CN103156888A - 脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用 - Google Patents
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Abstract
本发明涉及脆弱拟杆菌的应用技术领域，具体涉及脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用，实验证明脆弱拟杆菌安全无毒，药理作用强，对于炎症性肠病有很好的治疗作用，从而预示了脆弱拟杆菌具有很好的食用和药用前景。本发明发掘了脆弱拟杆菌新的用途，开拓了一个新的应用领域，脆弱拟杆菌作为一种益生菌，可用于制备治疗炎症性肠病的食品或药物组合物，为临床提供适合人体服用的保健食品或治疗药物。
Description
技术领域
本发明涉及脆弱拟杆菌的应用技术领域，具体涉及脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用。
背景技术
炎症性肠病是一种病因不明的慢性非特异性肠道炎性疾病，包括克罗恩病和溃疡性结肠炎。溃疡性结肠炎的临床表现为持续或反复发作的腹泻、黏液脓血便伴腹痛、里急后重和不同程度的全身症状，病程多在4～6周以上。可有皮肤、黏膜、关节、眼和肝胆等的肠外表现。克罗恩病的临床表现呈多样化，包括消化道表现、全身性表现、肠外表现及并发症。消化道表现主要有腹泻和腹痛，可有血便；全身性表现主要有体质量减轻、发热、食欲不振、疲劳、贫血等，青少年患者可见生长发育迟缓；肠外表现与UC相似。具体病情严重程度判断均应结合实验室检查、影像学、内镜表现及病理。目前均无特异性的能完全治愈炎症性肠病的药物，临床上主要的治疗药物为氨基水杨酸制剂、激素、硫唑嘌呤和英夫力西。
在益生菌中，被广泛关注的双歧杆菌和乳酸菌在摄入后对人和动物具有很好作用的菌株，它们的特定菌株能够在肠粘膜上定居，在肠道内建群并且防止有害微生物在其上粘附，是能通过保持肠内自然微生物区系促进生物个体健康的可生长的微生物制剂，帮助维持人和动物的健康。在大量的实验室研究中表明，双歧杆菌及乳酸杆菌对于肠道炎症改变有很好的预防及治疗作用。在很多临床实验中，尽管益生菌对于炎症性肠病的内镜下表现无明显改变，但是对于临床症状的缓解很有帮助。
脆弱拟杆菌（Bacteroides fragilis）作为一种革兰氏染色阴性、杆状、两端钝圆而浓染，有荚膜、无芽胞、无动力的专性厌氧细菌，分产肠毒素型和非产肠毒素型。脆弱拟杆菌作为人及动物肠道正常菌群的一部分，主要存于结肠中，此外，呼吸道、胃肠道及泌尿生殖道粘膜也可定植生长。研究较多的是脆弱拟杆菌作为一种条件致病菌，当宿主粘膜受损时，可侵犯粘膜下层，引起感染，也可经血液流动，引起身体其它器官如肠道、腹腔、肝、肺、脑组织化脓性感染并伴发脓肿和引起急慢性腹泻等。此外，其对结肠、直肠癌的发生也有促进作用。
然而，脆弱拟杆菌并非只是一种条件致病菌。1991年张季阶发表了《一种无毒脆弱拟杆菌的分离鉴定》，报导了关于1983年9月从一个发育良好的婴儿粪便中分离出量大而又较纯的细菌，经以系列的鉴定、基础试验和临床应用观察，属于脆弱拟杆菌群中的一株无毒菌，是人体的益生菌，定名为BF839菌株。由此，研究发现了，脆弱拟杆菌也是一种益生菌。但是，脆弱拟杆菌作为一种益生菌，并且在制备治疗炎症性肠病组合物的相关应用，目前尚未有报道。
发明内容
本发明的目的在于提供脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用。
为了解决上述问题，本发明所采用的技术方案是：
提供脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用，所述的脆弱拟杆菌保藏单位名称为中国微生物菌种保藏管理委员会普通微生物中心，保藏单位地址为北京市朝阳区北辰西路1号院3号，保藏日期为2013年3月12日，保藏编号为CGMCC NO.7280，分类命名为Bacteroides fragilis。
其中，所述组合物为至少含有能治疗炎症性肠病的脆弱拟杆菌的食品或药物组合物。
其中，所述组合物选自奶粉、干酪、凝乳、酸奶酪、冰激凌、奶基发酵食品、发酵谷类食品、婴儿食品或宠物食品中的任意一种。
其中，所述组合物为丸剂、片剂、颗粒制剂、胶囊、口服液或者管饲制剂。
其中，所述组合物为含有所述脆弱拟杆菌的液体细菌悬浮液。
其中，所述脆弱拟杆菌在所述组合物中的含量为108~1010cfu /ml。
本发明的有益效果是：
本发明发掘了脆弱拟杆菌新的用途，开拓了一个新的应用领域。本发明通过实验证明，脆弱拟杆菌安全无毒，药理作用强，对于炎症性肠病有很好的治疗作用，从而预示了脆弱拟杆菌具有很好的食用和药用前景。脆弱拟杆菌作为一种益生菌，可用于制备治疗炎症性肠病的食品或药物组合物，进而为临床提供适合人体服用的保健食品或治疗药物。
具体实施方式：
下面通过实施例对本发明做进一步详细说明，这些实施例仅用来说明本发明，并不限制本发明的范围。
实施例1 脆弱拟杆菌菌液的制备
（1）由婴儿粪便中分离脆弱拟杆菌
按“正常菌群检查法”称取0.5克大便，置于先装有4.5ml生理盐水的试管中，以此连续稀释成10-1~10-6，由高稀积度向低稀积度滴到Bd培养基平板上，置于厌氧产气盒中加厌氧产气袋进行厌氧培养。置37℃，2~7天后开罐检查。选取单一菌落进行纯培养、染色镜检、培养特性、生理生化检测。
（2）脆弱拟杆菌的增菌培养及菌液制备
选取纯化后的单个菌落接种于改良的胰蛋白胨肉汤中进行增菌培养，所得菌液离心沉淀，转速3000r/min，离心15min，去上清，沉淀物用生理盐水洗涤后，沉淀物用生理盐水稀释，用麦氏比浊管做菌数测定，稀释至108 cfu /ml，109 cfu /ml，1010 cfu /ml，保存备用。
实施例2 脆弱拟杆菌毒力实验
采用实施例1制备的脆弱拟杆菌菌液进行以下实验：
（1）小鼠急性毒力实验
取体重22±2克C57BR/C小鼠（雌雄各半）60只，分成高剂量组、低剂量组和对照组，各组20只。高剂量组每只小鼠每天灌胃1012 cfu /ml菌液0.5ml，低剂量组每天灌胃109 cfu /ml菌液0.5ml，对照组每天灌胃0.5ml生理盐水。连续观察14天。
实验结果：小鼠正常生长，未见死亡，LD50测不出。
（2）大鼠毒力实验
取150±20克SD大鼠30只（雌雄各半），分为3组：高低剂量组和对照组。高剂量组每只大鼠每天灌胃1012cfu/ml菌液2ml，低剂量组每天灌胃109cfu/ml菌液2ml，对照组每天灌胃2ml生理盐水。连续观察14天，14天后抽静脉血测血象、肝肾功。取胃肠肝脾组织做病理切片电镜观察。
实验结果：均未见明显异常。
（3）恒河猴毒力实验
取恒河猴10只（雌雄各半），分为2组：高低剂量组和对照组。高剂量组每只恒河猴每天口服1012cfu/ml菌液100ml，低剂量组每天口服109cfu/ml菌液100ml。连续观察60天。14天、30天、45天、60天后分别抽静脉血测血象、肝肾功，测心电图。取胃肠肝脾组织做病理切片电镜观察。
实验结果：均未见明显异常。
实施例3 脆弱拟杆菌对于炎症性肠病的短期治疗作用
采用实施例1制备的脆弱拟杆菌菌液进行以下实验：
实验动物：BALB/c小鼠
动物模型构建：化学药物诱导炎症性肠病（三硝基苯磺酸TNBS和乙醇诱导出克隆恩病、葡聚糖硫酸钠DSS诱导出溃疡性结肠炎）
取50只小鼠随机分为5组：TNBS组、DSS组、TNBS+Bd组、DSS+Bd组、对照组。
TNBS组、TNBS+Bd组、对照组的小鼠禁食（不禁水），先用50/L水合氯醛0.15ml腹腔注射使小鼠轻度麻醉，约 25min以后用套接了小号导尿管的1ml注射器抽吸药液，从肛门将导尿管缓慢插入约3.5cm，然后将药液缓慢注入，停20s后抽出导尿管，再将小鼠倒悬约30s后放入盒中；TNBS组和TNBS+Bd组灌注 20g/L TNBS 500ml/L的乙醇溶液 0.1ml；对照组灌注0.15ml乙醇；TNBS+Bd组造模成功后每天灌胃0.5ml 109cfu/ml的Bd悬液，连续7d。DSS 组小鼠饮用液体为 5g/L DSS蒸馏水溶液，连续7天；DSS+Bd组造模成功后每天灌胃0.5ml 109cfu/ml的Bd悬液，连续7d。
测量指标：第8天处死，观察指标为疾病活动指数 ( DAI )、病理组织学、抽血检测细胞因子IL-2、IL-6、IL-10、TNF-α。
实验结果：脆弱拟杆菌灌胃组的疾病活动指数较造模组明显降低，IL-10明显升高，TNF-α明显降低，但病理学无明显改变。
实施例4 脆弱拟杆菌对于炎症性肠病的长期治疗作用
实验动物：BALB/c小鼠
动物模型构建： 取60只小鼠，随机分为4组，Bd1组10只、Bd2组10只、Bd+DSS组20只、空白对照组20只。
Bd+DSS组：（1）保证小鼠每天饮用5ml 2g/L的DSS；（2）第三天起饮用水替换为含2%DSS的蒸馏水；（3）从（2）算起，5天后停用DSS满2周；（4）22-26天时重复（1）到（3）；第29天起停用DSS满2周；（5）43-47重复（1）到（3）；（6）第50天开始将DSS换为蒸馏水。
Bd1组：从第一天起每天灌胃0.5ml 109cfu/ml的脆弱拟杆菌菌液；
Bd2组：从第50天开始保证每天饮用2ml 109cfu/ml的菌液。
测量指标：Bd1组、Bd+DSS组10只、空白对照组10只小鼠第51天处死，观察指标为病理组织学、抽血检测细胞因子IL-2、IL-6、IL-10、TNF-α；余下小鼠第80天处死，观察指标为病理组织学、抽血检测细胞因子IL-2、IL-6、IL-10、TNF-α。
实验结果：Bd1组、Bd2组小鼠病理较Bd+DSS组明显接近正常，肠道粘膜完整，炎性细胞浸润明显减少；IL-10明显升高，TNF-α明显降低。
实施例3和实施例4的结果说明，脆弱拟杆菌对于炎症性肠病有很好的治疗作用。
Claims (6)
1.脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用。
2.根据权利要求1所述的脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用，其特征在于：所述组合物为至少含有能治疗炎症性肠病的脆弱拟杆菌的食品或药物组合物。
3.根据权利要求2所述的脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用，其特征在于：所述组合物选自奶粉、干酪、凝乳、酸奶酪、冰激凌、奶基发酵食品、发酵谷类食品、婴儿食品或宠物食品中的任意一种。
4.根据权利要求2所述的脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用，其特征在于：所述组合物为丸剂、片剂、颗粒制剂、胶囊、口服液或者管饲制剂。
5.根据权利要求1所述的脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用，其特征在于：所述组合物为含有所述脆弱拟杆菌的液体细菌悬浮液。
6.根据权利要求1所述的脆弱拟杆菌在制备治疗炎症性肠病组合物中的应用，其特征在于：所述脆弱拟杆菌在所述组合物中的含量为108~1010cfu /ml。
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