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1、肠道菌群紊乱与疾病北京大学人民医院 消化内科朱元民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):4
2、7S-57S Biasucci 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.人人体体消消化化道道细细菌菌分分布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 nutrit
3、ional support for 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（dys
4、biosis）可导致一些重要疾病，如炎症性肠病、结结肠肠癌癌、肥肥胖胖、糖尿病等。n肠道菌群可称为人体一个新的器官。益生菌 Probioticsn定定义义：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
5、菌、乳酸杆菌、粪链球菌等。nDysbiosis,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,espe
6、cially a reduced 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 Co
7、lorectal Cancern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 等报告老老年年人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。一些肠道疾病如克克罗罗恩恩病病、溃溃疡疡性性结结肠肠炎炎、肠易激综合征等患者结肠菌
8、群分别有其特殊性。Mkivuokko 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 bacte
9、rial microflora 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
10、ecology（？）Ley et al.1107011075PNASAugust2,2005vol.102no.31Early 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
11、bacteria-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 an
12、d antibiotics(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 gu
13、t microbiota 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
14、bacteria associated 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 Mechan
15、isms两个主要机制(Vannucci 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
16、Colorectal Cancer 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）nT
17、oll-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-炎症-肿瘤过程中起重要的介导作用 The innate immune receptor Nod1 protects the intestine fr
18、ominflammation-induced tumorigenesis Chen et al.nNod1 deficiency results in increased inflammation-induced colon tumorsnNod1 and the Apc tumor suppressor cooperate in colitis-associated tumorigenesisnSeverity of chemically-induced colitis is increased with Nod1 deficiencynNod1 deficiency results in
19、increased proinflammatory mediator production and increased intestinal epithelial proliferationnThe gut microbiota contributes to increased colitis-associated tumorigenesis with Nod1 deficiencyCancer Res.2008 December 15;68(24):1006010067.Roles for Inflammation and Regulatory T Cells in Colon Cancer
20、 ERDMAN et al.Toxicologic Pathology,38:76-87,2010一些益生菌具有免疫调节及免疫刺激的一些益生菌具有免疫调节及免疫刺激的作用作用n一些益生菌通过刺激而非抑制固有免疫系统。Pagnini等（2004）在多种益生菌给予小鼠后肠上皮细胞来源的TNF-释放增加并可减轻1,2 dymethylhydrazine(DMH)所导致的炎症反应。nLeblanc等（2006）报告给予酸奶治疗DMH诱导的小鼠结肠癌模型可减杀少结肠肿瘤的发生率，实验中Peyers Patches 中TNF-及IFN-的分泌增加。The formyl peptide receptor(F
21、PR)nFPR:FPR1,FPRL1(formyl peptide receptor-like 1;FPR2),and FPRL2(formyl peptide receptor-like 2;FPR3).nThe FPR is the high-affinity receptor for formylated peptides leaking from growing bacteria and therefore serves as an important innate immune recognition receptor.人类研究 初步研究表明：在散发性结肠腺瘤、癌患者的结肠正常黏膜中
22、存在慢性炎症，慢性炎症可能是人类结肠肿瘤发病的癌前病变。Myeloperoxidase-Positive Cell Infiltration in Colorectal Carcinogenesis as Indicator of Colorectal Cancer Risk Roncucci et al.结肠腺瘤患者正常黏膜炎症浸润程度增加图1 正常对照组CD45染色 400 图2 结直肠腺瘤患者正常粘膜CD45染色400（mean SD,101.91 28.23 VS 67.97 9.91 P 0.05)结直肠腺瘤患者正常粘膜和正常对照组神经内分泌细胞的浸结直肠腺瘤患者正常粘膜和正常对照组
23、神经内分泌细胞的浸润程度润程度图1 正常对照组CgA染色 400 图1结直肠腺瘤患者正常粘膜CgA染色400(mean SD,23.82 13.73versus 10.37 5.16;P 0.05)益生菌人类治疗研究益生菌人类治疗研究 Human studies n大量的体外实验及动物实验说明益生菌抑制炎症反应、抑制肿瘤的发生、抑制肿瘤细胞的生长。n目前尚缺乏足够的临床研究证据。n一个四年期的临床研究表明服用 Lactobacillus casei可以减少结肠息肉的复发率。（Ishikawa 2005）n一个12周的随机双盲对照实验合生原（益生菌+益生元）干预治疗可以显著增加患者粪便中Bifidobacterium 和Lactobacillus的数量及减少Clostridium perfringens的数量，也显著减少息肉切除后患者结直肠黏膜的增生。（Rafter 2007）Janelle C.Arthur,PhD and Christian Jobin,PhD结肠菌群紊乱与结肠肿瘤发生的关系结肠菌群紊乱结肠菌群紊乱免疫、炎症改变免疫、炎症改变肥胖肥胖结肠肿瘤发生结肠肿瘤发生