菌群与肠道疾病

肠道菌群与肠道疾病,天津市南开医院 曹泽伟 20091212,人体微生态系统,出生后012个月形成，终生维持稳定状态 人体正常菌群大约400500菌种 数量达100万亿个（人体体细胞只有10万亿个） 总重量12kg，约75以上的粪便成分是细菌及其副产物 如果将一个人的肠内细菌排成一列，其长度约可绕行地球2周多,肠黏膜屏障,正常菌丛（益生菌） 与肠道致病菌竞争机制 占领空间，竞争必需营养与上皮附着点 制造抗微生物成份，挥发性脂肪酸，修饰胆酸，不利致病菌生长环境 诱导免疫细胞汇集，激活适当的免疫与炎症反应,单位,消化链球菌 ， 双岐杆菌 乳酸菌 肠杆菌， 葡萄球菌,梭菌属， 醇母等等,HP, 乳酸菌 链球菌,葡萄球菌 肠杆菌, 醇母等,乳酸杆菌 链球菌 肠杆菌 葡萄球菌 醇母 双岐杆菌 类杆菌属,菌丛组,肠道细菌抗原递呈过程及其免疫应答,IBD病因与肠道微生物,遗传因素 Nod2 IBD5 自溶作用 IL23R,免疫失调,环境因素 吸烟 饮食 致癌物,宿主防御缺陷,IBD,微生物,肠内细菌的存在是 (IBD)发病的必要条件,肠黏膜细菌密度,Swidsinski A et al. Gastroenterology 2003，122：44,CD,正常对照,黏膜细菌密度高（72000 cfu/ml）,黏膜细菌密度低（300 cfu/ml）,关于埃希氏菌大肠杆菌 在IBD发病机制中的研究报告,IBD的可能原因,有害的肠道细菌导致IBD,对正常肠道菌群的异常免疫反应可导致IBD,促炎细胞因子,Figures from Sartor RB.Gastroenterol.（2008）134：577594,有害的肠道细菌,肠道细菌抗原识别,反应,是一种通过改善肠道微生物平衡从而对宿主产生有益作用的 活的微生物添加剂,反应,益生菌,Probiotics Definition,Nutritional supplement Contains 1 or more cultures of living organisms Typically bacteria or yeast Modify the endogenous microflora Have a positive effect on the host,微生态制剂,条件： 有益的生理作用 来源于健康人肠道 应用安全 在酸与胆汁环境中成活率高 能粘附于肠粘膜上，并可定植 能产生抗微生物物质 通过现代加工能存活,Probiotics 19th Century,Pasteur (1877) Observed antagonistic interaction between bacterial strains Suggested that non-pathogenic bacteria should be used to control pathogenic bacteria,Probiotics Early 20th Century,Metchnikoff (1907) Observed that lactic fermentation of milk arrested putrefaction Suggested that consumption of fermented products would offer the same benefit to humans Felt that longevity in Bulgarian peasants was due to ingestion of “soured milks”,Probiotics Mid to late 20th Century,1950s, Ferdinand Vergin publishes article discussing effects of antibiotics on beneficial intestinal bacteria 1980s Fuller establishes first definition of probiotics,益生元：一类非消化性物质，可被肠道 正常细菌所利用，能选择性地 刺激结肠内有益菌生长，改善 肠道功能，它包括果糖、乳果 糖、异麦芽糖和低聚糖类。 合生元：益生菌和益生元的混合制剂。,Probiotics,益生菌作用机制,维持内环境稳定,生物化学屏障,促进微生态平衡及保护宿主健康,胃肠免疫屏障,代谢与营养吸收,生物拮抗作用 消灭进入肠道内的病原体,免疫刺激 作用,Probiotics,From Fedorak RN and Madsen KL Inflamm Bowel Dis, 2004,肠腔内,固有层,增强黏膜 屏障完整性,益生菌从肠道不同层面减轻肠腔炎症反应 增强黏膜屏障功能。,嗜酸乳杆菌、 保加利亚乳杆菌、 乳酸乳杆菌、 粪链球菌、 大肠杆菌、 双歧杆菌 枯草杆菌 肠球菌、酵母菌等。,Probiotics种类,我国已有的益生菌有培菲康，金双歧，美常安，整肠生，贝飞达等,培菲康 原籍菌三联配方，含菌量大,天然益生元+长双歧杆菌+嗜酸乳杆菌+粪链球菌 每1克活菌含量108CFU,培菲康三联活菌治疗前后肠道菌群变化,菌 名 治 疗 前 治 疗4周 后 乳酸杆菌 7.551.16 8.850.54* 双岐杆菌 9.040.99 10.510.45* 拟杆菌 10.890.84 10.120.74* 产气荚膜梭菌 9.340.91 8.970.97 肠球菌 9.430.97 7.201.15* 肠杆菌科 9.330.81 9.300.77 注：与正常对照组比较，* p 0.05；* p 0.01,Probiotics Many Potential Uses,Infectious diarrhea and day care related illness Antibiotic Associated Diarrhea Clostridium difficile Inflammatory bowel disease Travelers diarrhea Prevention of NEC Allergy Irritable Bowel Syndrome,Prevention of Diarrheal Illness,18 Week Therapy in French Children (6-24 months) in Day Care,CA Pedone, et al. Int J Clin Pract 54(9):568-71, 2000,Prevention of Diarrheal Illness,12 Week Therapy in Israeli Infants in Day Care,Z Weizman, et al. Pediatrics 115:5-9, 2005,Prevention of Diarrheal Illness (After Antibiotics for Respiratory Illness),2 Week Therapy in Finnish Children (2 weeks to 12 years),T Arvola, et al. Pediatrics 104(5), 1999,Probiotics Antibiotic Associated Diarrhea,S. boulardii Reduced rate of diarrhea in 116 patients versus placebo Lactobacillus GG Decreased diarrhea in people treated with triple therapy for H. pylori Found to reduce days of diarrhea and side effects when coadministered with erythromycin in healthy volunteers,Probiotics Clostridium difficile,probiotics,138 hospitalized adults receiving antibiotics randomized to receive probiotics (Lactobacillus and Bifidobacterium) or placebo,placebo,46%,78%,C. difficile toxin,7.25%,2.9%,probiotics,placebo,developed diarrhea,Probiotics in IBD Preliminary Studies,UC patients All given steroids 59 given mesalamine (Pentasa, Asacol) 57 given a probiotic Remission rates similar (75% vs. 68%) Relapse rates similar (73% vs. 67%) Length of remission similar (206 days vs. 221 days),Rembacken et al Lancet, 1999,益生菌治疗UC,克罗恩病的维持治疗,32例临床缓解的CD 美沙拉嗪 美沙拉嗪 1克 tid 1克Bid+布拉地酵母菌 (saccharomyces boulardii) 疗程 6月 6月 复发 37.5% 6.25% (CDAI) Guslandi M等 DDS 2000,用益生菌处理小鼠的结肠内 炎性细胞数量减少,Lactobacilli and Bifidobacteria Why They Are Safe,Many exposures in pediatrics Fermented foods Probiotics The hosts own microflora Oral cavity Ileum and colon Vagina,Cases of infection extremely rare - Account for 0.05% to 0.4% of infective endocarditis and bacteremia - Less than 1 case per million people Review of 143 human clinical trials from 1961-1988 Over 7500 subjects No reported adverse events,Lactobacilli and Bifidobacteria Why They Are Safe,Lactobacilli and Bifidobacteria Why They Are Safe,Increasing prob