterium longum subsp. infantis LMG 11588 (also known as Bifidobacterium longum subsp. infantis NCC3039). Preferably, the Bifidobacterium longum subsp. infantis has at least 99.9% ANI to Bifidobacterium longum subsp. infantis LMG 11588. Bifidobacterium longum subsp. infantis LMG 11588 is sold by the Belgian Coordinated Collections of Microorganisms (BCCM) under the LMG accession number LMG 11588. Suitably, the Streptococcus thermophilus has at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Streptococcus thermophilus NCC 2496 (also known as Streptococcus thermophilus CNCM I-3915 or Streptococcus thermophilus ST496). Preferably, the Streptococcus thermophilus has at least 99.9% ANI to Streptococcus thermophilus NCC 2496. Streptococcus thermophilus NCC 2496 was deposited with the Institute Pasteur according to the Budapest Treaty on 5th February 2008 receiving the deposit no. CNCM I- 3915. In some embodiments, the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof. In one embodiment, the at least one probiotic is Lacticaseibacillus paracasei NCC 2461. In one embodiment, the at least one probiotic is Lactobacillus johnsonii NCC 533. In one embodiment, the at least one probiotic is Bifidobacterium animalis subsp. lactis NCC 2818. In one embodiment, the at least one probiotic is Bifidobacterium longum subsp. longum NCC 2705. In one embodiment, the at least one probiotic is Bifidobacterium longum subsp. infantis LMG 11588. In one embodiment, the at least one probiotic is Streptococcus thermophilus NCC 2496. In some embodiments, the composition comprises the at least one probiotic in an amount of 1×103 to 1.5×1012 cfu/g of the composition (dry weight). The nutritional composition according to the invention may contain from 103 to 1012 cfu of the at least one probiotic, more preferably between 107 and 1012 cfu such as between 108 and 1010 cfu of the at least one probiotic per g of composition on a dry weight basis. Suitably, the at least one probiotic is administered to the subject in an amount of at least about 106 cfu/day, at least about 107 cfu/day, or at least about 108 cfu/day. Suitably, the at least one probiotic is administered to the subject in an amount of about 1012 cfu/day or less, about 1011 cfu/day or less, or about 1010 cfu/day or less. In one embodiment the at least one probiotic is viable. In some embodiments, the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof. In one embodiment, the at least one probiotic is Lacticaseibacillus paracasei NCC 2461. In one embodiment, the at least one probiotic is Lactobacillus johnsonii NCC 533. In one embodiment, the at least one probiotic is Bifidobacterium animalis subsp. lactis NCC 2818. In one embodiment, the at least one probiotic is Bifidobacterium longum subsp. longum NCC 2705. In one embodiment, the at least one probiotic is Bifidobacterium longum subsp. infantis LMG 11588. In one embodiment, the at least one probiotic is Streptococcus thermophilus NCC 2496. In some embodiments, the L. rhamnosus-modulating agent is not L. rhamnosus. In some embodiments, the nutritional composition further comprises prebiotics. Suitably, the prebiotics may be those which are more catabolically accessible, such as FOS, inulin, GOS, HMOs (in particular for B. infantis), BMOs, pectins, arabinan/arabinoxylan, resistant starch, or any combination thereof. Suitably, the nutritional composition further comprises inulin and oligofructose. Use to enhance the growth of L. rhamnosus As described above, the combinations and compositions of the invention have surprisingly been found to enhance the growth of L. rhamnosus. In a further aspect, the present invention provides the use of the combination or nutritional composition of the invention for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child. In a further aspect, the present invention provides a method of enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, the method comprising administering the combination or composition of the invention to the infant, young child or child. In a further aspect, the present invention provides the use of at least one probiotic for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, wherein the at least one probiotic is as described herein elsewhere. In some embodiments, the use is therapeutic. In some embodiments, the use is non- therapeutic. Use as a bifidogenic factor As described above, the combinations and compositions of the invention have surprisingly been found to enhance growth of Bifidobacteria, indicating a surprising bifidogenic effect. In one aspect, the present invention provides use of the combinations and compositions of the invention as a bifidogenic factor. As used herein, a “bifidogenic factor” (also known as a “bifidus factor”) is an agent or composition that specifically enhances the growth of bifidobacteria in the gastrointestinal tract of humans. In some embodiments, the use of the combinations and compositions of the invention as a bifidogenic factor enhances the growth of Bifidobacteria in the gastrointestinal tract of a subject. In another aspect, the present invention provides the combinations and compositions of the invention for use in enhancing the growth of Bifidobacteria in the gastrointestinal tract of a subject. In another aspect, the present invention provides a method of enhancing the growth of Bifidobacteria in the gastrointestinal tract of a subject comprising administering a combination or composition of the invention to the subject. In some embodiments, the combinations and compositions of the invention enhance the growth of one or more bifidobacteria which are usually abundant in the gastrointestinal tract of humans (see e.g. Turroni, F., et al., 2009. The ISME journal, 3(6), pp.745-751 and Turroni, F., et al., 2012. PloS one, 7(5), p.e36957). For example, the combinations and compositions of the invention may enhance the growth of one or more bifidobacterial phylogenetic groups selected from the B. catenulatum group, the B. longum group, and the B. pseudolongum group. For example, the combinations and compositions of the invention may enhance the growth of one or more bifidobacterial species selected from: B. longum, B. animalis, B. adolescentis, B. bifidum, B. catenulatum, B. pseudocatenulatum, B. breve, B. pseudolongum, B. gallicum, B. angulatum, and B. faecal (see e.g., Rivière, A., et al., 2016. Frontiers in microbiology, 7, p.979). Suitably, the combinations and compositions of the invention may enhance the growth of B. catenulatum, B. longum, and B. pseudocatenulatum. In some embodiments, the use is therapeutic. In some embodiments, the use is non- therapeutic. Methods of treating or preventing infection or disease L. rhamnosus (including the strain with ATCC Accession No. 53103 and strain CGMCC1.3724 (LPR)) has been shown to have several beneficial health effects including enhancing the immune response to vaccination (Davidson et al., 2011, Eur J Clin Nutr. 65(4):501-7), and the treatment or prevention of healthcare-associated-diarrhea (Hojsak et al., 2010, Pediatrics 125 (5): e1171–e1177; and Szajewska et al., 2011, Aliment Pharmacol Ther, 34: 1079–1087), fungal infections (Manzoni et al., 2006, Clin Infect Dis, 42(12):1735-42) and acute respiratory infections (Kumpu et al., 2013, J Med Virol, 85(9):1632-8) such as rhinovirus infections (Luoto et al., 2014, J Allergy Clin Immunol, 133(2):405-13). SCFAs have a well-known role in immune protection against infection and regulation. In particular, SCFAs have been shown to promote host antibody responses (Kim et al., 2016, Cell Host & Microbe, 20(2): 202-214), protect against respiratory syncytial virus infection (Antunes et al., 2019, Nat Commun 10: 3273), enhance antimicrobial function of macrophages (and thereby boost the host defence against infections) (Schulthess et al., 2019, Immunity, 50(2): 432-445; and Machado et al., 2022, Front. Immunol., https://doi.org/10.3389/fimmu.2022.773261), protect against influenza virus infection or enhance the immune response to influenza virus (Trompette et al., 2018, Immunity, 48(5): 992-1005; and Moriyama and Ichinoe, 2019, PNAS, 116(8): 3118-3125), and protect against respiratory syncytial virus (RSV)–bronchiolitis (Lynxh et al., 2018, J Exp Med., 215(2): 537– 557). Bifidobacterium is one of the main genera of commensal bacteria present in the human gastrointestinal tracts and its presence has been related to health benefits in several studies (Hidalgo-Cantabrana, C., et al., 2017. Microbiology spectrum, 5(3), pp.5-3). The use of the combination or composition of the invention, which enhances the growth of L. rhamnosus and/or Bifidobacteria and/or increases the levels of SCFA in the gastrointestinal tract of the subject would be expected to have the same effects as the administration of the probiotics or SCFAs discussed above. In a further aspect, the present invention provides the combination or nutritional composition of the invention for use as a medicament. In a further aspect, the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament. The combination or nutritional composition of the invention may prevent or treat an infection or a disease by enhancing the growth of L. rhamnosus in the gastrointestinal tract of the subject. The combination or nutritional composition of the invention may prevent or treat an infection or a disease by enhancing the growth of Bifidobacteria in the gastrointestinal tract of the subject. The combination or nutritional composition of the invention may prevent or treat an infection or a disease by increasing the levels of SCFA in the gastrointestinal tract and systemic levels of SCFA of the subject. The increased systemic levels of SCFA in the subject facilitates the exertion of the effects of the combination or nutritional composition of the invention beyond the gastrointestinal tract (e.g., in the lungs). The combination or composition of the invention may be used to treat or prevent disorders associated with decreased numbers of Bifidobacteria in the gut (see e.g., Rivière, A., et al., 2016. Frontiers in microbiology, 7, p.979). In one aspect, the invention provides the combination or composition of the invention for use in treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut. In another aspect, the invention provides for use of the combination or composition of the invention for the manufacture of a medicament for treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut. In another aspect, the invention provides a method of treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut in a subject, comprising administering the combination or composition of the invention to the subject. Suitably, the disorder associated with decreased numbers of Bifidobacteria in the gut in a subject may be selected from: a gastrointestinal disease, obesity, an allergic disease, and regressive autism. Use of L. rhamnosus as a probiotic has been shown to act as an important adjuvant to improve influenza vaccine immunogenicity, i.e., to enhance the immune response to vaccination (Davidson et al., 2011, Eur J Clin Nutr. 65(4):501-7), and SCFAs produced by the host microbiome have been shown to promote host antibody responses, and in particular intestinal IgA and systemic IgG responses (Kim et al., 2016, Cell Host & Microbe, 20(2): 202- 214). Accordingly, in a further aspect, the present invention provides the combination or nutritional composition of the invention for use in enhancing the immune response to infection or vaccination in an infant, young child or child. In some embodiments, the antibody response to infection or vaccination is enhanced in the infant, young child or child. In a further aspect, the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament for enhancing the immune response to infection or vaccination in an infant, young child or child in an infant, young child or child. In a further aspect, the present invention provides a method of enhancing the immune response to infection or vaccination in an infant, young child or a child, the method comprising administering the composition of the invention to the infant, young child or child. In some embodiments, the antibody response to infection or vaccination is enhanced in the infant, young child or child. In some embodiments, the immune response to infection is enhanced. In some embodiments, the immune response to vaccination is enhanced. The use of L. rhamnosus as a probiotic has been shown to be effective for the treatment or prevention of various infections. For example, use of L. rhamnosus as a probiotic has been shown to reduce the incidence of respiratory tract infections, including rhinovirus infections, in preterm infants (Luoto et al., 2014, J Allergy Clin Immunol, 133(2):405-13) and to reduce the number of days with symptoms of respiratory tract infections in children attending day care (Kumpu et al., 2013, J Med Virol, 85(9):1632-8). In addition, use of L. rhamnosus as a probiotic has been shown to significantly reduce the risk of healthcare-associated infections, including gastrointestinal infections, respiratory tract infections, vomiting episodes, diarrheal episodes, episodes of gastrointestinal infections that lasted >2 days, and episodes of respiratory tract infections that lasted >3 days in hospitalised children (Hojsak et al., 2010, Pediatrics 125 (5): e1171–e1177). Moreover, a meta-analysis of the effect of L. rhamnosus as a probiotic on the prevention of healthcare-associated diarrhoea in children concluded that this probiotic can reduce the overall incidence of healthcare-associated diarrhoea in children (Szajewska et al., 2011, Aliment Pharmacol Ther, 34: 1079–1087). A further study has evidenced that oral supplementation with L. rhamnosus prevents enteric colonization by Candida species in preterm neonates (Manzoni et al., 2006, Clin Infect Dis, 42(12):1735-42). The well-known role of SCFAs in immune regulation is discussed above. Accordingly, in a further aspect, the present invention provides the combination or nutritional composition of the invention for use in preventing and/or reducing the risk of developing an infection in an infant, young child or child. In a further aspect, the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament for preventing and/or reducing the risk of developing an infection in an infant, young child or child in an infant, young child or child. In a further aspect, the invention provides a method of preventing and/or reducing the risk of developing an infection in an infant, young child or a child, the method comprising administering the composition of the invention to the infant, young child or child. As used herein, the term “preventing and/or reducing the risk of developing an infection” includes preventing and/or reducing the risk of infection, delaying or preventing the onset of symptoms of infection and/or reducing the number or severity of symptoms of the infection. The infection may be selected from respiratory tract infections (such as rhinovirus infections, respiratory syncytial virus infections, influenza virus infections), gastrointestinal tract infections (including candida infections, healthcare-associated infections and healthcare-associated diarrhea). In some embodiments, the composition of the invention may be administered once daily. In other embodiments, the composition of the invention is administered in multiple servings, for example in two servings (also known as “unit doses”) per day. When the nutritional composition is provided in the form of unit doses (or “servings”) it is particularly useful to define the amount of oligosaccharides and probiotics in terms of the daily dose to be administered to the infant, or young child or child. In some embodiments, the uses or methods are therapeutic. In some embodiments, the uses or methods are non-therapeutic. In some embodiments, a total amount ranging from 800 to 7500 mg COS/day administered to the infant, young child or child corresponds to 1290 to 12100 mg/100 g dry weight of composition. In some embodiments, a total amount ranging from 100 to 1500 mg/day (suitably, 250 to 1500 mg/day, or 800 to 1400 mg/day, or 800 to 1350 mg/day) of COS are administered to the infant, young child or child. In one preferred embodiment, a total amount ranging from 800 to 1500 mg/day, for example 800 to 1250 mg/day, or 1000 to 1500 mg/day of COS are administered to the infant, young child or child. It was found that the maximum dose of COS (e.g., cellobiose) and/or β-glucan well tolerated by infant, young child and children is preferably a up to 7500 mg per day. In some embodiments, 800 to 7500 mg COS/day are administered to the infant, young child or child. In some preferred embodiments, a total amount of at least 800 mg/day of COS (e.g., cellobiose) are administered to the infant, young child or child. In some embodiments, about 100 mg/day (suitably, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day, 550 mg/day, 600 mg /day, 650 mg/day, 700 mg/day, 750 mg/day, 800 mg/day, 850 mg/day, 900 mg/day, 950 mg/day, 1000 mg/day, 1050 mg/day, 1100 mg/day, 1150 mg/day, 1200 mg/day, 1250 mg/day, 1300 mg/day, 1350 mg/day, 1400 mg/day, 1450 mg/day or 1500 mg/day) of COS (e.g. cellobiose) are administered to the infant, young child or child. Preferably, about 800 mg/day to 1250 mg/day of COS are administered to the infant, young child or child. In some embodiments, a total amount ranging from 100 to 1000 mg/day (suitably, 150-800 mg/day or 200 to 600 mg/day) of β-glucan and COS (e.g. cellobiose) combined are administered to the infant, young child or child. In one embodiment, a total amount ranging from 200 to 600 mg/day of β-glucan and COS combined are administered to the infant, young child or child. In one embodiment, an amount 450 mg/day of β-glucan and an amount 150 mg/day of COS (preferably cellobiose) combined are administered to the infant, young child or child. In one embodiment, an amount 150 mg/day of β-glucan and an amount 450 mg/day of COS (preferably cellobiose) combined are administered to the infant, young child or child. In some embodiments, an amount ranging from 50 to 950 mg/day of β-glucan and an amount ranging from 50 to 950 mg/day of COS are administered to the infant, young child or child. In some embodiments, an amount ranging from 100 to 800 mg/day of β-glucan and an amount ranging from 100 to 800 mg/day of COS are administered to the infant, young child or child. In some preferred embodiments, an amount ranging from 150 to 450 mg/day of β- glucan and an amount ranging from 150 to 450 mg/day of COS are administered to the infant, young child or child. In some embodiments, about 50 mg/day (suitably, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day, 550 mg/day, 600 mg /day, 650 mg/day, 700 mg/day, 750 mg/day, 800 mg/day, 850 mg/day, 900 mg/day or 950 mg/day) of β-glucan and about 50 mg/day (suitably, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day, 550 mg/day, 600 mg /day, 650 mg/day, 700 mg/day, 750 mg/day, 800 mg/day, 850 mg/day, 900 mg/day or 950 mg/day) of COS are administered to the infant, young child or child. In one embodiment, about 150 mg/day of β-glucan and about 450 mg/day of COS are administered to the infant, young child or child. In one embodiment, about 300 mg/day of β- glucan and about 300 mg/day of COS are administered to the infant, young child or child. In one embodiment, about 450 mg/day of β-glucan and about 150 mg/day of COS are administered to the infant, young child or child. In one embodiment, about 50 mg/day of β- glucan and about 150 mg/day of COS are administered to the infant, young child or child. In one embodiment, about 100 mg/day of β-glucan and about 100 mg/day of COS are administered to the infant, young child or child. In one embodiment, about 150 mg/day of β- glucan and about 50 mg/day of COS are administered to the infant, young child or child. In some embodiments, the infant, young child or child is non-responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan. As used herein the term “non-responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan” refers to an infant, young child or a child who does not respond to the oral administration of β-glucan or β-glucan in combination with L. rhamnosus. Suitably, an infant, young child or a child who is non-responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan does not show increased levels of butyrate in the gastrotintestinal tract when β-glucan or β-glucan in combination with L. rhamnosus is administered compared to no administration of β-glucan or β-glucan in combination with L. rhamnosus. Suitably, an infant, young child or a child who is non- responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan is characterized by the presence of lower levels of Faecalibacterium spp. and Parabacteroides distasonis as measured by species level Operational Taxonomic Units (OTUs) in the fecal samples compared to an infant, young child or a child who is responsive to treatment with β- glucan or with a combination of L. rhamnosus and β-glucan. Thus, an infant, young child or a child may be identified as responsive or non-responsive to treatment β-glucan or β-glucan in combination with L. rhamnosus based upon the levels of Faecalibacterium spp. and Parabacteroides distasonis in fecal samples. Suitably, an infant, young child or a child who is responsive to treatment with β- glucan or with a combination of L. rhamnosus and β-glucan shows increased levels of butyrate in the gastrointestinal tract when β-glucan or β-glucan in combination with L. rhamnosus is administered compared to no administration of β-glucan or β-glucan in combination with L. rhamnosus. Suitably, an infant, young child or a child who is responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan is characterized by the presence of higher levels of Faecalibacterium spp. and Parabacteroides distasonis as measured by species level Operational Taxonomic Units (OTUs) in the fecal samples compared to an infant, young child or a child who is non-responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan. The species level OTUs and butyrate levels in the gastrointestinal tract may be determined by any suitable methods known in the art. For example, species level OTUs and butyrate levels in the gastrointestinal tract may be measured using the methods described herein (see Example 4). In a further aspect, the present invention provides the use of the nutritional composition of the invention for increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child. In a further aspect, the present invention provides a method of increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child, the method comprising administering the composition of the invention to the infant, young child or child. In some embodiments, the at least one SCFA is acetate, propionate, butyrate, or any combination thereof. In one preferred embodiment, the at least one SCFA is acetate. In one embodiment, the at least one SCFA is propionate. In one preferred embodiment, the at least one SCFA is butyrate. In a most preferred embodiment, the at least one SCFA is butyrate. In some embodiments, the at least one SCFA is butyrate and the infant, young child or child is non-responsive to treatment with β-glucan or with a combination of Lactobacillus rhamnosus and β-glucan. The combination or nutritional composition of the invention may be administered by any suitable method known to the skilled person. For example, the combination or nutritional composition of the invention may be administered by oral and/or enteral administration. In some embodiments, the combination or nutritional composition of the invention is orally administered. Healthcare-associated-diarrhea (HCAD) Diarrhea is a common complication in hospitalized patients and is associated with significant morbidity and decreased quality of life. Recent epidemiologic studies reaffirm that HCAD is predominantly a noninfectious condition most often caused by medications or underlying medical conditions, sometimes Clostridioides difficile, and occasionally viruses. Other infections are rare. Medication-induced diarrhea is common and may be due to the use of medications including antibiotics, laxatives, and enemas. L. rhamnosus has been shown to treat or prevent healthcare-associated-diarrhea (Hojsak et al., 2010, Pediatrics 125 (5): e1171–e1177; and Szajewska et al., 2011, Aliment Pharmacol Ther, 34: 1079–1087). Acute respiratory infections Acute respiratory infections (ARIs) are classified as upper respiratory tract infections (URIs) or lower respiratory tract infections (LRIs). Acute upper respiratory tract infections are common, especially among children, and include rhinitis, pharyngitis, tonsillitis, and laryngitis. Acute lower respiratory infections include pneumonia (infection of the lung alveoli), as well as infections affecting the airways such as acute bronchitis and bronchiolitis, influenza and whooping cough. Acute respiratory infections are responsible for 4.25 million deaths worldwide, with the great majority of deaths from respiratory infections being caused by LRIs - predominantly pneumonia. L. rhamnosus has been shown to treat or prevent acute respiratory infections (Kumpu et al., 2013, J Med Virol, 85(9):1632-8) such as rhinovirus infections (Luoto et al., 2014, J Allergy Clin Immunol, 133(2):405-13). SCFAs have been shown to protect against respiratory syncytial virus infection (Antunes et al., 2019, Nat Commun 10: 3273), protect against influenza virus infection or enhance the immune response to influenza virus (Trompette et al., 2018, Immunity, 48(5): 992-1005; and Moriyama and Ichinoe, 2019, PNAS, 116(8): 3118-3125), and protect against respiratory syncytial virus (RSV)–bronchiolitis (Lynch et al., 2018, J Exp Med., 215(2): 537– 557). Rhinovirus infections Rhinovirus infections are the predominant cause of the common cold. Most rhinovirus infections are mild, but they can sometimes lead to bronchiolitis and pneumonia. They chiefly cause URIs but may also infect the lower respiratory tract. Influenza virus infections Influenza is an acute respiratory infection caused by influenza viruses which circulate in all parts of the world. These viruses are easily transmitted from person to person. In a typical year, 5–15% of the population contracts influenza. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin from one to four days after exposure to the virus (typically two days) and last for about 2–8 days. In healthy individuals, influenza is typically self-limiting and rarely fatal, but it can be deadly in high-risk groups, including young children, the elderly, and people with chronic health conditions. There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year. Influenza infection may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection. Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease. Respiratory syncytial virus (RSV) infections RSV is a common respiratory virus that usually causes mild, cold-like symptoms. Most people recover in a week or two. RSV can also cause more severe infections such as bronchiolitis, an inflammation of the small airways in the lung, and pneumonia, an infection of the lungs. RSV is so common that most children have been infected with the virus by age 2. Fungal infections Fungal infections that are not life-threatening, such as skin, nail, or vaginal yeast infections, are common. Some infections can be more serious. Fungal infections are more prevalent in individuals with a weakened immune system. Colonization by Candida species is reported to be the most important predictor of the development of invasive fungal disease in preterm neonates, and the enteric reservoir is a major site of colonization. It has been evidenced that orally administered L. rhamnosus significantly reduces the incidence and the intensity of enteric colonization by Candida species among very low birth weight neonates (Manzoni et al., 2006, Clin Infect Dis, 42(12):1735-42). Methods of promoting and/or maintaining gastrointestinal health As described above, the use of probiotics, including L. rhamnosus and Bifidobacteria strains, in preventive medicine to maintain a healthy intestinal function is well-documented (Tojo, R., et al., 2014. World journal of gastroenterology: WJG, 20(41), p.15163). Further, the use of SCFA in preventive medicine to maintain a healthy intestinal function is also well- documented. The use of the combination or composition of the invention, which enhances the growth of L. rhamnosus and/or Bifidobacteria and/or increases the levels of SCFA in the gastrointestinal tract of the subject would be expected to have the same effects. In a further aspect, the present invention provides the combination or nutritional composition of the invention for use in promoting and/or maintaining gastrointestinal health in an infant, young child or child. In a further aspect, the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament for promoting and/or maintaining gastrointestinal health in an infant, young child or child. In a further aspect, the present invention provides a method of promoting and/or maintaining gastrointestinal health in an infant, young child or a child, the method comprising administering the combination or composition of the invention to the infant, young child or child. In one aspect, the invention provides the use of the combination or composition of the invention for promoting and/or maintaining gastrointestinal health. The combination or composition of the invention may promote and/or maintain gastrointestinal health by enhancing the growth of L. rhamnosus or Bifidobacteria, or by increasing the levels of SCFA, in the gastrointestinal tract of the subject. Methods of treating and/or preventing a gastrointestinal disease In some embodiments, promoting and/or maintaining gastrointestinal health includes treating and/or preventing a gastrointestinal disease. In one aspect, the invention provides the combination or composition of the invention for use in treating and/or preventing a gastrointestinal disease. In another aspect, the invention provides for use of the combination or composition of the invention for the manufacture of a medicament for treating and/or preventing a gastrointestinal disease. In another aspect, the invention provides a method of treating and/or preventing a gastrointestinal disease in a subject, comprising administering the combination or composition of the invention to the subject. As used herein, a “gastrointestinal disease” (also known as “GI disease” or “GI illness”) may refer to diseases involving the gastrointestinal tract, which includes the oesophagus, stomach, small intestine, large intestine and rectum. In some embodiments, the gastrointestinal disease is a gastric disease or an intestinal disease. In some embodiments, the gastrointestinal disease is a gastric disease. A “gastric disease” may refer to diseases affecting the stomach. In some embodiments, the gastrointestinal disease is an intestinal disease. An “intestinal disease” may refer to diseases affecting the small intestine (including the duodenum, jejunum, and ileum) or large intestine (including the cecum, colon, and rectum). In some embodiments, the gastrointestinal disease is selected from: healthcare- associated diarrhea, antibiotic-associated diarrhea, Helicobacter pylori infection, an inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, infectious diarrhea, and necrotizing enterocolitis. In some embodiments, the methods are therapeutic. In some embodiments, the methods are non-therapeutic. Antibiotic-associated diarrhea A common complication of antibiotic use is the development of gastrointestinal disease. This complication ranges from mild diarrhea to pseudomembranous colitis. Antibiotic-associated diarrhea typically occurs in 5–35% of patients taking antibiotics and varies depending upon the specific type of antibiotic, the health of the host and exposure to pathogens. The pathogenesis of antibiotic-associated diarrhea may be mediated through the disruption of the normal microbiota resulting in pathogen overgrowth or metabolic imbalances (McFarland, L.V., 2008. Future Microbiology, 3(5), p.563). A probiotic mixture which contains several Bifidobacteria strains, among which are B. breve, B. infantis, and B. longum, displayed an ability to reduce the incidence of antibiotic- associated diarrhea (Selinger, C.P., et al., 2013. Journal of Hospital Infection, 84(2), pp.159- 165). Helicobacter pylori infection Helicobacter pylori is a gram-negative microaerophilic bacterium that infects the epithelial lining of the stomach. Helicobacter pylori is the main cause of chronic gastritis and the principal etiological agent for gastric cancer and peptic ulcer disease. A recent global systematic review estimated that more than half the world’s population is infected with Helicobacter pylori (Hooi, J.K., et al., 2017. Gastroenterology, 153(2), pp.420-429). A Helicobacter pylori eradication rate of 32.5% has been reported in adults after 10 days of administration of a probiotic mixture which contains several Bifidobacteria strains, among which are B. breve, B. infantis, and B. longum (Boltin, D., 2016. Best Practice & Research Clinical Gastroenterology, 30(1), pp.99-109). Moreover, such a probiotic mixture has be shown to accelerate gastric ulcer healing (Dharmani, P., et al., 2013. PLoS One, 8(3), p.e58671). Inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine. Exemplary IBDs include Crohn’s disease (CD), ulcerative colitis (UC), and pouchitis. Is has been suggested that dysbiosis (that is, abnormal microbiota composition) and decreased complexity of the gut microbial ecosystem are common features in patients with IBD (see Manichanh, C., et al., 2012. Nature reviews Gastroenterology & hepatology, 9(10), pp.599-608). In IBD, a probiotic mixture which contains several Bifidobacteria strains, among which are B. breve, B. infantis, and B. longum, was able to reduce the UC symptoms in adults (Tursi, A., et al., 2010. The American journal of gastroenterology, 105(10), p.2218) as well as the remission of the disease in children (Miele, E., et al., 2009. American Journal of Gastroenterology, 104(2), pp.437-443). In some embodiments, the IBD is Crohn’s disease, ulcerative colitis, or pouchitis. Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disorder characterised by chronic and recurrent abdominal pain and altered bowel habit (Chey, W.D., et al., 2015. Jama, 313(9), pp.949-958). A growing body of evidence indicates dysbiosis as a hallmark of IBS (Rodiño- Janeiro, B.K., et al., 2018. Advances in therapy, 35(3), pp.289-310). Administration of a probiotic mixture which contains several Bifidobacteria strains, among which are B. breve, B. infantis, and B. longum, for 6 weeks resulted in the reduction of IBS symptoms and the improvement of the quality of life in children (Guandalini, S., et al., 2010. Journal of pediatric gastroenterology and nutrition, 51(1), pp.24-30). Other gastrointestinal diseases Lactose intolerance is a common condition caused by a decreased ability to digest lactose. Administration of Bifidobacteria has been used to improve the symptoms of lactose intolerance (Hidalgo-Cantabrana, C., et al., 2017. Microbiology spectrum, 5(3), pp.5-3). Infectious diarrhea (also known as gastroenteritis) is inflammation of the gastrointestinal tract caused by an infection. Gastroenteritis is usually caused by viruses (e.g. rotavirus, norovirus, adenovirus, astrovirus, and coronavirus), however, bacteria (e.g. C. jeuni, E. coli, Salmonella, Shigella, C. difficile, and S. aureus), parasites (e.g. Giardia lamblia), and fungus can also cause gastroenteritis. There is evidence that that viable Bifidobacterium lactis has some protective effect against acute diarrhea in healthy children (Chouraqui, J.P., et al., 2004. Journal of pediatric gastroenterology and nutrition, 38(3), pp.288-292). Necrotizing enterocolitis (NEC) is an intestinal disease that affects premature infants. It has been shown that probiotic supplementation with Bifidobacteria can reduce both the incidence and severity of NEC in a premature neonatal population (Bin-Nun, A., et al., 2005. The Journal of pediatrics, 147(2), pp.192-196). In one aspect, the invention provides the combination or composition of the invention for use in treating and/or preventing lactose intolerance, infectious diarrhea, or necrotizing enterocolitis. In another aspect, the invention provides for use of the combination or composition of the invention for the manufacture of a medicament for treating and/or preventing lactose intolerance, infectious diarrhea, or necrotizing enterocolitis. In another aspect, the invention provides a method of treating and/or preventing lactose intolerance, infectious diarrhea, or necrotizing enterocolitis in a subject, comprising administering the combination or composition of the invention to the subject. Subject In some embodiments of the methods and uses of the invention, the combination or composition is administered to an infant. In some embodiments of the methods and uses of the invention, the combination or composition is administered to a young child. In some embodiments of the methods and uses of the invention, the combination or composition is administered to a child. In a further embodiment, the infant has an age ranging from 0 months to 12 months, for example 9 or 6 months. In some embodiments, the young child has an age ranging from one year to three years, for example 2 years. In some embodiments, the child has an age ranging from three years to nine years, for example from three years to seven years. In some preferred embodiments, the child has an age ranging from three years to five years, for example four years. Some specific populations of infants, young children and children are particularly in need of compositions of the invention. Such infants, young children and children are for example preterm infants, low birth weight infant, and/or growth-retarded infants, young children or children. Indeed such subjects are often experiencing adverse medical conditions and require significantly more frequent medical intervention than term infants and infants having experienced normal development. The nutritional composition according to the invention is for use in infants, young children and/or children. The infants, young children and/or children may be born term or preterm. In a particular embodiment the nutritional composition of the invention is for use in infants, young children and/or children that were born preterm, having a low birth weight and/or born small for gestational age (SGA). In a particular embodiment the nutritional composition of the invention is for use in preterm infants, infants having a low birth weight and/or infants born small for gestational age (SGA). The nutritional composition of the present invention may also be used in an infant, young child or child that was born by C-section or that was vaginally delivered. In some embodiments the composition according to the invention can be for use before and/or during the weaning period. The nutritional composition can be administered (or given or fed) at an age and for a period that depends on the needs. The nutritional composition can be for example given immediately after birth of the infants. The composition of the invention can also be given during the first week of life of the infant, or during the first 2 weeks of life, or during the first 3 weeks of life, or during the first month of life, or during the first 2 months of life, or during the first 3 months of life, or during the first 4 months of life, or during the first 6 months of life, or during the first 8 months of life, or during the first 10 months of life, or during the first year of life, or during the first two years of life or even more. In some particularly advantageous embodiments of the invention, the nutritional composition is given (or administered) to an infant within the first 4, 6 or 12 months of birth of said infant. In some other embodiments, the nutritional composition of the invention is given few days (e.g.1, 2, 3, 5, 10, 15, 20...), or few weeks (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10...), or few months (e.g.1 , 2, 3, 4, 5, 6, 7, 8, 9, 10...) after birth. This may be especially the case when the infant is premature, but not necessarily. In one embodiment the composition of the invention is given to the infant or young child as a supplementary composition to the mother’s milk. In some embodiments the infant or young child receives the mother’s milk during at least the first 2 weeks, first 1, 2, 4, or 6 months. In one embodiment the nutritional composition of the invention is given to the infant or young child after such period of mother’s nutrition, or is given together with such period of mother’s milk nutrition. In another embodiment the composition is given to the infant or young child as the sole or primary nutritional composition during at least one period of time, e.g., after the1st, 2nd or 4th month of life, during at least 1, 2, 4 or 6 months. The subject may have or may be at risk of a low abundance of L. rhamnosus in their gastrointestinal tract. The subject may have or may be at risk of a low abundance of Bifidobacteria in their gastrointestinal tract. The abundance of L. rhamnoosus or Bifidobacteria in the gastrointestinal tract may be determined by any method known to the skilled person (e.g., any method described in Tang, Q., et al., 2020. Frontiers in cellular and infection microbiology, 10, p.151). For example, abundance of L. rhamnoosus or Bifidobacteria in the gastrointestinal tract may be determined by the methods disclosed herein (see Examples 4 and 6). A gastrointestinal tract sample may be obtained from or obtainable from fecal samples, endoscopy samples (e.g., biopsy samples, luminal brush samples, laser capture microdissection samples), aspirated intestinal fluid samples, surgery samples, or by in vivo models or intelligent capsule. Suitably, a gastrointestinal tract sample may be obtained from or obtainable from fecal samples. Fecal samples are naturally collected, non-invasive and can be sampled repeatedly. The abundance of L. rhamnoosus or Bifidobacteria may be determined from the samples by any suitable method. For example, the abundance of L. rhamnoosus or Bifidobacteria may be obtained by or obtainable from the samples by sequencing methods (e.g., next-generation sequencing (NGS) methods), PCR-based methods, semi-quantitative detection methods, cycling temperature capillary electrophoresis, immunological-based methods, cell-based methods, or any combination thereof. The subject may have or may be at risk of a disorder associated with decreased numbers of L. rhamnosus or Bifidobacteria in the gut. Such disorders are described by Rivière, A., et al., 2016. Frontiers in microbiology, 7, p.979, and may include gastrointestinal diseases, obesity, allergies, and regressive autism. The subject may have or may be at risk of a gastrointestinal disease. Such gastrointestinal diseases are described in more detail in the section entitled “Methods of treating and/or preventing a gastrointestinal disease”. In some embodiments, the subject may have or may be at risk of an antibiotic-associated diarrhea. In some embodiments, the subject may have or may be at risk of a Helicobacter pylori infection. In some embodiments, the subject may have or may be at risk of an IBD. In some embodiments, the subject may have or may be at risk of IBS. In some embodiments, the subject may have or may be at risk of lactose intolerance, infectious diarrhea, or necrotizing enterocolitis. Other ingredients The nutritional composition according to the present invention may also comprise other types of oligosaccharide(s) (i.e., other than COS and β-glucan mentioned above) and/or a fiber(s) and/or a precursor(s) thereof. The other oligosaccharide and/or fiber and/or precursor thereof may be selected from the list comprising human milk oligosaccharides (HMOs), fructo-oligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose and any combination thereof. They may be in an amount between 0 and 10% by weight of composition. In a particular embodiment, the nutritional composition or the growing-up milk can also contain at least one BMO (bovine milk oligosaccharide). HMOs which may be included in the combination or nutritional composition according to the present invention may be selected from the group consisting of 2-FL (2- fucosyllactose), 3-FL (3- fucosyllactose), Lacto-difucotetraose (LDFT)), lacto-N- fucopentaose (e.g. lacto-N-fucopentaose I, lacto-N-fucopentaose II, lacto-N- fucopentaose III, lacto-N- fucopentaose V), lacto-N-fucohexaose, lacto-N-difucohexaose I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose I, difucosyllacto-N-neohexaose II, para-lacto-N-neohexaose (para-LNnH), LNT (lacto-N-tetraose), LNnT (lacto-N-neotetraose), lacto-N-hexaose, lacto- N-neohexaose, para-lacto-N-hexaose, para-lacto-N-neohexaose, lacto-N-octaose, lacto-N- neooctaose, iso- lacto-N-octaose, para- lacto-N-octaose, lacto-N- decaose, 3-SL (3' sialyllactose) , 6-SL (6’ sialyllactose) and any combination thereof. In some embodiments, the combination or nutritional composition according to the invention comprises at least one additional HMO. In other embodiments, the combination or nutritional composition according to the present invention is devoid of any further HMOs. The nutritional composition of the present invention can further comprise at least one further probiotic (or probiotic strain), such as at least one further probiotic bacterial strain. The probiotic microorganisms most commonly used are principally bacteria and yeasts of the following genera: Lactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp. In some particular embodiments, the probiotic is a probiotic bacterial strain. In some specific embodiments, it is particularly Bifidobacteria and/or Lactobacilli. Suitable probiotic bacterial strains include Lactobacillus paracasei CNCM I-2116, Lactobacillus johnsonii CNCM I-1225, Streptococcus salivarius DSM 13084 sold by BLIS Technologies Limited of New Zealand under the designation KI2, Bifidobacterium lactis CNCM 1-3446 sold inter alia by the Christian Hansen company of Denmark under the trademark Bb 12, Bifidobacterium breve sold by Danisco under the trademark Bb-03, Bifidobacterium breve sold by Morinaga under the trade mark M-16V, Bifidobacterium infantis sold by Procter & GambIe Co. under the trademark Bifantis and Bifidobacterium breve sold by Institut Rosell (Lallemand) under the trademark R0070. The nutritional composition according to the invention may contain from 103 to 1012 cfu of the at least one further probiotic strain, more preferably between 107 and 1012 cfu such as between 108 and 10x10 cfu of probiotic strain per g of composition on a dry weight basis. In one embodiment the probiotics are viable. The nutritional composition according to the invention can be for example an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier such as a human milk fortifier, or a supplement. In some particular embodiments, the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first 4 or 6 months of age. In a preferred embodiment the nutritional composition of the invention is an infant formula. In some other embodiments the nutritional composition of the present invention is a fortifier. The fortifier can be a breast milk fortifier (e.g., a human milk fortifier) or a formula fortifier such as an infant formula fortifier or a follow-on/follow-up formula fortifier. When the nutritional composition is a supplement, it can be provided in the form of unit doses. In such cases it is particularly useful to define the amount of oligosaccharides and probiotics in terms of daily dose to be administered to the infant, young child or child, such as described above. When the nutritional composition is a supplement, it may comprise 2’-FL and no other additional nutrient on top of the excipients necessary to obtain a stable nutritional composition. The nutritional composition of the present invention can be in solid (e.g., powder), liquid or gelatinous form. In a specific embodiment the nutritional composition is a supplement, wherein the supplement is in powder form and provided in a sachet, preferably a sachet with 0.1 to 20 g per sachet, for example 1 to 10 g per sachet, or in the form of a syrup, preferably a syrup with a total solid concentration of 5 to 75 g/100 mL (5 to 75% (w/v)). When the supplement is in powder form, it may comprise a carrier. It is however preferred that the supplement is devoid of a carrier. When the supplement is in the form of a syrup, the components are preferably dissolved or suspended in water acidified with citrate. The nutritional composition according to the invention generally contains a protein source. The protein can be in an amount of from 1.6 to 3 g per 100 kcal. In some embodiments, especially when the composition is intended for premature infants, the protein amount can be between 2.4 and 4 g/100kcal or more than 3.6 g/100kcal. In some other embodiments the protein amount can be below 2.0 g per 100 kcal, e.g., between 1.8 to 2 g/100 kcal, or in an amount below 1.8 g per 100 kcal. Protein sources based on whey, casein and mixtures thereof may be used as well as protein sources based on soy. As far as whey proteins are concerned, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha- lactalbumin and beta-lactoglobulin in any desired proportions. In some advantageous embodiments the protein source is whey predominant (i.e., more than 50% of proteins are coming from whey proteins, such as 60% or 70%). The proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins. By the term “intact” is meant that the main part of the proteins are intact, i.e. the molecular structure is not altered, for example at least 80% of the proteins are not altered, such as at least 85% of the proteins are not altered, preferably at least 90% of the proteins are not altered, even more preferably at least 95% of the proteins are not altered, such as at least 98% of the proteins are not altered. In a particular embodiment, 100% of the proteins are not altered. The term “hydrolysed” means in the context of the present invention a protein which has been hydrolysed or broken down into its component amino acids. The proteins may be either fully or partially hydrolysed. It may be desirable to supply partially hydrolysed proteins (degree of hydrolysis between 2 and 20%), for example for infants or young children believed to be at risk of developing cow’s milk allergy. If hydrolysed proteins are required, the hydrolysis process may be carried out as desired and as is known in the art. For example, whey protein hydrolysates may be prepared by enzymatically hydrolysing the whey fraction in one or more steps. If the whey fraction used as the starting material is substantially lactose free, it is found that the protein suffers much less lysine blockage during the hydrolysis process. This enables the extent of lysine blockage to be reduced from about 15% by weight of total lysine to less than about 10% by weight of lysine; for example about 7% by weight of lysine which greatly improves the nutritional quality of the protein source. In an embodiment of the invention at least 70% of the proteins are hydrolysed, preferably at least 80% of the proteins are hydrolysed, such as at least 85% of the proteins are hydrolysed, even more preferably at least 90% of the proteins are hydrolysed, such as at least 95% of the proteins are hydrolysed, particularly at least 98% of the proteins are hydrolysed. In a particular embodiment, 100% of the proteins are hydrolysed. In one particular embodiment the proteins of the nutritional composition are hydrolyzed, fully hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the protein can be between 8 and 40, or between 20 and 60 or between 20 and 80 or more than 10, 20, 40, 60, 80 or 90. The protein component can alternatively be replaced by a mixture or synthetic amino acid, for example for preterm or low birth weight infants. In a particular embodiment the nutritional composition or the growing-up milk according to the invention is a hypoallergenic composition. In another particular embodiment the composition according to the invention is a hypoallergenic nutritional composition or growing-up milk. The nutritional composition according to the present invention generally contains a carbohydrate source. This is particularly preferable in the case where the nutritional composition of the invention is an infant formula. In this case, any carbohydrate source conventionally found in infant formulae such as lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof may be used although one of the preferred sources of carbohydrates is lactose. The nutritional composition according to the present invention generally contains a source of lipids. This is particularly relevant if the nutritional composition of the invention is an infant formula. In this case, the lipid source may be any lipid or fat which is suitable for use in infant formulae. Some suitable fat sources include palm oil, structured triglyceride oil, high oleic sunflower oil and high oleic safflower oil, medium-chain-triglyceride oil. The essential fatty acids linoleic and α-linolenic acid may also be added, as well small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils. The fat source may have a ratio of n-6 to n-3 fatty acids of about 5:1 to about 15:1; for example about 8:1 to about 10:1. The nutritional composition of the invention may also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present in the composition of the invention include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended population. If necessary, the nutritional composition of the invention may contain emulsifiers and stabilisers such as soy, lecithin, citric acid esters of mono- and diglycerides, and the like. The nutritional composition of the invention may also contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, and the like. The nutritional composition of the invention may also contain carotenoid(s). In some particular embodiments of the invention, the nutritional composition of the invention does not comprise any carotenoid. The nutritional composition according to the invention may be prepared in any suitable manner. A composition will now be described by way of example. For example, a formula such as an infant formula may be prepared by blending together the protein source, the carbohydrate source and the fat source in appropriate proportions. If used, the emulsifiers may be included at this point. The vitamins and minerals may be added at this point but they are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The temperature of the water is conveniently in the range between about 50°C and about 80°C to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture. The fucosylated oligosaccharide(s) and the N-acetylated oligosaccharide(s) may be added at this stage, especially if the final product is to have a liquid form. If the final product is to be a powder, they may likewise be added at this stage if desired. The liquid mixture is then homogenised, for example in two stages. The liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range between about 80°C and about 150°C for a duration between about 5 seconds and about 5 minutes, for example. This may be carried out by means of steam injection, an autoclave or a heat exchanger, for example a plate heat exchanger. Then, the liquid mixture may be cooled to between about 60°C and about 85°C for example by flash cooling. The liquid mixture may then be again homogenised, for example in two stages between about 10 MPa and about 30 MPa in the first stage and between about 2 MPa and about 10 MPa in the second stage. The homogenised mixture may then be further cooled to add any heat sensitive components, such as vitamins and mineraIs. The pH and solids content of the homogenised mixture are conveniently adjusted at this point. If the final product is to be a powder, the homogenised mixture is transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder. The powder should have a moisture content of less than about 5% by weight. The oligosaccharide(s) may also or alternatively be added at this stage by dry-mixing or by blending them in a syrup form of crystals, along with the probiotic strain(s), and the mixture is spray-dried or freeze-dried. If a liquid composition is preferred, the homogenised mixture may be sterilised then aseptically filled into suitable containers or may be first filled into the containers and then retorted. In another embodiment, the composition of the invention may be a supplement. The supplement may be in the form of tablets, capsules, pastilles or a liquid for example. The supplement may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents and gel forming agents. The supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatine of any origin, vegetable gums, lignin-sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like. Further, the supplement may contain an organic or inorganic carrier material suitable for oral or parenteral administration as well as vitamins, minerals trace elements and other micronutrients in accordance with the recommendations of Government bodies such as the USRDA. Preferred embodiments of the invention will now be described by way of the following numbered paragraphs (paras): 1. A nutritional composition comprising Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent, wherein the L. rhamnosus-modulating agent is preferably selected from the list consisting of: a combination of FOS and inulin, cello-oligosaccharides (COS), a combination of β-glucan and COS, at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium, and any combination thereof. 2. The nutritional composition of para 1, wherein the composition comprises L. rhamnosus in an amount of 1×103 to 1.5×1012 cfu/g of the composition (dry weight). 3. The nutritional composition of para 1 or para 2, wherein the L. rhamnosus has at least 99% Average Nucleotide Identity (ANI) to L. rhamnosus CGMCC1.3724 (LPR), preferably at least 99.9% ANI to L. rhamnosus CGMCC1.3724 (LPR). 4. The nutritional composition of any one of the preceding paras, wherein the L. rhamnosus comprises or consists of selected from L. rhamnosus LC705 (DSM 7061) and L. rhamnosus CGMCC1.3724 (LPR), preferably wherein the L. rhamnosus is CGMCC1.3724 (LPR). 5. The nutritional composition of any one of the preceding paras, wherein the L. rhamnosus-modulating agent is cello-oligosaccharides (COS), preferably cellobiose and/or cellotriose, more preferably cellobiose. 6. The nutritional composition of para 5, wherein the COS are derived from a plant, preferably a cereal. 7. The nutritional composition of para 5 or para 6, wherein the COS are derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. 8. The nutritional composition of any one of paras 5 to 7, wherein the COS is obtained from partial hydrolysis of a cereal fraction comprising β-glucan and/or COS. 9. The nutritional composition of any one of paras 1 to 4, wherein the L. rhamnosus- modulating agent is a combination of β-glucan and cello-oligosaccharides (COS). 10. The nutritional composition of para 9, wherein the β-glucan and/or COS is derived from a plant, preferably a cereal. 11. The nutritional composition of para 9 or para 10, wherein the β-glucan and/or COS is derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt. 12. The nutritional composition of any one of paras 9 to 11, wherein the β-glucan and/or COS is obtained from partial hydrolysis of a cereal fraction comprising β-glucan and/or COS. 13. The nutritional composition of any one of paras 5 to 12, wherein the COS comprises or consists of cellobiose and/or cellotriose. 14. The nutritional composition of any one of paras 9 to 13, wherein the weight ratio of COS:β-glucan is from 10:90 to 90:10 dry weight, preferably from 25:75 to 75:25 dry weight. 15. The nutritional composition of any one of paras 9 to 14, wherein the β-glucan is present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition. 16. The nutritional composition according to any one of the preceding paras, wherein the nutritional composition further comprises a probiotic of the genus Lactobacillus, Streptococcus, Enterococcus, Bifidobacterium and Saccharomyces. 17. The nutritional composition according to any one of paras 1 to 4, wherein the L. rhamnosus-modulating agent comprises at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium. 18. The nutritional composition according to para 17, wherein the at least one probiotic is of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium. 19. The nutritional composition according to para 17, wherein the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof. 20. The nutritional composition according to any one of paras 17 to 19, wherein the nutritional composition further comprises inulin and oligofructose. 21. The nutritional composition according to any one of the preceding paras, wherein the nutritional composition is formulated for an infant, young child and/or child. 22. The nutritional composition according to any one of the preceding paras, wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow- up infant formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier or a supplement. 23. The nutritional composition according to any one of the preceding paras for use as a medicament. 24. The nutritional composition according to any one of paras 1 to 22 for use in enhancing the immune response to infection or vaccination, for use in promoting and/or maintaining gut health, or for use in preventing and/or reducing the risk of developing an infection in an infant, young child or child. 25. The nutritional composition for use according to para 24, wherein the antibody response to infection or vaccination is enhanced in the infant, young child or child. 26. The nutritional composition for use according to any one of paras 22 to 25, wherein 150 to 450 mg/day of β-glucan and 150 to 450 mg/day of COS are administered to the infant, young child or child. 27. The nutritional composition for use according to any one of paras 23 to 26, wherein the infant, young child or child is non-responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan. 28. Use of the nutritional composition according to any one of paras 1 to 22 for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child. 29. Use of the nutritional composition according to any one of paras 1 to 22 for enhancing the growth of Bifidobacteria in the gastrointestinal tract of an infant, young child or child. 30. Use of the nutritional composition according to any one of paras 1 to 22 for increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child. 31. The use according to para 30, wherein the at least one SCFA is acetate, propionate, butyrate or any combination thereof. 32. The use according to para 30 or para 31, wherein the at least one SCFA is butyrate and wherein the infant, young child or child is non-responsive to treatment with β-glucan or with a combination of L. rhamnosus and β-glucan. 33. Use of at least one probiotic for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, wherein the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium, optionally wherein the at least one probiotic is of the genus Lactobacillus, Streptococcus and/or Bifidobacterium. 34. The use according to para 33, wherein the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof. 35. The nutritional composition for use according to any one of paras 23 to 27, or the use according to any one of paras 28 to 32, wherein 800 to 1500 mg/day of COS (preferably cellobiose and/or cellotriose, more preferably cellobiose), for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS are administered to the infant, young child or child. 36. The nutritional composition according to any one of paras 1 to 22, formulated to provide one, two, three or more servings per day, preferably one or two servings per day, more preferably two servings per day, comprising 800 to 1500 mg/day of COS, for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS, COS being preferably cellobiose and/or cellotriose, COS being more preferably cellobiose. 37. The nutritional composition according to para 36, further comprising β-glucan. Examples Materials and methods Preclinical experiment 3-week-old C57BL/6 female mice were purchased from Charles River Laboratories (L’Arbresle, France). All animal experiments were performed in accordance with institutional guidelines and Swiss federal and cantonal laws on animal protection. Mice were fed a low- fiber diet (KLIBA NAFAG diet 2122, Kliba Nafag AG, Kaiseraugst, Switzerland) at arrival and throughout the duration of the experiment. One-week post-arrival, mice received sodium acetate, sodium propionate, and sodium butyrate (Sigma-Aldrich, St. Louis, MO) in the drinking water at a final concentration of 100 mM each. Mice were monitored weekly prior to influenza infection to ensure that the SCFA mix was well-tolerated by the animals. Probiotic L rhamnosus (1x109 cfu per mouse) was diluted in sterile PBS and given by gavage every other day until the end of experiment in 200 ^l final volume. The synbiotic group received the probiotic as above along with a prebiotic blend diluted in the drinking water and changed every other day until the end of experiment (mouse adapted dose calculated from 600mg/day of cellobiose & oat b-glucan mix at 25:75 ratio equivalent to 30 mg oat ^-glucan and 10 mg Cello-oligosaccharide per mouse per day). Adult (7-week-old) female mice were anesthetized with a mixture of ketamine and xylazine (Dr. E. Graeub AG, Bern, Switzerland) and infected intranasally with 100 PFUs of the influenza virus strain PR8 (A/Puerto Rico8/34, H1N1) (Virapur LLC, San Diego, CA) in 50 ^l sterile saline. Mice were monitored daily during the first 2 weeks post-infection and weekly thereafter until the end of the experiment (day 28 post-infection). Mice were euthanized when not complying with the criteria outlined in the appropriate animal license’s scoresheet. Endogenous antibody levels were measured in serum obtained from a few drops of blood by ELISA. Ex vivo fecal fermentation study This study was conducted with Cryptobiotix SA, using their proprietary ex-vivo human Gastro Intestinal Tract (GIT) replica model and microbiota colonic incubations. NIDO milk matrices were pre-digested, and then spiked with Prebio1, LPR and one of six additional probiotic strains. These various combinations were then added to a replica colonic incubation, containing the ex-vivo faecal microbiota of 1–2-year-old toddlers. Nine arms were used in the study. These consisted of: 1. Blank (ex vivo microbiota and NIDO milk matrix) 2. Prebio1 3. Lacticaseibacillus rhamnosus LPR 4. Prebio1 & LPR 5. Prebio1 & LPR & Lacticaseibacillus paracasei ST11 6. Prebio1 & LPR & Lactobacillus johnsonii LA1 7. Prebio1 & LPR & Bifidobacterium animalis subsp. lactis BL818 8. Prebio1 & LPR & Bifidobacterium longum subsp. infantis NCC3039 9. Prebio1 & LPR & Streptococcus thermophilus ST496 Each arm was conducted in 6 replicates (n=6), with each bioreactor replicate seeded with the faecal microbiota of one of 6 individual donors. The same 6 donors were used for all arms. The study was designed this way to account for inter-individual biological variability between donors and their microbiota compositions. Donors were 1-2-year-old toddlers. The standardised protocol for food digestion simulation INFOGEST 2.0 method was used for the upper GIT digestions (see Brodkorb, A., Egger, L., Alminger, M. et al., INFOGEST static in vitro simulation of gastrointestinal food digestion. Nat Protoc 14, 991–1014 (2019). https://doi.org/10.1038/s41596-018-0119-1). Intestinal absorption and colonic incubation conditions were then conducted using Cryptobiotix’s proprietary “ex-vivo SIFR” protocols. Prebio1 (70% FOS, 30% inulin) was dosed at a final concentration of 3g/L (0.82 g/L inulin, 1.94 g/L FOS). The NIDO milk matrix as dosed at a concentration of 17.35 g/L. All probiotics, including (LPR) were dosed at a concentration of 1.5x107 cfu/mL. Colonic incubations were carried out for 24-hours, with sampling at 0 and 24 hours for: ^ pH ^ LPR plate counts ^ 16S rRNA sequencing and flow cytometry 16S rRNA sequencing was performed using Illumina sequencing, paired with flow cytometry to facilitate absolute quantification. Statistical evaluation of the treatment effects on LPR plate counts, LPR abundance and pH across 6 different donors was performed using a repeated measures ANOVA analysis (based on paired t-testing, thus accounting for fact that values are compared between samples of a given donor). The results are depicted in figures 17-19. Example 1 An example of the composition of an infant formula according to the present invention is given in the below table 1. This composition is given by way of illustration only. Table 1: Composition of the infant formula of Example 1 Nutrients per 100kcal per litre Energy (kcal) 100 670 Protein (g) 1.83 12.3 Fat (g) 5.3 35.7 Linoleic acid (g) 0.79 5.3 α-Linolenic acid (mg) 101 675 Lactose (g) 11.2 74.7 Minerals (g) 0.37 2.5 Na (mg) 23 150 K (mg) 89 590 Cl (mg) 64 430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 7 50 Mn (µg) 8 50 Se (µg) 2 13 Vitamin A (µg RE) 105 700 Vitamin D (µg) 1.5 10 Vitamin E (mg TE) 0.8 5.4 Vitamin K1 (µg) 8 54 Vitamin C (mg) 10 67 Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1.0 Niacin (mg) 1 6.7 Vitamin B6 (mg) 0.075 0.50 Folic acid (µg) 9 60 Pantothenic acid (mg) 0.45 3 Vitamin B12 (µg) 0.3 2 Biotin (µg) 2.2 15 Choline (mg) 10 67 Fe (mg) 1.2 8 l (µg) 15 100 Cu (mg) 0.06 0.4 Zn (mg) 0.75 5 COS (g) 0.06 0.8 β-glucan (g) 0.2 1.4 L. rhamnosus LPR (cfu) 1.2x108 9.3x108 Example 2 Lacticaseibacillus rhamnosus LPR (CGMCC1.3724) was retrieved from the Nestle Culture Collection (NCC; Nestlé Research, Lausanne, Switzerland). The strain was grown in a modified de Man, de Rogosa & Sharpe medium lacking carbohydrates (MRS-C) previously described by Duboux et al. (Duboux, S., et al., Sci Rep, 2021. 11(1): p. 7236). MRS-C was supplemented with 0.5% of different carbohydrates (glucose, cellobiose, cellotriose, cellotetratose, polygalacturonic acid (Sigma-Aldrich Chemie GmbH, Buchs, Switzerland) using filter sterilized (0.22 µm) stock solutions prepared at 100 g/L in water. The strain was then cultured in a microbiorector system (BioLector; m2p-labs GmbH, Baesweiler, Germany) in anaerobiosis for 48h. Growth was recorded using the integrated biomass measurement system and is depicted in Error! Reference source not found.. Results demonstrated that L. rhamnosus LPR was able to grow on different cello- oligosaccharides (COS), cellobiose and cellotriose respectively, at levels which appeared higher than glucose. The strain was however not able to grow on COS displaying higher degrees of polymerization (DP), i.e. cellotretraose and polygalacturonic acid. Example 3 To evaluate synbiotic growth, L. rhamnosus LPR was further co-supplemented with glucose and cellobiose, in a controlled fermentation system (Prodigest, Gent, Belgium). Both sugars were supplemented from filter sterilized stock solutions, which were then supplemented at 1% (final concentration) to sterile sugar-depleted nutritional medium (nutritional medium representative for the colonic environment). The strain was then inoculated (equivalent of 3E7 viable cells) and incubated for 24h under anaerobic conditions at 37°C. The resulting viable and non-viable counts (assessed by flow cytometry), pH change, as well as metabolic outputs (lactate and acetate) were then evaluated. Results demonstrated that after 24 hours of growth, a higher number of cells was achieved on cellobiose as compared to glucose. Furthermore, the cells appeared to be in a better physiological status when grown on cellobiose, as after 24h of incubation, most of them where alive, in contrary to what was observed on glucose (Error! Reference source not found.). It also appeared that the central carbon metabolic fluxes of L. rhamnosus LPR is modified when grown on cellobiose. On that substrate (and compared to glucose), lower levels of lactate and higher levels of acetate are produced by the strain (Error! Reference source not found.). Example 4 An ex-vivo fecal fermentation study was performed using the SIFR® technology (Cryptobiotix, Ghent, Belgium), simulating the colonic fermentation by the gut microbiota derived from 1.5-year-old toddlers (n = 6). For this, different mixes of cellobiose (sourced from Savanna GmbH, Elsdorf, German) and oat β-glucan (medium viscosity, from Megazyme/Neogen, USA) were supplemented at different doses (equivalent to 200 and 600 mg/day). Those mixes aimed at representing different degrees of hydrolysis of an oat-based ingredient (non- hydrolyzed = 0:100 COS:β-glucan dry weight; 25% hydrolyzed = 25:75 COS:β-glucan dry weight; 50% hydrolyzed = 50:50 COS:β-glucan dry weight; 75% hydrolyzed = 75:25 COS:β- glucan dry weight; 100% hydrolyzed = 100:0 COS:β-glucan dry weight) were co-administered with L. rhamnosusLPR (CGMCC1.3724), inoculated at an initial level of 1x107 cfu/ml. After 24h of incubation, LPR levels were assessed using LAMVAB agar (acidified MES containing vancomycin), microbiota composition was assessed by shotgun metagenomics sequencing and the resulting Short Chain Fatty Acids (SCFA, acetate, propionate, butyrate and valerate) produced by the microbiota were assessed in each combination. Results demonstrated that cellobiose was able to promote the growth of LPR, but only when sufficiently high levels were concomitantly added (equivalent dose of 800 mg per day) (Figure 20). Levels below 800 mg daily equivalent were not sufficient to increase the levels of LPR. Surprisingly, when cellobiose and β-glucan were administered as a mix, they promoted the levels of LPR after 24h of fermentation. This effect was observed using 200 and 600 mg/day dose equivalents. At a dose equivalent of 600 mg per day, the LPR promoting effect observed with a wide range of cellobiose and β-glucan mixes, namely 75:25, 50:50 and 25:75) (Error! Reference source not found.B). Surprisingly, the addition of LPR together with 600 mg daily equivalent of a mix of cellobiose:β-glucan (25:75, representing a 25% hydrolysed oat) resulted in a marked bifidogenic effect. The effect was observed first at family level, where the addition of both LPR and the cellobisoe/β-glucan mix increased Bifidobacteriaceae to higher levels than LPR or the mix alone (Error! Reference source not found.). This effect was driven by a significant increase in several Bifidobacterium species, namely B. longum, B. catenulatum and B. pseudocatenulatum (Error! Reference source not found.). Bifidobacteria are known to produce acetate as one of their metabolic product outputs. Looking at the Short Chain Fatty Acids (SCFA) produced during the incubation period, we could observe a marked increase when both LPR and the mix of cellobiose:β-glucan was administered. This increase in SCFA could be observed with two different daily dose equivalents, 200 mg and 600 mg daily equivalents, respectively (Error! Reference source not found.). The increase was mostly driven by acetate, with a contribution of propionate, while butyrate increase was strongly donor dependant (Error! Reference source not found.). Interestingly, the LPR mediated SCFA increase was independent of the ratio of cellobiose:β- glucan (75:25, 50:50 and 25:75) and the dose administered (200 mg/day, Figure 8; 600 mg/day, Figure 9) Amongst the 6 donors, two of them produced relatively high butyrate levels when β-glucan was concomitantly administered with L. rhamnosus LPR, highlighting the possible microbiome diversity found in the set of toddlers’ fecal samples tested. In particular, donors 1 and 5 were shown to produce higher levels of butyrate (7.3 and 12.8 mM, respectively) (Figure 10). Looking at the species level Operational Taxonomic Units (OTUs), the fecal samples producing higher levels of butyrate (donors 1 and 5) were characterized by the presence of higher levels of Faecalibacterium spp. and Parabacteroides distasonis (Figure 11). It is interesting to note that Parabacteroides distasonis has been proposed, depending on the context, to promote digestive health and to exert protective effects against certain diseases, like diabetes or inflammatory bowel disease (Ezeji et al., 2021, Gut Microbes, 13: 1922241). It produces as metabolic outputs hydrogen, carbon dioxide, formic acid, acetic acid, carboxylic acid and succinic acid, the latter being proposed as an inflammatory regulation signal (Ezeji et al., 2021, Gut Microbes, 13: 1922241). On the other hand, members of the Faecalibacterium spp. are known to consume acetate to produce butyrate and other bioactive anti-inflammatory molecules (Sokol et al., 2008, Proc Natl Acad Sci USA, 105:16731-6). Butyrate produced by members of the human microbiome is an important bioactive molecule, impacting the homeostatic regulation of the digestive ecosystem in health and inflammatory bowel diseases (Gasaly et al., 2021, Int J Mol Sci, 22: 3061). Out of the 6 toddler fecal samples we tested, 2 of them (donors 1 and 5) produced butyrate as soon as β- glucan was present in the administered mix together with LPR (Figure 12 A). In the other 4 toddlers’ fecal samples, addition of cellobiose or β-glucan alone (600 mg equivalent doses) together with LPR did not increase the levels of butyrate produced. However, in those 4 samples, administering a mix of cellobiose and β-glucan together with LPR increased significatively the levels of butyrate produced (Figure 12 B). The study shows that a combination of cellobiose, β-glucan and LPR synergistically increases the levels of LPR compared to any of these components alone or any two components taken together. This effect was observed to be independent of the dosage of cellobiose or β-glucan. The combination of cellobiose, β-glucan and LPR also provided a marked bifidogenic effect and increase in SCFA levels, independent of both the dose of cellobiose and β-glucan and the ratio of COS:β-glucan. Taken together, the data suggest that a selective mix of cellobiose/beta-glucan together with LPR may augment SCFA levels, and in particular butyrate levels, within the gastrointestinal tract of all toddlers independent of their Faecalibacterium spp. and Parabacteroides distasonis levels. Enhancing butyrate levels in the gastrointestinal tract is relevant for health benefits as butyrate can promote protective immune responses within the intestine and beyond (including the lungs). Overall, the data show that the combination of cellobiose, β-glucan and LPR increased the levels of LPR, Bifidobacteria and SCFAs, each of which are well-known to have health benefits in the intestine and beyond (including the lungs). Example 5 A preclinical experiment was set up (Figure 13) to evaluate whether addition of LPR together with a mix of cellobiose:β-glucan (25:75, representing a 25% hydrolysed oat) increases endogenous antibody production and its impact on protection against flu infection. This mix was shown to increase short chain fatty acids (Figure 6B) known to promote antibody responses. Three weeks after nutritional interventions, SCFA mix increased endogenous serum immunoglobulin G (IgG) levels (Figure 14A and 14B), as previously demonstrated by Kim et al. (Kim et al., 2016, Cell Host & Microbe, 20: 202–214). Surprisingly, both synbiotic and probiotic supplementation significantly increased serum IgG levels vs. SCFA mix with synbiotic demonstrating the highest levels of serum IgG when measuring changes in absolute levels of serum IgG (Figure 14A) and fold change in serum IgG expression (Figure 14B). Following low dose flu infection, there was a gradual increase in disease score from day6 post infection with peak disease score observed at day9 post infection (Figure 15A). While reduced disease score was observed in all 3 groups (SCFA mix, probiotic and synbiotic), synbiotic supplementation resulted in the lowest disease score at the peak of infection (day9 post infection) with fastest recovery from infection characterized by the significant decrease in disease score (only observed when comparing synbiotic vs. control), recovery of body temperature (Figure 15B) and body weight (Figure 15C). Taken together, the results demonstrate synbiotic supplemented animals with the highest levels of serum IgG coped best with the flu infection and outperformed SCFA and probiotic treated group. Correlation analysis (Figure 16) confirmed these findings demonstrating an inverse relationship between levels of serum IgG (measured prior to infection) and disease score at the peak of infection (day9 post infection). The results suggest that the synbiotic mix of LPR and cellobiose/beta-glucan can protect the host against infections by augmenting protective immune responses including the total antibody levels (prior to infection) which results in a less severe infection and faster recovery upon exposure to flu infection. Example 6 An ex-vivo fecal fermentation study was performed using the SIFR® technology (Cryptobiotix, Ghent, Belgium) as described herein above, modifications as described hereafter. Prior to colonic fermentation simulation, food digestion simulation INFOGEST 2.0 method was used (see Brodkorb, A., Egger, L., Alminger, M. et al., INFOGEST static in vitro simulation of gastrointestinal food digestion. Nat Protoc 14, 991–1014 (2019). https://doi.org/10.1038/s41596-018-0119-1) for the upper GIT digestions of the formula matrices. Intestinal absorption and colonic incubation conditions were then conducted using Cryptobiotix’s proprietary “ex-vivo SIFR” protocols. Prebio1 (70% FOS, 30% inulin) was dosed at a final concentration of 3g/L (0.82 g/L inulin, 1.94 g/L FOS). The NIDO milk matrix as dosed at a concentration of 17.35 g/L. All probiotics, including (LPR) were dosed at a concentration of 1.5x107 cfu/mL. Levels of LPR were measured using 2 methods: plate counts for viable L. rhamnosus cultures, and 16S rRNA sequencing paired with flow cytometry. By both measures, at 24 hours, LPR was significantly increased by the presence of Prebio1, as compared to the LPR-only control (Figures 17 and 18). Furthermore, LPR levels at 24 hours were significantly increased, beyond that achieved with LPR and Prebio1, with the co-supplementation of LA1, BL818, LMG 11588 and ST11 (Figures 17 and 18). It was noted that for ST11 as the secondary probiotic, significantly increased LPR (compared to the combination of LPR and prebiotic alone) was only observed in the 16S sequencing data, and not the plate counts. Conversely, for LMG 11588 significantly increased LPR (compared to the combination of LPR and prebiotic alone) was only observed in the plate counts, and not the 16S sequencing data. For all other strains of interest (BL818 and LA1), significantly increased LPR (compared to the combination of LPR and prebiotic alone) was observed both in the plate counts and 16S data. Significant decreases in pH were observed in all arms, compared to the blank control, except for LPR alone (Figure 19). As such, the presence of LPR alone had no significant impact on pH. Conversely, the inclusion of Prebio1 significantly decreased pH in all arms where it was present, including the combination of LPR and the prebiotic alone. Furthermore, the combination of LPR and the prebiotic with LA1 or BL818 resulted in a significant decrease in pH compared to compared to the combination of LPR and prebiotic alone. In the cases of LMG 11588 and ST11 as the secondary probiotics, decreases in pH were also observed, but not reaching significance. Based on these findings, a correlation was identified between increased LPR abundance and decreased pH. The optimal pH range for L. rhamnosus growth is between 4.5 and 6.4. As such, the enhanced acidification, induced by metabolic activity of these key secondary strains, creates a more acidic environment, closer to the median of the optimal pH range for L. rhamnosus, and thus may allow LPR to proliferate more successfully. This enhanced acidification is likely mediated by increased organic acid production by the secondary strains successfully catabolising longer-chain FOS molecules and/or inulin, where L. rhamnosus cannot. As such, the conclusion drawn from these findings is that the incorporation of certain additional strains of probiotics to the synbiotic combination of L. rhamnosus LPR and Prebio1 (FOS-inulin), can increase the survival and growth of LPR in an infant gut model. While Prebio1 certainly has a far greater effect in terms of increasing LPR abundance, co- supplementation with these key strains (LA1, BL818 and LMG 11588) can be used to enhance this effect. This increased abundance may in turn lead to an increased effect in terms of the benefits associated with LPR. In turn, the addition of this second probiotic strain, which is also capable of utilising at least some components of Prebio1, can also provide its own associated health benefits. The findings of this work may enable the generation of new combinations of probiotics for compositions. The finding that addition of a second probiotic strain further enhances LPR survival and engraftment in an ex-vivo toddler gut microbiota model, and therefore the beneficial effects of LPR to the host, enables improved health benefits.
Claims 1. A nutritional composition comprising Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent, wherein the L. rhamnosus-modulating agent is preferably selected from the list consisting of: a combination of FOS and inulin, cello-oligosaccharides (COS), a combination of β-glucan and COS, at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium, and any combination thereof. 2. The nutritional composition of claim 1, wherein the L. rhamnosus has at least 99% Average Nucleotide Identity (ANI) to L. rhamnosus CGMCC1.3724 (LPR) or wherein the L. rhamnosus is LPR. 3. The nutritional composition of claim 1 or claim 2, wherein the L. rhamnosus- modulating agent comprises or consists of cello-oligosaccharides (COS), preferably cellobiose and/or cellotriose, more preferably cellobiose; preferably wherein the L. rhamnosus- modulating agent is present in an amount ranging from 0.20 to 12.10 g/100g dry weight of composition, more preferably from 1.29 to 12.10 g/100g dry weight of composition, even more preferably from 1.29 to 1.61 g/100g dry weight of nutritional composition. 4. The nutritional composition of any one of the preceding claims, wherein the L. rhamnosus-modulating agent comprises or consists of a combination of β-glucan and cello- oligosaccharides (COS), wherein the cello-oligosaccharides (COS) is preferably cellobiose and/or cellotriose, more preferably cellobiose. 5. The nutritional composition of claim 3 or claim 4, wherein the β-glucan and/or COS is derived from a plant, preferably wherein the β-glucan and/or COS is derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt, preferably comprising glucose residues which are linked by both β-(1–4) and β-(1–3) glycosidic bonds, such as having a linear (1,3;1,4) β-glucan structure. 6. The nutritional composition of claim 5, wherein the β-glucan and/or COS is obtained from partial hydrolysis of a cereal fraction comprising β-glucan and/or COS, preferably comprising glucose residues which are linked by both β-(1–4) and β-(1–3) glycosidic bonds, such as having a linear (1,3;1,4) β-glucan structure. 7. The nutritional composition of any one of claims 4 to 6, wherein the weight ratio of COS:β-glucan is from 10:90 to 90:10 dry weight, preferably from 25:75 to 75:25 dry weight, or from 50:50 to 25:75 dry weight. 8. The nutritional composition of any one of claims 3 to 7, wherein the β-glucan is present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.85 g/100g dry weight of composition. 9. The nutritional composition according to claim 1 or claim 2, wherein the L. rhamnosus-modulating agent comprises at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium, optionally wherein the at least one probiotic is of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium. 10. The nutritional composition according to claim 9, wherein the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof. 11. The nutritional composition according to claim 9 or claim 10, wherein the nutritional composition further comprises inulin and oligofructose. 12. The nutritional composition according to any one of the preceding claims, wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier or a supplement. 13. The nutritional composition according to any one of the preceding claims, formulated to provide one, two, three or more servings per day, preferably one or two servings per day, more preferably two servings per day, comprising 800 to 1500 mg/day of COS, for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS, COS being preferably cellobiose and/or cellotriose, COS being more preferably cellobiose. 14. The nutritional composition according to claim 13, further comprising β-glucan. 15. The nutritional composition according to any one of the preceding claims for use as a medicament. 16. The nutritional composition according to any one of claims 1 to 14 for use in enhancing the immune response to infection or vaccination, for use in promoting and/or maintaining gut health, or for use in preventing and/or reducing the risk of developing an infection in an infant, young child or child. 17. Use of the nutritional composition according to any one of claims 1 to 14 for enhancing the growth of L. rhamnosus in the gastrointestinal tract, for enhancing the growth of Bifidobacteria in the gastrointestinal tract, or for increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child. 18. Use of at least one probiotic for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, wherein the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium, optionally wherein the at least one probiotic is of the genus Lactobacillus, Streptococcus and/or Bifidobacterium. 19. The nutritional composition for use according to claim 15 or claim 16 or the use according to claim 17, wherein 800 to 1500 mg/day of COS (preferably cellobiose and/or cellotriose, more preferably cellobiose), for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS are administered to the infant, young child or child.
Abstract The present invention relates to a combination of Lacticaseibacillus rhamnosus and an L. rhamnosus modulating agent, or nutritional compositions comprising the combination. The present invention also relates to uses of the combination, or of a nutritional composition comprising the combination.

Claims

Claims
1. A nutritional composition comprising Lacticaseibacillus rhamnosus and an L. rhamnosus-modulating agent, wherein the L. rhamnosus-modulating agent is preferably selected from the list consisting of: a combination of FOS and inulin, cello-oligosaccharides (COS), a combination of -glucan and COS, at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium, and any combination thereof.
2. The nutritional composition of claim 1, wherein the L. rhamnosus has at least 99% Average Nucleotide Identity (ANI) to L. rhamnosus CGMCC1.3724 (LPR) or wherein the L. rhamnosus is LPR.
3. The nutritional composition of claim 1 or claim 2, wherein the L. rhamnosus- modulating agent comprises or consists of cello-oligosaccharides (COS), preferably cellobiose and/or cellotriose, more preferably cellobiose; preferably wherein the L. rhamnosus- modulating agent is present in an amount ranging from 0.20 to 12.10 g/lOOg dry weight of composition, more preferably from 1.29 to 12.10 g/lOOg dry weight of composition, even more preferably from 1.29 to 1.61 g/lOOg dry weight of nutritional composition.
4. The nutritional composition of any one of the preceding claims, wherein the L. rhamnosus-modulating agent comprises or consists of a combination of -glucan and cello- oligosaccharides (COS), wherein the cello-oligosaccharides (COS) is preferably cellobiose and/or cellotriose, more preferably cellobiose.
5. The nutritional composition of claim 3 or claim 4, wherein the -glucan and/or COS is derived from a plant, preferably wherein the -glucan and/or COS is derived from a cereal selected from oat, wheat, rye, maize, quinoa, millet, buckwheat, rice, wild rice, or spelt, preferably comprising glucose residues which are linked by both |3-(l-4) and |3-(l-3) glycosidic bonds, such as having a linear (1,3;1,4) -glucan structure.
6. The nutritional composition of claim 5, wherein the -glucan and/or COS is obtained from partial hydrolysis of a cereal fraction comprising -glucan and/or COS, preferably comprising glucose residues which are linked by both p-(l— 4) and p-(l— 3) glycosidic bonds, such as having a linear (1,3;1,4) -glucan structure.
7. The nutritional composition of any one of claims 4 to 6, wherein the weight ratio of COS:|3-glucan is from 10:90 to 90:10 dry weight, preferably from 25:75 to 75:25 dry weight, or from 50:50 to 25:75 dry weight.
8. The nutritional composition of any one of claims 3 to 7, wherein the -glucan is present in an amount ranging from 0.15 to 0.85 g/lOOg dry weight of composition and/or the COS are present in an amount ranging from 0.15 to 0.85 g/lOOg dry weight of composition.
9. The nutritional composition according to claim 1 or claim 2, wherein the L. rhamnosus-modulating agent comprises at least one probiotic which is a lactic acid bacterium and/or a Bifidobacterium, optionally wherein the at least one probiotic is of the genus Lactobacillus, Lacticaseibacillus, Limosilactobacillus, Streptococcus and/or Bifidobacterium.
10. The nutritional composition according to claim 9, wherein the at least one probiotic is selected from Lacticaseibacillus paracasei NCC 2461, Lactobacillus johnsonii NCC 533, Bifidobacterium animalis subsp. lactis NCC 2818, Bifidobacterium longum subsp. longum NCC 2705, Bifidobacterium longum subsp. infantis LMG 11588, Streptococcus thermophilus NCC 2496, and any combination thereof.
11. The nutritional composition according to claim 9 or claim 10, wherein the nutritional composition further comprises inulin and oligofructose.
12. The nutritional composition according to any one of the preceding claims, wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier or a supplement.
13. The nutritional composition according to any one of the preceding claims, formulated to provide one, two, three or more servings per day, preferably one or two servings per day, more preferably two servings per day, comprising 800 to 1500 mg/day of COS, for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS, COS being preferably cellobiose and/or cellotriose, COS being more preferably cellobiose.
14. The nutritional composition according to claim 13, further comprising p-glucan.
15. The nutritional composition according to any one of the preceding claims for use as a medicament.
16. The nutritional composition according to any one of claims 1 to 14 for use in enhancing the immune response to infection or vaccination, for use in promoting and/or maintaining gut health, or for use in preventing and/or reducing the risk of developing an infection in an infant, young child or child.
17. Use of the nutritional composition according to any one of claims 1 to 14 for enhancing the growth of L. rhamnosus in the gastrointestinal tract, for enhancing the growth of Bifidobacteria in the gastrointestinal tract, or for increasing the levels of at least one short chain fatty acid (SCFA) in the gastrointestinal tract of an infant, young child or child.
18. Use of at least one probiotic for enhancing the growth of L. rhamnosus in the gastrointestinal tract of an infant, young child or child, wherein the at least one probiotic is a lactic acid bacterium and/or a Bifidobacterium, optionally wherein the at least one probiotic is of the genus Lactobacillus, Streptococcus and/or Bifidobacterium.
19. The nutritional composition for use according to claim 15 or claim 16 or the use according to claim 17, wherein 800 to 1500 mg/day of COS (preferably cellobiose and/or cellotriose, more preferably cellobiose), for example 800 to 1250 mg/day or 1000 to 1500 mg/day of COS are administered to the infant, young child or child.
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