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1、肠道菌群紊乱与疾病肠道细菌的建立及功能肠道菌群 Gut Microbiota n人体结肠细菌细胞细胞数量高达100万亿,是人体细胞数量的10倍。n在分娩过程中细菌即植入新生儿肠道内。分娩方式、喂奶方式等影响新生儿的肠道菌群结构。n母乳喂养的婴儿粪便中双歧杆菌的比例增加，配方喂奶婴儿粪便中肠球菌比例增加。Orrhage K,Nord CE.Factors controlling the bacterial colonization of the intestine in breast fed infants.Acta Paediatr.1999;88(430):47S-57S Biasucci
2、G,Rubini M,Riboni S,Retetangos C,Morelli L,Bessi E.Mode of delivery affects the bacterial community in the newborn gut.Early Hum Dev.2010 Feb 4.人体消化道细菌分布人体消化道细菌分布人体结肠菌群结构肠道菌群 Gut MicrobiotanMicrobes act as a defending barrier against invading pathogens,aid in digestion,provide nutritional support fo
3、r enterocytes,and play a crucial role in the development of the immune system.nSpecific pathogens(e.g.,Salmonella,Campylobacter jejuni,and enterotoxigenic C.perfringens)have been implicated in acute and chronic gastrointestinal disease.n婴幼儿年龄阶段的环境因素对成年期肠道菌群结构及肠道免疫功能有重要影响。n 肠道菌群紊乱（dysbiosis）可导致一些重要疾病
4、，如炎症性肠病、结肠癌结肠癌、肥胖肥胖、糖尿病等。n肠道菌群可称为人体一个新的器官。益生菌 Probioticsn定义：定义：live micro-organisms which confer a health benefit on the host when administered in adequate amounts.WHO（2001）n饮食,年龄,抗生素使用,肠道pH值,肠道细菌间相互影响,肠道内一些发酵物质等均可影响肠道内细菌结构。n益生菌可以黏附在结肠黏膜上，减少有害细菌的数量，调节肠道免疫功能，并可减轻炎症反应，抑制肿瘤增殖等。n常见益生菌如双歧杆菌、乳酸杆菌、粪链球菌等。nD
5、ysbiosis,an imbalance between harmful and protective bacteria“卫生”学说 “hygiene hypothesis”。n剖腹产、配方喂奶的婴儿日后患过敏性疾病如皮疹、哮喘以及炎症性肠病的几率显著升高。n粪便中细菌的多态性与婴儿的湿疹发生呈负相关。nCommonly observed microbial changes are increased Proteobacteria(i.e.,Escherichia coli)with concurrent decreases in Firmicutes,especially a reduce
6、d diversity in Clostridium clusters XIVa and IV(i.e.,Lachnospiraceae,Ruminococcaceae,Faecalibacterium spp.).This would indicate that these bacterial groups,important short-chain fatty acid producers,may play an important role in promoting intestinal health.结肠菌群与结肠癌的关系结肠菌群与结肠癌的关系结肠癌 Colorectal Cancer
7、n每年世界范围内发病人数超过100万，死亡过半。n结直肠癌在我国的发病率正逐年升高，年均增长率接近5%。n年龄、肥胖、炎症性肠病等是结肠癌发病的危险因素。肠道细菌与结肠癌危险因素相关n结肠菌群结肠菌群变化与肥胖关系密切。nMkivuokko 等报告老年人老年人肠道细菌数量减少,并且Bacteroidetes数量增加,Firmicutes 数量减少。使用NSAIDs老年人肠道细菌数量多于未使用NSAIDs老年人。n Enck等报告人一些特殊的菌群随年龄增长而增加，如大肠杆菌、肠球菌等。一些肠道疾病如克罗恩病、克罗恩病、溃疡性结肠炎溃疡性结肠炎、肠易激综合征等患者结肠菌群分别有其特殊性。Mkivu
8、okko H,Tiihonen K,Tynkkynen S,Paulin L,Rautonen N.The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition.J Nutr.2010;103(2):227-34.Enck P,Zimmermann K,Rusch K,Schwiertz A,Klosterhalfen S,Frick JS.The effects of ageing on the colonic bacterial microflor
9、a in adults.Gastroenterol.2009;47(7):653-8无菌小鼠 Germ-free(GF)mouse GF 动物盲肠大且平滑，常规饲养（CV）的动物小肠则比较大。GF 动物肠系膜淋巴结较 CV对照发育差。The gut microbiota as an environmental factor that regulates fat storage Fredrik Backhed et al.1571815723 PNAS November 2,2004 vol.101 no.44Obesity alters gut microbial ecology（？）Ley
10、et al.1107011075 PNAS August 2,2005 vol.102 no.31 Early differences in fecal microbiota composition in children may predict overweightKalliomaki et al.体重保持正常的儿童幼儿期间粪便双歧杆菌数量（bifidobacterial）显著高于以后变为肥胖儿童幼儿期粪便数量(P=0.02)Am J Clin Nutr 2008;87:5348结肠菌群与结肠黏膜免疫、炎症的关系结肠菌群与结肠黏膜免疫、炎症的关系Hypothesis for bacteria
11、-induced metabolic disease Cani et al.Diabetes 57:14701481,2008Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat DietInduced Obesity and Diabetes in Mice Cani et al.normal diet(CT),normal diet and antibiotics(CT-Ab),high-fat diet(HF),or high-fat diet and antibi
12、otics(HF-Ab)for 4 weeks.The conclusionsnThis new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia,inflammation,and associated disorders by a mechanism that could increase intestinal permeability.n It would thus be useful to develop strategies for changing gut microb
13、iota to control,intestinal permeability,metabolic endotoxemia,and associated disorders.结肠菌群紊乱结肠菌群紊乱炎症炎症肥胖肥胖结肠肿瘤发生结肠肿瘤发生？炎症与肿瘤n约20%的肿瘤发生与炎症有关。n溃疡性结肠炎病史越长，癌变率越高。炎症相关性结肠癌（colitis-assocated cancer CAC）n在经典的氧化偶氮甲烷（AOM）致癌动物模型中给予硫酸葡聚糖（DSS）可以显著增加结肠癌的发生率。n炎症增加结肠癌的发病几率。The types and numbers of bacteria associ
14、ated with biopsy samples were distinctly different for UC and CD patients.(B)CD patients;(C)UC patients.Bibiloni R,et al.The bacteriology of biopsies differs between newly diagnosed,untreated,Crohns disease and ulcerative colitis patients.J Med Microbiol.2006;55(Pt 8):1141-9.机制 Mechanisms两个主要机制(Vann
15、ucci et al.2009)细菌感染后所产生的慢性炎症细菌所产生的毒性代谢产物。主要涉及的细胞及组织mucosal cells,gut-associated lymphatic tissue GALT,intraepithelial lymphocytes IEL,dendritic cells DC,and cells of the mesenteric lymph nodes MLN)(Vannucci et al.2009)Modulation of the Intestinal Microbiota Alters Colitis-Associated Colorectal Canc
16、er Susceptibility Uronis et al.conventionalized-IL10-/-mice Germ-free IL10-/-micewild-type(WT)mice.IL10-/-mice mono-associated micePLoS ONE,June 2009|Volume 4|Issue 6|e6026肠道微生物识别 microbial recognitionn一些受体可感受细菌细胞壁、细胞核成分。n结直肠黏膜通过模式识别受体（pattern recognition receptors PRRs）nToll-like receptors，TLRs；nucleotide-binding domain leucine-rich repeat proteins(NLR;also known as Nod-like receptors)；retinoic acid inducible gene-I like RNA helicases(RLH),C-type lectin receptors(CLR)。n研究最为深入和广泛的是TLRs。TLRs在细菌-炎
