腸道菌群紊亂與疾病

腸道菌群紊亂與疾病北京大學(xué)人民醫(yī)院消化內(nèi)科朱元民腸道細(xì)菌的建立及功能腸道菌群GutMicrobiota人體結(jié)腸細(xì)菌細(xì)胞細(xì)胞數(shù)量高達(dá)100萬億,是人體細(xì)胞數(shù)量的10倍。在分娩過程中細(xì)菌即植入新生兒腸道內(nèi)。分娩方式、喂奶方式等影響新生兒的腸道菌群結(jié)構(gòu)。母乳喂養(yǎng)的嬰兒糞便中雙歧桿菌的比例增加，配方喂奶嬰兒糞便中腸球菌比例增加。OrrhageK,NordCE.Factorscontrollingthebacterialcolonizationoftheintestineinbreastfedinfants.ActaPaediatr.1999;88(430):47S-57SBiasucciG,RubiniM,RiboniS,RetetangosC,MorelliL,BessiE.Modeofdeliveryaffectsthebacterialcommunityinthenewborngut.EarlyHumDev.2010Feb4.人體消化道細(xì)菌分布人體結(jié)腸菌群結(jié)構(gòu)腸道菌群GutMicrobiotaMicrobesactasadefendingbarrieragainstinvadingpathogens,aidindigestion,providenutritionalsupportforenterocytes,andplayacrucialroleinthedevelopmentoftheimmunesystem.Specificpathogens(e.g.,Salmonella,Campylobacterjejuni,andenterotoxigenicC.perfringens)havebeenimplicatedinacuteandchronicgastrointestinaldisease.嬰幼兒年齡階段的環(huán)境因素對(duì)成年期腸道菌群結(jié)構(gòu)及腸道免疫功能有重要影響。腸道菌群紊亂（dysbiosis）可導(dǎo)致一些重要疾病，如炎癥性腸病、結(jié)腸癌、肥胖、糖尿病等。腸道菌群可稱為人體一個(gè)新的器官。益生菌Probiotics定義：livemicro-organismswhichconferahealthbenefitonthehostwhenadministeredinadequateamounts.WHO（2001）飲食,年齡,抗生素使用,腸道pH值,腸道細(xì)菌間相互影響,腸道內(nèi)一些發(fā)酵物質(zhì)等均可影響腸道內(nèi)細(xì)菌結(jié)構(gòu)。益生菌可以黏附在結(jié)腸黏膜上，減少有害細(xì)菌的數(shù)量，調(diào)節(jié)腸道免疫功能，并可減輕炎癥反應(yīng)，抑制腫瘤增殖等。常見益生菌如雙歧桿菌、乳酸桿菌、糞鏈球菌等。Dysbiosis,animbalancebetweenharmfulandprotectivebacteria“衛(wèi)生”學(xué)說“hygienehypothesis”。

剖腹產(chǎn)、配方喂奶的嬰兒日后患過敏性疾病如皮疹、哮喘以及炎癥性腸病的幾率顯著升高。糞便中細(xì)菌的多態(tài)性與嬰兒的濕疹發(fā)生呈負(fù)相關(guān)。CommonlyobservedmicrobialchangesareincreasedProteobacteria(i.e.,Escherichiacoli)withconcurrentdecreasesinFirmicutes,especiallyareduceddiversityinClostridiumclustersXIVaandIV(i.e.,Lachnospiraceae,Ruminococcaceae,Faecalibacteriumspp.).Thiswouldindicatethatthesebacterialgroups,importantshort-chainfattyacidproducers,mayplayanimportantroleinpromotingintestinalhealth.結(jié)腸菌群與結(jié)腸癌的關(guān)系結(jié)腸癌ColorectalCancer每年世界范圍內(nèi)發(fā)病人數(shù)超過100萬，死亡過半。結(jié)直腸癌在我國的發(fā)病率正逐年升高，年均增長(zhǎng)率接近5%。年齡、肥胖、炎癥性腸病等是結(jié)腸癌發(fā)病的危險(xiǎn)因素。腸道細(xì)菌與結(jié)腸癌危險(xiǎn)因素相關(guān)結(jié)腸菌群變化與肥胖關(guān)系密切。M?kivuokko等報(bào)告老年人腸道細(xì)菌數(shù)量減少,并且Bacteroidetes數(shù)量增加,Firmicutes數(shù)量減少。使用NSAIDs老年人腸道細(xì)菌數(shù)量多于未使用NSAIDs老年人。Enck等報(bào)告人一些特殊的菌群隨年齡增長(zhǎng)而增加，如大腸桿菌、腸球菌等。一些腸道疾病如克羅恩病、潰瘍性結(jié)腸炎、腸易激綜合征等患者結(jié)腸菌群分別有其特殊性。

M?kivuokkoH,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無菌小鼠

Germ-free(GF)mouseGF動(dòng)物盲腸大且平滑，常規(guī)飼養(yǎng)（CV）的動(dòng)物小腸則比較大。GF動(dòng)物腸系膜淋巴結(jié)較CV對(duì)照發(fā)育差。ThegutmicrobiotaasanenvironmentalfactorthatregulatesfatstorageFredrikBackhedetal.15718–15723PNASNovember2,2004vol.101no.44Obesityaltersgutmicrobialecology（？）

Leyetal.11070–11075PNASAugust2,2005vol.102no.31Earlydifferencesinfecalmicrobiotacompositioninchildrenmaypredictoverweight

Kalliomakietal.體重保持正常的兒童幼兒期間糞便雙歧桿菌數(shù)量（

bifidobacterial）顯著高于以后變?yōu)榉逝謨和變浩诩S便數(shù)量(P=0.02)AmJClinNutr2008;87:534–8結(jié)腸菌群與結(jié)腸黏膜免疫、炎癥的關(guān)系Hypothesisforbacteria-inducedmetabolicdiseaseCanietal.Diabetes57:1470–1481,2008ChangesinGutMicrobiotaControlMetabolicEndotoxemia-InducedIn?ammationinHigh-FatDiet–InducedObesityandDiabetesinMiceCanietal.normaldiet(CT),normaldietandantibiotics(CT-Ab),high-fatdiet(HF),orhigh-fatdietandantibiotics(HF-Ab)for4weeks.TheconclusionsThisnew?ndingdemonstratesthatchangesingutmicrobiotacontrolsmetabolicendotoxemia,in?ammation,andassociateddisordersbyamechanismthatcouldincreaseintestinalpermeability.Itwouldthusbeusefultodevelopstrategiesforchanginggutmicrobiotatocontrol,intestinalpermeability,metabolicendotoxemia,andassociateddisorders.結(jié)腸菌群紊亂炎癥肥胖結(jié)腸腫瘤發(fā)生？炎癥與腫瘤約20%的腫瘤發(fā)生與炎癥有關(guān)。潰瘍性結(jié)腸炎病史越長(zhǎng)，癌變率越高。炎癥相關(guān)性結(jié)腸癌（colitis-assocatedcancerCAC）在經(jīng)典的氧化偶氮甲烷（AOM）致癌動(dòng)物模型中給予硫酸葡聚糖（DSS）可以顯著增加結(jié)腸癌的發(fā)生率。炎癥增加結(jié)腸癌的發(fā)病幾率。ThetypesandnumbersofbacteriaassociatedwithbiopsysamplesweredistinctlydifferentforUCandCDpatients.

(B)CDpatients;(C)UCpatients.BibiloniR,etal.Thebacteriologyofbiopsiesdiffersbetweennewlydiagnosed,untreated,Crohn’sdiseaseandulcerativecolitispatients.JMedMicrobiol.2006;55(Pt8):1141-9.機(jī)制Mechanisms兩個(gè)主要機(jī)制(Vannuccietal.2009)細(xì)菌感染后所產(chǎn)生的慢性炎癥細(xì)菌所產(chǎn)生的毒性代謝產(chǎn)物。主要涉及的細(xì)胞及組織mucosalcells,gut-associatedlymphatictissue[GALT],intraepitheliallymphocytes[IEL],dendriticcells[DC],andcellsofthemesentericlymphnodes[MLN])

(Vannuccietal.2009)ModulationoftheIntestinalMicrobiotaAltersColitis-AssociatedColorectalCancerSusceptibilityUronisetal.conventionalized-IL10-/-miceGerm-freeIL10-/-micewild-type(WT)mice.IL10-/-micemono-associatedmicePLoSONE,June2009|Volume4|Issue6|e6026腸道微生物識(shí)別microbialrecognition一些受體可感受細(xì)菌細(xì)胞壁、細(xì)胞核成分。結(jié)直腸黏膜通過模式識(shí)別受體（patternrecognitionreceptorsPRRs）Toll-likereceptors，TLRs；nucleotide-bindingdomainleucine-richrepeatproteins(NLR;alsoknownasNod-likereceptors)；retinoicacidinduciblegene-IlikeRNAhelicases(RLH),C-typelectinreceptors(CLR)。研究最為深入和廣泛的是TLRs。TLRs在細(xì)菌-炎癥-腫瘤過程中起重要的介導(dǎo)作用

TheinnateimmunereceptorNod1protectstheintestinefrom

inflammation-inducedtumorigenesisChenetal.Nod1deficiencyresultsinincreasedinflammation-inducedcolontumorsNod1andtheApctumorsuppressorcooperateincolitis-associatedtumorigenesisSeverityofchemically-inducedcolitisisincreasedwithNod1deficiencyNod1deficiencyresultsinincreasedproinflammatorymediatorproductionandincreasedinte