肠道菌群紊乱与疾病.ppt

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GutMicrobiota,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。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。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。,OrrhageK,NordCE.Factorscontrollingthebacterialcolonizationoftheintestineinbreastfedinfants.ActaPaediatr.1999;88(430):47S-57SBiasucciG,RubiniM,RiboniS,RetetangosC,MorelliL,BessiE.Modeofdeliveryaffectsthebacterialcommunityinthenewborngut.EarlyHumDev.2010Feb4.,人体消化道细菌分布,人体结肠菌群结构,肠道菌群GutMicrobiota,Microbesactasadefendingbarrieragainstinvadingpathogens,aidindigestion,providenutritionalsupportforenterocytes,andplayacrucialroleinthedevelopmentoftheimmunesystem.Specificpathogens(e.g.,Salmonella,Campylobacterjejuni,andenterotoxigenicC.perfringens)havebeenimplicatedinacuteandchronicgastrointestinaldisease.,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。肠道菌群紊乱（dysbiosis）可导致一些重要疾病，如炎症性肠病、结肠癌、肥胖、糖尿病等。肠道菌群可称为人体一个新的器官。,益生菌Probiotics,定义：livemicro-organismswhichconferahealthbenefitonthehostwhenadministeredinadequateamounts.WHO（2001）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。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。常见益生菌如双歧杆菌、乳酸杆菌、粪链球菌等。,Dysbiosis,animbalancebetweenharmfulandprotectivebacteria,“卫生”学说“hygienehypothesis”。,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。粪便中细菌的多态性与婴儿的湿疹发生呈负相关。,CommonlyobservedmicrobialchangesareincreasedProteobacteria(i.e.,Escherichiacoli)withconcurrentdecreasesinFirmicutes,especiallyareduceddiversityinClostridiumclustersXIVaandIV(i.e.,Lachnospiraceae,Ruminococcaceae,Faecalibacteriumspp.).Thiswouldindicatethatthesebacterialgroups,importantshort-chainfattyacidproducers,mayplayanimportantroleinpromotingintestinalhealth.,结肠菌群与结肠癌的关系,结肠癌ColorectalCancer,每年世界范围内发病人数超过100万，死亡过半。结直肠癌在我国的发病率正逐年升高，年均增长率接近5%。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,结肠菌群变化与肥胖关系密切。Mkivuokko等报告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。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、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。,MkivuokkoH,TiihonenK,TynkkynenS,PaulinL,RautonenN.Theeffectofageandnon-steroidalanti-inflammatorydrugsonhumanintestinalmicrobiotacomposition.JNutr.2010;103(2):227-34.EnckP,ZimmermannK,RuschK,SchwiertzA,KlosterhalfenS,FrickJS.Theeffectsofageingonthecolonicbacterialmicroflorainadults.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。,ThegutmicrobiotaasanenvironmentalfactorthatregulatesfatstorageFredrikBackhedetal.,1571815723PNASNovember2,2004vol.101no.44,Obesityaltersgutmicrobialecology（？）Leyetal.,1107011075PNASAugust2,2005vol.102no.31,EarlydifferencesinfecalmicrobiotacompositioninchildrenmaypredictoverweightKalliomakietal.,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),AmJClinNutr2008;87:5348,结肠菌群与结肠黏膜免疫、炎症的关系,Hypothesisforbacteria-inducedmetabolicdiseaseCanietal.,Diabetes57:14701481,2008,ChangesinGutMicrobiotaControlMetabolicEndotoxemia-InducedInammationinHigh-FatDietInducedObesityandDiabetesinMiceCanietal.,normaldiet(CT),normaldietandantibiotics(CT-Ab),high-fatdiet(HF),orhigh-fatdietandantibiotics(HF-Ab)for4weeks.,Theconclusions,Thisnewndingdemonstratesthatchangesingutmicrobiotacontrolsmetabolicendotoxemia,inammation,andassociateddisordersbyamechanismthatcouldincreaseintestinalpermeability.Itwouldthusbeusefultodevelopstrategiesforchanginggutmicrobiotatocontrol,intestinalpermeability,metabolicendotoxemia,andassociateddisorders.,结肠菌群紊乱,炎症,肥胖,结肠肿瘤发生,？,炎症与肿瘤,约20%的肿瘤发生与炎症有关。溃疡性结肠炎病史越长，癌变率越高。炎症相关性结肠癌（colitis-assocatedcancerCAC）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。炎症增加结肠癌的发病几率。,ThetypesandnumbersofbacteriaassociatedwithbiopsysamplesweredistinctlydifferentforUCandCDpatients.,(B)CDpatients;(C)UCpatients.,BibiloniR,etal.Thebacteriologyofbiopsiesdiffersbetweennewlydiagnosed,untreated,Crohnsdiseaseandulcerativecolitispatients.JMedMicrobiol.2006;55(Pt8):1141-9.,机制Mechanisms,两个主要机制(Vannuccietal.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mucosalcells,gut-associatedlymphatictissueGALT,intraepitheliallymphocytesIEL,dendriticcellsDC,andcellsofthemesentericlymphnodesMLN),(Vannuccietal.2009),ModulationoftheIntestinalMicrobiotaAltersColitis-AssociatedColorectalCancerSusceptibilityUronisetal.,conventionalized-IL10-/-mice,Germ-freeIL10-/-mice,wild-type(WT)mice.,IL10-/-micemono-associatedmice,PLoSONE,June2009|Volume4|Issue6|e6026,肠道微生物识别microbialrecognition,一些受体可感受细菌细胞壁、细胞核成分。结直肠黏膜通过模式识别受体（patternrecognitionreceptorsPRRs）Toll-likereceptors，TLRs；nucleotide-bindingdomainleucine-richrepeatproteins(NLR;alsoknownasNod-likereceptors)；retinoicacidinduciblegene-IlikeRNAhelicases(RLH),C-typelectinreceptors(CLR)。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,TheinnateimmunereceptorNod1protectstheintestinefrominflammation-inducedtumorigenesisChenetal.,Nod1deficiencyresultsinincreasedinflammation-inducedcolontumorsNod1andtheApctumorsuppressorcooperateincolitis-associatedtumorigenesisSeverityofchemically-inducedcolitisisincreasedwithNod1deficiencyNod1deficiencyresultsinincreasedproinflammatorymediatorproductionandincreasedintestinalepithelialproliferationThegutmicrobiotacontributestoincreasedcolitis-associatedtumorigenesiswithNod1deficiency,CancerRes.2008December15;68(24):1006010067.,RolesforInflammationandRegulatoryTCellsinColonCancerERDMANetal.,ToxicologicPathology,38:76-87,2010,一些益生菌具有免疫调节及免疫刺激的作用,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1,2dymethylhydrazine(DMH)所导致的炎症反应。Leblanc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PeyersPatches中TNF-及IFN-的分泌增加。,Theformylpeptidereceptor(FPR),FPR:FPR1,FPRL1(formylpeptidereceptor-like1;FPR2),andFPRL2(formylpeptidereceptor-like2;FPR3).TheFPRisthehigh-afnityreceptorforformylatedpeptidesleakingfromgrowingbacteriaandthereforeservesasanimportantinnateimmunerecognitionreceptor.,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-PositiveCellInfiltratio