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1、肠道菌群与肠道疾病肠道菌群与肠道疾病天津市南开医院天津市南开医院曹泽伟曹泽伟20091212人体微生态系统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周多肠黏膜屏障肠黏膜屏障正常菌丛（益生菌）正常菌丛（益生菌）与肠道致病菌竞争机制与肠道致病菌竞争机制占领空间，竞争必需占领空间，竞争必需营养与上皮附着点营养与上皮附着点制造抗微生物成份，制造抗微生物成份，挥发性脂肪酸，修饰挥发性脂肪酸，修饰胆酸，不利致病菌生
2、胆酸，不利致病菌生长环境长环境诱导免疫细胞汇集，诱导免疫细胞汇集，激活适当的免疫与炎激活适当的免疫与炎症反应症反应单位 消化链球菌消化链球菌 ，双岐杆菌双岐杆菌乳酸菌乳酸菌 肠杆菌，肠杆菌，葡萄球菌,梭菌属，醇母等等HP, 乳酸菌乳酸菌链球菌链球菌,葡萄球菌葡萄球菌 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遗传因素Nod2 IBD5自溶作用自溶作用IL23R免疫失调免疫失调环境因素环境因素 吸烟吸烟饮食饮食致癌物致癌物宿主防御缺陷宿主防御缺陷IBDIBD微生物微生物肠
3、内细菌的存在是肠内细菌的存在是 (IBD)发病的必要条件发病的必要条件肠黏膜细菌密度肠黏膜细菌密度Swidsinski A et al. Gastroenterology 2019，122：44CD正常对照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关于埃希氏菌大肠杆菌 在在IBDIBD发病机制中的研究报告发病机制中的研究报告IBDIBD的可能原因的可能原因有害的肠道细有害的肠道细菌导致菌导致IBD对正常肠道菌群的异常免对正常肠道菌群的异常免疫反应可导致疫反应可导致IBD促炎细促炎细胞因子胞因子Figures from Sart
4、or RB.Gastroenterol.（2019）134：577594有害的肠道有害的肠道细菌细菌肠道细菌抗原识别反应反应是一种通过改善肠道微生物平衡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从而对宿主产生有益作用的活的微生物添加剂活的微生物添加剂反应反应益生菌益生菌ProbioticsDefinitionNutritional supplementContains 1 or more cultures of living organisms Typically bacteria or yeastModify the endogenous microfloraHave a posi
5、tive effect on the host微生态制剂微生态制剂条件：条件： 有益的生理作用有益的生理作用 来源于来源于健康人肠道健康人肠道 应用安全应用安全 在酸与胆汁环境中在酸与胆汁环境中成活率高成活率高 能粘附于肠粘膜上，并可定植能粘附于肠粘膜上，并可定植 能产生抗微生物物质能产生抗微生物物质 通过现代加工能存活通过现代加工能存活 Probiotics19th CenturyPasteur (1877)Observed antagonistic interaction between bacterial strainsSuggested that non-pathogenic bact
6、eria should be used to control pathogenic bacteriaProbioticsEarly 20th CenturyMetchnikoff (1907)Observed that lactic fermentation of milk arrested putrefaction Suggested that consumption of fermented products would offer the same benefit to humansFelt that longevity in Bulgarian peasants was due to
7、ingestion of “soured milks” ProbioticsMid to late 20th Century1950s, Ferdinand Vergin publishes article discussing effects of antibiotics on beneficial intestinal bacteria1980s Fuller establishes first definition of probiotics 益生元：益生元：一类非消化性物质，可被肠道一类非消化性物质，可被肠道 正常细菌所利用，能选择性地正常细菌所利用，能选择性地 刺激结肠内有益菌生长，
8、改善刺激结肠内有益菌生长，改善 肠道功能，它包括果糖、乳果肠道功能，它包括果糖、乳果 糖、异麦芽糖和低聚糖类。糖、异麦芽糖和低聚糖类。合生元：合生元：益生菌和益生元的混合制剂。益生菌和益生元的混合制剂。Probiotics益生菌作用机制益生菌作用机制维持内环境稳定维持内环境稳定生物化学屏障生物化学屏障促进微生态平衡及保护宿主健康促进微生态平衡及保护宿主健康胃肠免胃肠免疫屏障疫屏障代谢与代谢与营养吸营养吸收收生物拮抗作用生物拮抗作用消灭进入肠道内消灭进入肠道内的病原体的病原体免疫刺激免疫刺激作用作用From Fedorak RN and Madsen KL Inflamm Bowel Dis,
9、2019 肠腔内肠腔内固有层固有层 增强黏膜增强黏膜 屏障完整性屏障完整性 益生菌从肠道不同层面减轻肠腔炎症反应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。增强黏膜屏障功能。嗜酸乳杆菌、嗜酸乳杆菌、保加利亚乳杆菌、保加利亚乳杆菌、乳酸乳杆菌、乳酸乳杆菌、粪链球菌、粪链球菌、大肠杆菌、大肠杆菌、双歧杆菌双歧杆菌枯草杆菌枯草杆菌肠球菌、酵母菌肠球菌、酵母菌等等。Probiotics种类我国已有的益生菌有培菲康，我国已有的益生菌有培菲康，金双歧，美常安，整肠生，贝金双歧，美常安，整肠生，贝飞达等飞达等培菲康培菲康 原籍菌三联配方，含菌量原籍菌三联配方，含菌量大大天然益生元+长双歧杆菌+嗜酸
10、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培菲康三联活菌治疗前后肠道菌群变化 菌菌 名名 治治 疗疗 前前 治治 疗疗4周周 后后乳酸杆菌乳酸杆菌 7.551.16 8.850.54*双岐杆菌双岐杆菌 9.040.99 10.510.45*拟杆菌拟杆菌 10.890.84 10.120.74*产气荚膜梭菌产气荚膜梭菌 9.340.91 8.970.97肠球菌肠球菌 9.430.97 7.201.15*肠杆菌科肠杆菌科 9.330.81 9.300.77 注：与正常对照组比较，注：与正常对照组比较，* p 0.05；* p 0.01ProbioticsMany
11、Potential UsesInfectious diarrhea and day care related illnessAntibiotic Associated Diarrhea Clostridium difficile Inflammatory bowel diseaseTravelers diarrhea Prevention of NEC Allergy Irritable Bowel SyndromeYogurt (364)Yogurt+L. casei(360)P-valueChildren with diarrhea87 (22%)61 (16%)0.029Duration
12、 of diarrhea (days)3.953.530.24Rotavirus positive stool2.2%0.3%Prevention of Diarrheal Illness18 Week Therapy in French Children (6-24 months) in Day CareCA Pedone, et al. Int J Clin Pract 54(9):568-71, 2000CA Pedone, et al. Int J Clin Pract 54(9):568-71, 2000Controls (60)B. lactis (73)L. reuteri (6
13、8)P-valueDays with diarrhea0.590.370.150.001Episodes of diarrhea0.310.130.020.001Clinic visits0.550.510.230.002Absences0.430.410.140.015Prevention of Diarrheal Illness12 Week Therapy in Israeli Infants in Day CareZ Weizman, et al. Pediatrics 115:5-9, 2019Z Weizman, et al. Pediatrics 115:5-9, 2019Con
14、trols(58)Lactobacillus GG (61)P-valueChildren with diarrhea9 (16%)3 (5%)0.05Duration of diarrhea (days)44NSStool frequency (per day)55NSPrevention 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
15、), 2019T Arvola, et al. Pediatrics 104(5), 2019ProbioticsAntibiotic Associated DiarrheaS. boulardii Reduced rate of diarrhea in 116 patients versus placeboLactobacillus GGDecreased diarrhea in people treated with triple therapy for H. pyloriFound to reduce days of diarrhea and side effects when coad
16、ministered with erythromycin in healthy volunteersProbioticsClostridium difficile080406010020 probiotics138 hospitalized adults receiving antibiotics randomized to receive probiotics (Lactobacillus and Bifidobacterium) or placeboplacebo46%78%C. difficile toxin08 461027.25%2.9% probioticsplacebodevel
17、oped diarrheaProbiotics in IBDPreliminary StudiesUC patientsAll given steroids59 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, 2019益生菌治疗益生菌治疗UCU
18、C克罗恩病的维持治疗克罗恩病的维持治疗3232例临床缓解的例临床缓解的CDCD 美沙拉嗪美沙拉嗪 美沙拉嗪美沙拉嗪 1 1克克 tid 1tid 1克克Bid+Bid+布拉地酵母菌布拉地酵母菌 ( (saccharomyces boulardii)saccharomyces boulardii)疗程疗程 6 6月月6 6月月复发复发 37.5% 6.25%37.5% 6.25%(CDAI) (CDAI) Guslandi MGuslandi M等等 DDS 2000DDS 2000用益生菌处理小鼠的结肠内用益生菌处理小鼠的结肠内炎性细胞数量减少炎性细胞数量减少Lactobacilli and
19、Bifidobacteria Why They Are SafeMany exposures in pediatricsFermented foodsProbiotics The hosts own microfloraOral cavityIleum and colonVaginaCases of infection extremely rare - Account for 0.05% to 0.4% of infective endocarditis and bacteremia - Less than 1 case per million peopleReview of 143 huma
20、n clinical trials from 1961-1988Over 7500 subjectsNo reported adverse eventsLactobacilli and Bifidobacteria Why They Are SafeLactobacilli and Bifidobacteria Why They Are SafeIncreasing probiotic consumption has not led to increased opportunistic infectionsNational Public Health Institute-Finland 2019-2019Increasing cases of bacteremia (all types)Increasing use of probioticsConstant level of Lactobacillus bacteremia
