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WO2018150077A1 - Biomarqueurs de la bétaïne pour l'état nutritionnel, le régime nutritionnel, le métabolisme endogène ou le risque de maladies cardiovasculaires ou métaboliques - Google Patents

Biomarqueurs de la bétaïne pour l'état nutritionnel, le régime nutritionnel, le métabolisme endogène ou le risque de maladies cardiovasculaires ou métaboliques Download PDF

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Publication number
WO2018150077A1
WO2018150077A1 PCT/FI2017/050099 FI2017050099W WO2018150077A1 WO 2018150077 A1 WO2018150077 A1 WO 2018150077A1 FI 2017050099 W FI2017050099 W FI 2017050099W WO 2018150077 A1 WO2018150077 A1 WO 2018150077A1
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Prior art keywords
betaine
subject
sample
compounds
biological sample
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Inventor
Kati HANHINEVA
Jenna PEKKINEN
Olli KÄRKKÄINEN
Jukka LEPPÄNEN
Seppo AURIOLA
Marko Lehtonen
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Afekta Technologies Oy
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Afekta Technologies Oy
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6806—Determination of free amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6848—Methods of protein analysis involving mass spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers

Definitions

  • Betaine biomarkers for nutritional status, nutritional regimen, endogenous metabolism, or risk of cardiovascular or metabolic diseases are betaine biomarkers for nutritional status, nutritional regimen, endogenous metabolism, or risk of cardiovascular or metabolic diseases
  • a method for assessing or aiding in the assessment of nutritional status and/or effectiveness of a nutritional regimen, endogenous metabolism, and/or a risk of developing a cardiovascular and/or metabolic disease in a subject comprises analysing a biological sample from the subject to determine the level (s) of one or more betaine compounds selected from alanine betaine, pipecolic acid betaine, norvaline betaine, 5-aminovaleric acid betaine, 4- aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine in the biological sample.
  • the method may further comprise comparing the level (s) of the one or more betaine compounds in the biological sample to a reference value or to the level (s) of the one or more betaine compounds in a control sample in order to assess the nutritional status and/or the effectiveness of the nutritional regimen the endogenous metabolism, and/or the risk of developing the cardiovascular and/or metabolic disease in the subject.
  • Figure 1 illustrates identification of amino-acid derived betaines in the plasma samples.
  • 20 V MSMS fragmentation patterns and abundance in mouse plasma are shown for: a, 5- aminovaleric acid betaine, b, alanine betaine, c, valine betaine, d, phenylalanine betaine, e, pipecolic acid betaine, and f, glycine betaine.
  • HF high-fat controls
  • Rl/2 rye bran groups 1 and 2
  • Al/4 aleurone groups 1 and 4.
  • Figure 2 shows the abundances of betaines in fasting plasma samples from three human dietary intervention trials (a, c, e, g, i, k, m, o, q) and the correlations of the levels of the abundances with glycinde betaine abundance (b, d, f, h, j, 1, n, p, r) .
  • Kuopio HG intervention had three dietary groups: A, healthy diet including whole grains; B, whole grain rich diet; C, control diet. s. Correlations of grain intake with plasma levels of some of the betainized compounds in the intervention trials.
  • FIG 3 shows a. betaines in plasma of conventional (MPF) and germ free (GF) mice, b. Betaines in the colon contents of the mice fed with bran enriched diets, c. betaines in the in vitro 24-h fermentation model with human microbiota incubated with rye bran fractions, d. betaines in tissue matrices from the intestinal tract of the mouse fed with bran enriched feed.
  • FBL faecal background
  • Rl rye bran
  • R2 bioprocessed rye bran.
  • Figure 4 illustrates betaines in tissues and effects of 5-AVAB to the energy metabolism of neonatal mouse cardiomyocytes .
  • BET glycine betaine.
  • betainized compounds have now been found to be associated with endogenous metabolism.
  • the fact that these betainized compounds have now been found in human blood and tissues indicates that they may be produced endogenously , e.g. in human cells (or cells of other subjects) or by gut microbiota, rather than simply being obtained from nutritional sources and excreted e.g. in urine.
  • the betainized compounds may remain in plasma and tissues for a prolonged time period, so that the changes may be observed e.g. after fasting, or after a change in lifestyle, including nutrition. They therefore indicate a potential metabolic role in endogenous metabolism in plasma and various tissues. They may also be predictive biomarkers of metabolic disorders, such as cardiometabolic disorders.
  • Certain betainized compounds described in this specification have not earlier been identified in blood or tissues and/or as potential biomarkers in humans.
  • Betainized compounds may also be used as biomarkers in personalized nutrition, in particular within dietary regimens or schemes involving high intake of whole grains and/or products derived from them.
  • Nutritional regimen may affect their levels; for instance, glycine betaine obtainable from nutritional sources may serve as a precursor for them or may induce their production in humans.
  • Individual subjects may exhibit different responses to a particular diet or to particular components of a diet, and therefore universal dietary recommendations may have limited utility. Based on the method according to one or more aspects or embodiments described in this specification, it may be possible to assess and/or monitor the nutritional status of a subject or the effectiveness of a nutritional regimen and, based on the assessment, to take appropriate action to improve the nutritional status, the nutritional regimen or to treat the subject.
  • the nutritional regimen may include intake of whole grains and/or products derived from them.
  • the nutritional regimen may include high or low intake of whole grains and/or products derived from them.
  • the nutritional regimen may include intake of foodstuffs rich in glycine betaine.
  • the nutritional regimen may include high or low intake of foodstuffs rich in glycine betaine. Examples of foodstuffs rich in glycine include whole grains, beetroot (also known as red beet), and quinoa, but other foodstuffs may also be contemplated.
  • a method for assessing or aiding in the assessment of nutritional status and/or effectiveness of a nutritional regimen, endogenous metabolism, and/or a risk of developing a cardiovascular or metabolic disease, in a subject comprising:
  • analysing a biological sample from the subject to determine the level (s) of one or more betaine compounds selected from alanine betaine, pipecolic acid betaine, norvaline betaine, 5-aminovaleric acid betaine, 4-aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine in the biological sample; and comparing the level (s) of the one or more betaine compounds in the biological sample to a reference value or to the level (s) of the one or more betaine compounds in a control sample in order to assess the endogenous metabolism, the risk of developing the cardiovascular or metabolic disease, the nutritional status or the effectiveness of the nutritional regimen in the subject.
  • betaine compounds selected from alanine betaine, pipecolic acid betaine, norvaline betaine, 5-aminovaleric acid betaine, 4-aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine in the biological sample
  • a method for determining the level (s) of one or more betaine compounds in a biological sample from a subject comprising determining the level (s) of the one or more betaine compounds in the biological sample, wherein the one or more betaine compounds is/are selected from alanine betaine, pipecolic acid betaine, norvaline betaine, 5-aminovaleric acid betaine, 4-aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine.
  • betaine compound or “betainized compound” may refer to a compound having a positively charged cationic functional group, for example a quaternary ammonium group, and a carboxylate group.
  • the carboxylate group may or may not be adjacent to the cationic group.
  • the quaternary ammonium group may, in one embodiment, be trimethylated .
  • Betaine compounds may include alanine betaine, pipecolic acid betaine, norvaline betaine, 5-aminovaleric acid betaine, 4-aminovaleric acid betaine, valine betaine, phenylalanine betaine, and/or tryptophan betaine.
  • subject may refer to any animal, or a mammal, such as a human. It may also refer to a non-human primate, a dog, a cat, a horse, a sheep, a goat, a cow, a rabbit, a pig and/or a rodent, such as a mouse or a rat.
  • the subject may be an individual subject. In an embodiment, the subject is a human subject.
  • sample or “biological sample” may refer to any biological sample obtained from a subject or a group or population of subjects.
  • the biological sample may be a fasting sample, i.e. a sample obtainable after a period of fasting, e.g. after a period of at least 8 hours.
  • the biological sample may comprise or be a blood sample, such as a plasma sample, a serum sample, a fasting blood sample, a fasting plasma sample, a fasting serum sample, or a fraction obtainable therefrom.
  • the biological sample may, additionally or alternatively, comprise or be a sample or one or moreother body fluids or biofluids, for example a urine sample, a saliva sample, a bile sample, a tear sample and/or a spinal fluid sample.
  • the biological sample may comprise or be, additionally or alternatively, a tissue sample, such as a liver sample, a pancreas sample, a heart sample, a muscle sample, a gastrointestinal wall sample, an adipose tissue sample, or a fraction obtainable therefrom.
  • the adipose tissue sample may comprise or be a subcutaneous adipose tissue (SAT), a visceral adipose tissue (VAT) and/or brown adipose tissue (BAT) sample.
  • the method may comprise obtaining a biological sample from the subject prior to analysing the biological sample. Taking a blood sample or a tissue sample of a subject or patient is a part of normal clinical practice.
  • the collected blood or tissue sample can be prepared and serum or plasma can be separated using techniques well known to a skilled person. Methods for separating one or more fractions from biological samples, such as blood samples or tissue samples, are also available to a skilled person.
  • the term "fraction" may, in the context of this specification, also refer to a portion or a component of the biological sample separated according to one or more physical properties, for instance solubility, hydrophilicity or hydrophobicity, or molecular size.
  • level of one or more betaine compounds may, in the context of this specification, refer to the absolute or relative amount or concentration of the betaine compound (s) in the biological sample.
  • the level (s) of one or more betaine compound (s) may refer to the total level of the one or more betaine compound(s), combined, and/or to individual levels of the one or more betaine compound (s) .
  • the wording "compared to a control sample” or “comparing to a control sample” as used in this specification may be understood as including embodiments in which control samples are actually analysed in respect of one or more betaine compounds of interest, i.e.
  • the above wording may also include embodiments in which the corresponding information on the level (s) or concentration ( s ) of the one or more betaine compounds is merely taken from the literature, or has been previously determined, calculated or extrapolated, or is yet to be determined, calculated or extrapolated.
  • a reference level or reference value may refer to a level or value that is indicative of a particular status of endogenous metabolism, a cardiovascular and/or metabolic disease, nutritional status, and/or the effectiveness of a nutritional regimen.
  • the reference level or reference value may be obtained from a control sample, e.g. a control sample described above.
  • the reference level or reference value may be predetermined, for instance determined, calculated or extrapolated prior to analysing the level (s) of the one or more betaine compounds in the biological sample.
  • the reference level or reference value of one or more betaine compound (s) may be predetermined as an average level or a target level of the one or more betaine compound (s) in a control sample, control subject, control group, control population, or one or more samples obtained therefrom.
  • a suitable reference level or reference value may be selected based on various criteria. For instance, for assessing or aiding in the assessment of a nutritional status or the effectiveness of a nutritional regimen, the reference level or value may be a reference level or value in a control subject, group or population that has a suitable or desired nutritional status and/or that has been subjected to a particular nutritional regimen or diet, or in one or more samples obtained therefrom. For assessing or aiding in the assessment of a risk of developing a cardiovascular and/or metabolic disease, i.e. detecting and/or diagnosing a cardiovascular and/or metabolic disease, the reference level or value may be a reference level or value in or obtained from a control sample, control subject, group or population that e.g.
  • the reference value may be determined from a comparative biological sample, such as the same body fluid or the same tissue in a control subject, group or population from which the biological sample of the individual subject is obtained.
  • control sample is from a healthy individual or a generalized population of healthy individuals.
  • the method is a method for assessing or aiding in the assessment of endogenous metabolism in a human subject.
  • endogenous metabolism may refer to metabolism originating in or from within the subject (as opposed to metabolites, such as betaine compounds, being merely taken into the subject from outside, e.g. by nutrition), such as the production of metabolites produced by or within the subject.
  • Endogenous metabolites may be produced in the subject, and may include metabolites produced by the colonic microbiota in the subject.
  • the endogenous metabolism may, alternatively or additionally, comprise or refer to metabolism by colonic microbiota in the subject.
  • the endogenous metabolism may comprise or refer to at least one of endogenous metabolic homeostasis, methylation homeostasis, energy metabolism, methylation metabolism, cellular respiration, or mitochondrial beta-oxidation.
  • the method is a method for assessing or aiding in the assessment of a risk of developing a cardiovascular and/or metabolic disease in a human subject.
  • the probability that the subject will progress from being normal to having a cardiovascular and/or metabolic disease may be determined, or the assessment may assist in the determination of the risk of developing a cardiovascular and/or metabolic disease.
  • Metabolic and cardiovascular diseases may jointly be referred to as cardiometabolic diseases.
  • the cardiovascular disease may comprise at least one of a coronary artery disease, stroke, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, heart arrhythmia, valvular heart disease, carditis, aortic aneurysm, peripheral artery disease, or venous thrombosis.
  • Coronary artery disease may include e.g. angina and/or myocardial infarction.
  • the cardiovascular disease comprises at least one of a coronary artery disease, stroke, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, heart arrhythmia, valvular heart disease, carditis, aortic aneurysm, peripheral artery disease, and venous thrombosis.
  • the metabolic disease may comprise at least one of type 2 diabetes, metabolic syndrome, insulin resistance or prediabetes .
  • the metabolic disease comprises at least one of type 2 diabetes, metabolic syndrome, insulin resistance, and prediabetes.
  • the method is a method for assessing or aiding in the assessment of nutritional status and/or effectiveness of a nutritional regimen in the subject.
  • the nutritional regimen may refer e.g. to a diet and/ or regimen of intake of at least one dietary supplement or dietary item.
  • the at least one dietary supplement or dietary item may comprise whole grains and/or products derived from them. Additionally or alternatively, at least one dietary supplement or dietary item may comprise one or more foodstuffs rich in glycine betaine.
  • the one or more betaine compounds may be elevated in a subject, such as a human, after whole grain rich dietary interventions.
  • the one or more betaine compounds may also be elevated in a subject, such as a human, after glycine betaine supplementation.
  • Dietary betaine compounds such as glycine betaine, may be a source, e.g. a precursor, for one or more betaine compounds according to one or more embodiments described in this specification. Therefore nutrition may have an effect on their level (s) in the subject.
  • Dietary betaine compounds, such as glycine betaine may, alternatively or additionally, induce the production of the one or more betaine compounds according to one or more embodiments described in this specification .
  • a decreased or increased (i.e. compared to the control sample or to a reference value) level or levels of the one or more betaine compounds in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a decreased or increased level or levels of the one or more betaine compounds in the biological sample from the subject may be indicative of a particular nutritional status or nutritional regimen.
  • An example of such a nutritional status or nutritional regimen may be the amount of whole grain intake, so that an increased level (s) of the one or more betaine compounds in the biological sample may be indicative of high whole grain intake or of a diet high in whole grain.
  • a decreased level or levels of the one or more betaine compounds in the biological sample from the subject may be indicative of a metabolic and/or cardiovascular disease or of an increased risk of developing a cardiovascular and/or metabolic disease.
  • a decreased level or levels of the one or more betaine compounds may, in some cases, also be at least partially indicative of a diet devoid of or low in whole grain and therefore not necessarily always indicative of a cardiovascular and/or metabolic disease.
  • a level or levels that is/are decreased or increased at least 1.1-fold in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a level or levels that is/are decreased at least 1.1-fold in the biological sample from the subject may be indicative of a cardiovascular and/or metabolic disease or of an increased risk of developing a cardiovascular and/or metabolic disease.
  • a level or levels that is/are decreased or increased at least 1.1-fold in the biological sample from the subject may be indicative of a particular nutritional status or the effectiveness of a nutritional regimen.
  • the indicative difference (decrease or increase in the level (s)) may depend e.g. on the type of the biological sample. For example, differences in the level (s) in fasting plasma samples may be relatively small, or smaller than e.g. in tissue samples.
  • a level or levels that is/are decreased or increased at least 1.2-fold in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a level or levels that is/are decreased at least 1.2-fold in the biological sample from the subject may be indicative of a cardiovascular and/or metabolic disease or of an increased risk of developing a cardiovascular and/or metabolic disease.
  • a level or levels that is/are decreased or increased at least 1.2-fold in the biological sample from the subject may be indicative of a particular nutritional status or the effectiveness of a nutritional regimen.
  • a level or levels that is/are decreased or increased at least 1.3-fold in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a level or levels that is/are decreased at least 1.3-fold in the biological sample from the subject may be indicative of a cardiovascular and/or metabolic disease or of an increased risk of developing a cardiovascular and/or metabolic disease.
  • a level or levels that is/are decreased or increased at least 1.3-fold in the biological sample from the subject may be indicative of a particular nutritional status or the effectiveness of a nutritional regimen.
  • a level or levels that is/are decreased or increased at least 1.4-fold in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a level or levels that is/are decreased at least 1.4-fold in the biological sample from the subject may be indicative of a cardiovascular and/or metabolic disease or of an increased risk of developing a cardiovascular and/or metabolic disease.
  • a level or levels that is/are decreased or increased at least 1.4-fold in the biological sample from the subject may be indicative of a particular nutritional status or the effectiveness of a nutritional regimen.
  • a level or levels that is/are decreased or increased at least 1.5-fold in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a level or levels that is/are decreased at least 1.5-fold in the biological sample from the subject may be indicative of a cardiovascular and/or metabolic disease or of an increased risk of developing a cardiovascular and/or metabolic disease.
  • a level or levels that is/are decreased or increased at least 1.5-fold in the biological sample from the subject may be indicative of a particular nutritional status or the effectiveness of a nutritional regimen.
  • a level or levels that is/are decreased or increased at least 2-fold in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a level or levels that is/are decreased at least 2-fold in the biological sample from the subject may be indicative of a cardiovascular and/or metabolic disease or of an increased risk of developing a cardiovascular and/or metabolic disease.
  • a level or levels that is/are decreased or increased at least 2-fold in the biological sample from the subject may be indicative of a particular nutritional status or the effectiveness of a nutritional regimen.
  • a level or levels that is/are decreased or increased at least 2.5-fold in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a level or levels that is/are decreased at least 2.5-fold in the biological sample from the subject may be indicative of a cardiovascular and/or metabolic disease or of an increased risk of developing a cardiovascular and/or metabolic disease.
  • a level or levels that is/are decreased or increased at least 2.5-fold in the biological sample from the subject may be indicative of a particular nutritional status or the effectiveness of a nutritional regimen.
  • a level or levels that is/are decreased or increased at least 3-fold in the biological sample from the subject may be indicative of a particular status of endogenous metabolism.
  • a level or levels that is/are decreased at least 3-fold in the biological sample from the subject may be indicative of a cardiovascular and/or metabolic disease or of an increased risk of developing a cardiovascular and/or metabolic.
  • a level or levels that is/are decreased or increased at least 3-fold in the biological sample from the subject may be indicative of a particular nutritional status or the effectiveness of a nutritional regimen.
  • the one or more betaine compounds may be differentially present (increased or decreased) in a biological sample from a subject or a group of subjects having a first phenotype as compared to a subject or a group of subjects having a second phenotype .
  • the one or more betaine compounds comprise (s) at least one betaine compound selected from alanine betaine, norvaline betaine, 5-aminovaleric acid betaine, 4- aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine.
  • the one or more betaine compounds comprise (s) or is 5-aminovaleric acid betaine.
  • 5-amino valeric acid betaine may accumulate in particular in the heart tissue and other metabolically active tissues, including muscle and brown adipose tissue. It also has structural similarity with meldonium, a drug used to treat coronary artery disease. 5-AVAB may therefore have an inhibitive effect on mitochondrial beta- oxidation similar to meldonium, for instance via inhibition of carnitine-dependent transportation of fatty acids. Increased (or decreased) levels of 5-AVAB may be indicative of endogenous metabolism, including e.g. a shift in energy homeostasis. 5-AVAB may also have other added utility. For example, it may be relatively abundant in various biological samples.
  • the one or more betaine compounds comprise (s) at least one of valine/norvaline betaine or alanine betaine.
  • These betaine compounds may be indicative of a particular nutritional regimen, such as a nutritional regimen high in bran.
  • Valine and norvaline betaine being very similar chemically and having the same mass/charge ratio, may in some embodiments be detected and determined simultaneously.
  • the term "valine/norvaline betaine” may, in some embodiments, therefore refer to valine betaine, norvaline betaine or to both valine betaine and norvaline betaine.
  • the biological sample may be analysed using at least one of liquid chromatography, mass spectrometry, 1 H-NMR, or any combinations thereof.
  • the biological sample is analysed using one or more techniques selected from liquid chromatography, mass spectrometry, 1 H-NMR, and any combinations thereof.
  • the liquid chromatography (LC) may be hydrophilic interaction liquid chromatography (HILIC) , which is well suited for the analysis of betainized compounds, although other techniques may also be contemplated.
  • the liquid chromatography and mass spectrometry (MS) may be used in combination, often referred to as LC-MS .
  • the term / l H-NMR may be understood as referring to proton nuclear magnetic resonance, i.e. nuclear magnetic resonance (NMR) with respect to hydrogen-l nuclei.
  • the method comprises analysing a first biological sample from the subject, wherein the first biological sample is obtained from the subject at a first time point, and a second biological sample from the subject, wherein the second biological sample is obtained from the subject at a second time point, and comparing the level (s) of the one or more betaine compounds in the first biological sample to the level (s) of the one or more betaine compounds in the second biological sample in order to monitor the progressive endogenous metabolism (or progressive status of endogenous metabolism) , the progressive risk of developing a cardiovascular or metabolic disease, the progressive nutritional status or effectiveness of a nutritional regimen in the subject.
  • the method further comprises spiking the biological sample with at least one of (or all of) the one or more betaine compounds prior to determining the level (s) of the one or more betaine compounds.
  • the method may further comprise administering a treatment to the subject to thereby treat the subject in order to improve the endogenous metabolism of the subject, the nutritional status of the subject and/or in order to treat the subject at risk to develop a cardiovascular and/or a metabolic disease.
  • the treatment may be e.g. a treatment effective to prevent and/or treat a cardiovascular and/or metabolic disease. Examples of such treatments may be e.g. administering to the subject an effective amount of a lipid-lowering, cholesterol lowering or cholesterol balancing medicament.
  • the medicament may be e.g. a statin.
  • the method may further comprise e.g. providing a lifestyle recommendation to the subject based on the assessment of the nutritional status or the effectiveness of the nutritional regimen in the subject.
  • a lifestyle recommendation may be e.g. a nutritional recommendation to increase intake of whole grains and/or products derived therefrom, and/or intake of foodstuffs rich in glycine betaine, and/or other nutritional recommendation.
  • a kit for determining the level (s) of one or more betaine compounds in a sample or for performing the method according to one or more embodiments described in this specification is also disclosed.
  • the kit may comprise one or more betaine compounds selected from alanine betaine, pipecolic acid betaine, norvaline betaine, 5- aminovaleric acid betaine, 4-aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine.
  • the kit may further comprise reagents for determining the level (s) or for performing said methods and optionally further components, such as a carrier or a solvent.
  • the kit may further comprise instructions for use.
  • the instructions for use may comprise instructions for assessing or aiding in the assessment of endogenous metabolism, a risk of developing a cardiovascular and/or metabolic disease, nutritional status and/or effectiveness of a nutritional regimen in a subject; or instructions for determining the level (s) of the one or more betaine compounds in a biological sample from a subject.
  • the one or more betaine compounds is/are selected from alanine betaine, norvaline betaine, 5- aminovaleric acid betaine, 4-aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine.
  • the one or more betaine compounds comprise (s) or is 5-aminovaleric acid betaine (5-AVAB).
  • the one or more betaine compounds comprise (s) at least one of valine/norvaline betaine or alanine betaine .
  • Use of the kit according to one or more embodiments described in this specification for assessing or aiding in the assessment of nutritional status or effectiveness of a nutritional regimen, endogenous metabolism, and/or a risk of developing a cardiovascular or metabolic disease, nutritional status or effectiveness of a nutritional regimen in a subject, and/or for determining the level (s) of the one or more betaine compounds in a biological sample from a subject is further disclosed .
  • betaine compounds selected from alanine betaine, pipecolic acid betaine, norvaline betaine, 5- aminovaleric acid betaine, 4-aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine for assessing or aiding in the assessment of endogenous metabolism, a risk of developing a cardiovascular or metabolic disease, nutritional status or effectiveness of a nutritional regimen in a subject and/or for determining the level (s) of the one or more betaine compounds in a biological sample from a subject is further disclosed.
  • the subject may be any subject described in this specification.
  • the biological sample may also be any biological sample described in this specification.
  • the nutritional regimen may also be any nutritional regimen described in this specification.
  • the one or more betaine compounds is/are selected from alanine betaine, norvaline betaine, 5- aminovaleric acid betaine, 4-aminovaleric acid betaine, valine betaine, phenylalanine betaine, and tryptophan betaine.
  • the one or more betaine compounds comprise (s) or is 5-aminovaleric acid betaine (5-AVAB) .
  • the one or more betaine compounds comprise (s) at least one of valine/norvaline betaine or alanine betaine .
  • mice were obtained from National Laboratory Animal Center (Kuopio, Finland) at the age of 9 weeks.
  • the mice were acclimatized for one week and housed 3-4 animals per cage during the weeks 1 to 12 and in single cages from the week 13 until the end of the study.
  • the environment in the animal facility was regulated: temperature 22 ⁇ 1 °C, relative air humidity 55 ⁇ 15% and 12/12 h light/dark cycle with lights on at 7 am.
  • the mice were fed ad libitum a commercial high-fat diet (D12451, Research Diets Inc., USA) for 9 weeks to induce obesity.
  • D12450B commercial low-fat control diet
  • Rye diets contained either rye bran (Rl) or bioprocessed, enzymatically treated and yeast fermented rye bran (R2) where as aleurone diets contained wheat aleurone (Al) or bioprocessed, enzymatically treated aleurone (A4) . More detailed description of the diets have been included in Rosa et al . , J. Agric. Food Chem. 62, 10101-10109 (2014) and Pekkinen et al . , Mol. Nutr. Food Res. 59, 1550-1562 (2015).
  • Frozen tissue samples were cryo-ground either in 10 ml grinding steel jars with stainless steel ball for 60 seconds with 15 Hz (liver, subcutaneous adipose tissue), or in 2 ml microcentrifuge tubes with 4- or 7-mm stainless steel beads in a precooled 2 ⁇ 24 adapters that was shaken for 45 s at 30 Hz (BAT, muscle, heart) using TissueLyser II (Qiagen Finland, Helsinki, Finland) .
  • Samples containing 100 mg ( ⁇ 2 mg) of tissue powder were cryo-weighted into 1.5 mL microcentrifuge tubes and 90% methanol was added (v/v H 2 0, LC-MS Ultra CHROMASOLV®, Fluka) in a ratio of 300 pL solvent/100 mg tissue. The samples were shaken for 20 min. Colon contents were weighed, mixed with 90 % methanol (500 ⁇ methanolper 100 mg content) and shaken with 4- mm stainless steel beads for 45 s at 20 Hz.
  • the supernatant was filtered through 0.2- ⁇ polytetrafluoroethylene filters in a 96-well plate format. Aliquots of 2 ⁇ i were taken from at least half of the plasma samples, mixed together in 1 tube, and used as the quality control (QC) sample in the analysis; a solvent blank was prepared in the same manner.
  • QC quality control
  • betaines can be measured from human subjects participating in clinical trials involving intervention with supplement products, for example glycine betaine (described e.g. in Schwab et al . , 2006, J. Nutr. 136(1), 34-38), or intervention with whole diets, for example increased intake of whole grains (described e.g. in Lankinen et al . , 2011, PLoS One 2011 ; 6 : e22646 ) .
  • betaines can be measured from other sample types, for example in vitro colonic fermentation (described e.g. in Hanhineva et al . , 2012, PloS One 7(6) :e39322) .
  • the samples were analyzed by the ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-qTOF-MS ) system (Agilent Technologies, a 1290 LC system, a Jetstream electrospray ionization (ESI) source, and a 6540 UHD accurate-mass qTOF spectrometer) .
  • Hydrophilic interaction (HILIC) chromatography was used. The sample tray was kept at 4°C during the analysis.
  • the data acquisition software was the MassHunter Acquisition B.04.00 (Agilent Technologies) .
  • the MS conditions were: Jetstream ESI source, operated in positive ionization mode, conditions were a drying gas temperature of 325°C and flow of 10 L/min, a sheath gas temperature of 350°C and flow of 11 L/min, a nebulizer pressure of 45 pounds per square inch, capillary voltage of 3500 V, nozzle voltage of 1000 V, fragmentor voltage of 100 V, and a skimmer of 45 V.
  • Jetstream ESI source operated in positive ionization mode
  • conditions were a drying gas temperature of 325°C and flow of 10 L/min, a sheath gas temperature of 350°C and flow of 11 L/min, a nebulizer pressure of 45 pounds per square inch, capillary voltage of 3500 V, nozzle voltage of 1000 V, fragmentor voltage of 100 V, and a skimmer of 45 V.
  • a 2-GHz extended dynamic range mode was used, and the instrument was set to acquire over the m/ z 50-1600.
  • Data were collected in the cent
  • QC samples were used for the automatic data-dependent MS/MS analyses. From every precursor scan cycle 4 most abundant ions were selected for fragmentation. These ions were excluded after 2 product ion spectra and released again for fragmentation after a 0.25-min hold. The precursor scan time was based on ion intensity, ending at 20, 000 counts or after 300 ms . The product ion scan time was 300 ms . The collision energies were 10, 20, and 40 V in subsequent assays. The continuous mass axis calibration was performed by monitoring two reference ions from an infusion solution throughout the assays. The reference ions were m/z 121.050873 and m/z 922.009798.
  • betaines can be analysed by typical/general analytical methods used for measuring metabolism-related phenomena/events in biological samples, such as measuring blood glucose and/or insulin levels, analyzing the expression of genes related to carbohydrate and fat metabolism, or conducting a mitochondrial stress test, utilizing for example Seahorse XF24 Analyzer (Agilent Technologies, CA, USA) using suitable cultured cells, such as cardiomyocytes , according to the manufacturer's instructions. Methods e.g. for analysing gene expression and for measuring blood glucose and/or insulin levels are well known to a skilled person. Further, a number of genes related to carbohydrate and fat metabolism are known. The results from such test(s) can be correlated with the altered levels of betaines and linked thus with the metabolic status and health implications thereafter.
  • typical/general analytical methods used for measuring metabolism-related phenomena/events in biological samples, such as measuring blood glucose and/or insulin levels, analyzing the expression of genes related to carbohydrate and fat metabolism, or conducting a mitochondrial stress test, utilizing for example
  • a group of compounds tentatively identified as betainized metabolites, i.e. betaine compounds, that were increased in the urine of mice were brought to light in a recent non-targeted metabolite profiling on C57BL/6J mouse model fed with rye bran enriched (high fat) feed (Pekkinen et al . , Mol. Nutr. Food Res. 59, 1550-1562 (2015)).
  • the chemical structure of these compounds was verified via chemical synthesis and LC-MS analysis, and they were concluded to include alanine betaine, valine betaine, tryptophan betaine, phenylalanine betaine, pipecolic acid betaine, and 5-aminovaleric acid betaine (5-AVAB) (Fig. 1A-1E) .
  • the compounds are shown in Table 1 and in Fig. 1.
  • RT refers to retention time using the LC-MS method described in the examples and m/ z to the mass/charge ratio
  • a semi-targeted method was set up for the novel betaines and plasma samples from a mouse feeding trial comprising native (Rl) or bioprocessed (R2) rye bran (Pekkinen et al . , 2015), or native (Al) or bioprocessed (A4) wheat aleurone fractions (Rosa et al . , 2014, J. Agric. Food Chem. 62, 10101-10109) were examined.
  • Figure 1 illustrates identification of amino-acid derived betaines in the plasma samples.
  • Figure 2 shows the abundances of betaines in fasting plasma samples from the three human dietary intervention trials (a, c, e, g, i, k, m, o, q) and the correlations of the levels of the abundances with glycinde betaine abundance (b, d, f, h, j, 1, n, p, r) .
  • Kuopio HG intervention had three dietary groups: A, healthy diet including whole grains; B, whole grain rich diet; C, control diet.
  • FIG. 3 shows a. betaines in plasma of conventional (MPF) and germ free (GF) mice, b. betaines in the colon contents of the mice fed with bran enriched diets, c. betaines in the in vitro 24-h fermentation model with human microbiota incubated with rye bran fractions.
  • FBL faecal background
  • Rl rye bran
  • R2 bioprocessed rye bran.
  • Glycine betaine found in the rye bran may be a key component keeping up the production, and indeed, its level decreased during the 24 hour incubation (Fig. 3c). Additionally, investigation of tissue matrices from the intestinal tract of the mouse fed with bran enriched feed showed that the betainized compounds are found in particular in the lower parts of intestine active with microbial fermentation, caecum and colon, suggesting that they are absorbed efficiently. Again, the level of glycine betaine was at a constant level, but the betainized compounds increased in the groups fed with bran enriched feed (Fig. 3d) .
  • the molecular structure of 5-AVAB has similarity with meldonium ( 2- [ 2-Carboxyethyl ] -1 , 1 , 1-trimethylhydrazinium, also known as mildronate, THP and MET-88), drug used to treat coronary artery disease.
  • meldonium 2- [ 2-Carboxyethyl ] -1 , 1 , 1-trimethylhydrazinium, also known as mildronate, THP and MET-88
  • the mechanism of action of meldonium has been associated with reduction of cellular levels of L- carnitine by inhibition of the type 2 organic cation/carnitine transporter (0CTN2, SLC22A5) and L-carnitine biosynthesis enzyme ⁇ -butyrobetaine hydroxylase (Dambrova et al., Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity. Pharmacol. Res. 2016).
  • FIG. 4 illustrates betaines in tissues and effects of 5-AVAB to the energy metabolism of neonatal mouse cardiomyocytes.
  • BET glycine betaine;
  • BET glycine betaine;
  • b Betaines in human heart;
  • c 5-AVAB dose dependently decreases the ability of neonatal mouse cardiomyocytes to utilize palmitoyl acid as an energy source for mitochondrial respiration,
  • d Comparison of 100 ⁇ concentration of 5-AVAB, meldonium (MELDO) and glycine betaine (GLYB) showed that 5-AVAB produces similar effect to meldonium (but glycine betaine does not) .
  • MELDO meldonium
  • GLYB glycine betaine
  • L-Carnitine and acetyl-L-carnitine are in a key role for use of fatty acids in mitochondrial beta-oxidation and degreased levels lead to reduced utilization of fatty acids in energy metabolism.
  • Decreased use of fatty acids in energy metabolism has been considered to protect cardiomyocytes in low oxygen conditions, because use of fatty acids in production of ATP is more oxygen demanding than use of glucose (Dambrova et al . , 2016) .
  • 5-AVAB decreased the use of fatty acids in energy metabolism, oxygen consumption of the neonatal mice cardiomyocytes exposed to different concentrations of 5-AVAB (0-250 ⁇ ) in a medium containing only palmitate as an energy source was measured.
  • 5-AVAB is a novel betaine compound not previously described in humans and a compound modulating the energy homeostasis via inhibition of carnitine transportation, and promoting beneficial health effects related to whole grain consumption including cardioprotective effect and reduction of type 2 diabetes risk.
  • the reduced efficacy to use lipids as energy source forces the body to prefer glucose as energy source over lipids and these biological effects of 5-AVAB could be one of the molecular mechanisms how whole grain diets precondition the hearts tolerance to ischemic insults.
  • the present results demonstrate another group of metabolites produced by the microbiota, which may have a direct involvement with host metabolism. Thus they further highlight the role of microbiota in host metabolism, i.e. endogenous metabolism.

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Abstract

L'invention concerne un procédé d'évaluation ou d'aide à l'évaluation de l'état nutritionnel et/ou de l'efficacité d'un régime nutritionnel, du métabolisme endogène et/ou d'un risque de développement d'une maladie cardiovasculaire et/ou métabolique chez un sujet. Le procédé comprend l'analyse d'un échantillon biologique provenant du sujet afin de déterminer le(s) niveau(x) d'un ou plusieurs composés de bétaïne choisis parmi la bétaïne d'alanine, la bétaïne d'acide pipécolique, la bétaïne de norvaline, la bétaïne d'acide 5-aminovalérique, la bétaïne d'acide 4-aminovalérique, la bétaïne valine, la bétaïne phénylalanine et la bétaïne tryptophane dans l'échantillon biologique. Le procédé peut comprendre en outre la comparaison du/des niveau(x) desdits composés de bétaïne dans l'échantillon biologique à une valeur de référence ou au(x) niveau(x) desdits composés de bétaïne dans un échantillon témoin afin d'évaluer l'état nutritionnel et/ou l'efficacité du régime nutritionnel du métabolisme endogène, et/ou le risque de développement de la maladie cardiovasculaire et/ou métabolique chez le sujet.
PCT/FI2017/050099 2017-02-16 2017-02-16 Biomarqueurs de la bétaïne pour l'état nutritionnel, le régime nutritionnel, le métabolisme endogène ou le risque de maladies cardiovasculaires ou métaboliques Ceased WO2018150077A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113058037A (zh) * 2020-02-20 2021-07-02 郑乐民 Tmava拮抗剂的用途以及用于诊断脂肪肝或心力衰竭的系统
CN113138234A (zh) * 2020-01-17 2021-07-20 上海透景生命科技股份有限公司 一种检测多种肠道微生物代谢物的定量分析方法及试剂盒
WO2024061250A1 (fr) * 2022-09-23 2024-03-28 合肥瀚微生物科技有限公司 Biomarqueur de diagnostic pour la dépression et utilisation associée

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150362510A1 (en) * 2013-01-31 2015-12-17 Metabolon, Inc. Biomarkers Related to Insulin Resistance Progression and Methods Using the Same
EP2222220B1 (fr) * 2007-12-05 2016-03-16 The Cleveland Clinic Foundation Composés de triméthylamine en tant que prédicteurs de risque de maladie cardiovasculaire

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2222220B1 (fr) * 2007-12-05 2016-03-16 The Cleveland Clinic Foundation Composés de triméthylamine en tant que prédicteurs de risque de maladie cardiovasculaire
US20150362510A1 (en) * 2013-01-31 2015-12-17 Metabolon, Inc. Biomarkers Related to Insulin Resistance Progression and Methods Using the Same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HANHINEVA, K. ET AL.: "Discovery of urinary biomarkers of whole grain rye intake in free-living subjects using nontargeted LC-MS metabolite profiling", MOLECULAR NUTRITION & FOOD RESEARCH, vol. 59, no. 11, November 2015 (2015-11-01), pages 2315 - 2325, XP055606752 *
HANHINEVA, K. ET AL.: "Nontargeted metabolite profiling discriminates diet-specific biomarkers for consumption of whole grains, fatty fish, and bilberries in a randomized controlled trial", THE JOURNAL OF NUTRITION, vol. 145, no. 1, January 2015 (2015-01-01), pages 7 - 17, XP055470059, DOI: doi:10.3945/jn.114.196840 *
LI, C. ET AL.: "Determination of betaine metabolites and dimethylsulfoniopropionate in coral tissues using liquid chromatography- time-of-flight mass spectrometry and stable isotope-labeled internal standards", JOURNAL OF CHROMATOGRAPHY B, vol. 878, no. 21, July 2010 (2010-07-01), pages 1809 - 1816, XP027091705 *
PEKKINEN, J. ET AL.: "Amino acid-derived betaines dominate as urinary markers for rye bran intake in mice fed high-fat diet-A nontargeted metabolomics study", MOLECULAR NUTRITION & FOOD RESEARCH, vol. 59, no. 8, August 2015 (2015-08-01), pages 1550 - 1562, XP055606750 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113138234A (zh) * 2020-01-17 2021-07-20 上海透景生命科技股份有限公司 一种检测多种肠道微生物代谢物的定量分析方法及试剂盒
CN113138234B (zh) * 2020-01-17 2024-05-24 上海脉示生物技术有限公司 一种检测多种肠道微生物代谢物的定量分析方法及试剂盒
CN113058037A (zh) * 2020-02-20 2021-07-02 郑乐民 Tmava拮抗剂的用途以及用于诊断脂肪肝或心力衰竭的系统
WO2021164790A1 (fr) * 2020-02-20 2021-08-26 郑乐民 Utilisation d'un antagoniste du tmava et système de diagnostic d'une stéatose hépatique ou d'une insuffisance cardiaque
US20230113511A1 (en) * 2020-02-20 2023-04-13 Proglead, Inc Use of tmava antagonist and system for diagnosing fatty liver or heart failure
WO2024061250A1 (fr) * 2022-09-23 2024-03-28 合肥瀚微生物科技有限公司 Biomarqueur de diagnostic pour la dépression et utilisation associée

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