胆汁酸代谢、肠道菌群与自身免疫性肝病-马雄

马雄上海市消化疾病研究所上海交通大学医学院附属仁济医院胆汁酸代谢、肠道菌群与自身免疫性肝病自身免疫性肝病HirshfieldGM,etal.Gastroenterology2010;139:1481自身免疫性肝炎（AutoimmuneHepatitis,AIH）原发性胆汁性胆管炎（PrimaryBiliaryCholangitis,PBC）原发性硬化性胆管炎(PrimarySclerosingCholangitis,PSC)IgG4相关硬化性胆管炎（IgG4related-Sclerosingcholangitis）重叠综合征(OverlapSyndrome)OLIGOGENICPOLIGENICFamilialSporadicENVIRONMENTGENETICSCFTR,ABCB4INFCETIONSAutoimmunity自身免疫性疾病发病机制“CommonGround”HypothesisofPathogenesisCausedbyDysbioticGutMicrobiotaLynchSV,PedersenO.NEnglJMed.2016;375:2369-2379.StudyYearPatientsControlsReplicationcase/contPopulationLociimplicatedKarlsen,etal.2010285298766/2935Scandinavian,GermanHLAMelum,etal.201171529621025/2174Scandinavian,GermanHLA,BCL2L11,MST1Folseraas,etal201271529621221/3508Scandinavian,Germandiscovery;Scandinavian,CentralEuropeanandUSreplicationMMEL1-TNFRSF14Srivastava,etal.20129925162N/AUKCaucasiansMST1,IL2RAEllinghaus,etal201339229771012/2694German,ScandinavianGPR35,TCF4Liu,etal2013378925079Pan-European,NAmericaHLA,MMEL1-TNFSF14,CD28,MST1,IL2/IL21,BACH2,IL2RA,SIK2,HDAC7,SH2B3,CD226,FUT2,PSMG1Ellinghaus,etal2016340834213Pan-EuropeanCCL20,NFKB1,RIC8B,LOC107984859Ji,etal20162871120191925/7936Pan-European,NAmerica,Africa,Chinese,JapaneseCCDC88B,CLEC16A,FOXP1,UBASH3APSC全基因组关联分析研究StudyYearPatientsControlsReplicationcase/contPopulationLociimplicatedHirschfieldetal.20095361536526/1206WhiteNAmericanHLA,IL12A,IL12RB2Hirschfieldetal.20104941502857/3198WhiteNAmericanIRF-TNPO3,MMEL1,IZF3Liu,etal2010453945NoneItalianandmetaNAmericanSPIB,IKZF3,IRF5-TNPO3Mells,etal.201118405163620/2514NEuropeanDENND1B,STAT4,CD80,NFKB1,IL7R,CXCR5,TNFRSF1A,RAD51L1,CLEC16A,MAP3KK71P1;PLCL2,RPS6KA4,TNFAIP2Cordell,etal2015274598023616/4261NEuropean,Italian,NAmericanIL1R1,CCL20,DGKQ,C5ORF30,IL12B,TNFAIP3Nakamura,etal2012487476787/615JapaneseHLA,TNFSF15,POU2AF1Qiu,etal201711224074900/1200ChineseHanIL21,IL21R,CD28/CTLA4/ICOS,CD58,ARID3A,IL166PBC全基因组关联分析研究QiuF,…,LiuX,MaX.NatureCommunications2017.Stage1：1122cases：4074controlsStage2：907cases：2127controlsPBC全基因组关联分析研究中国汉族人群AGenome-WideAssociationStudyIdentifiesSixNovelRiskLociforPBCTfhcells,IL-21andBCellMaturationLSECsTfhPDC-E2BBECsTMacrophageCXCL13BiliaryDuctsHepaticsinusoidNKIL-21IL-10IL-4IL-6IL-21NaïveBBregBBTfhBmBpIL-6IFN-γAMANaïveBLiY,etal.Hepatolgy2015;61:1998-2007.WangLF,etal.Hepatology2015;61:627-38.IL-21producedbyTfhcellspromotesB-cellmaturationandautoantibodyproductioninPBCpatients肠道微生物组：人类第二基因组•肠道细菌重量约1kg•种类1000余种•细胞数量是人体细胞总数的10倍•基因数量3,300,000，是人体自身基因组的150倍2001年人类基因组工作草图发表2010年人体肠道菌群基因集构建人体与肠道菌群已形成了紧密的共生关系ThegutmicrobiotainthedevelopmentanddiseasesNicholsonJK,etal.Science2012;336:1262.Aschematicofaconceptualenergylandscapeharbouringmultiplepossiblestablestatesofsymbiosisanddysbiosis.LevyM,etal.NatRevImmunol2017Typesofdysbiosis:•Bloomofpathobionts;•Lossofcommensals;•Lossofdiversity.肠道菌群失调与疾病LevyM,etal.NatRevImmunol2017致病菌过度生长共生菌丢失微生物多样性降低VariationinMicrobiomeLPSImmunogenicityContributestoAutoimmunityinHumansVatanenT,etal.Cell2016RuffWE,KriegelMA.TrendsMolMed2015;21:233-44.肠道菌群参与肠道和肠外自身免疫性疾病的发生发展表位扩散肠菌抗原组织损伤APC自身抗原CD４旁观者效应TLRNLR超抗原打破免疫耐受分子模拟自身抗原模拟物与肠菌抗原交叉反应潜在机制肠道菌群自身免疫性疾病肠–肝轴•肝脏与肠道在解剖位置和生理功能方面密切联系•肝脏70%血液来自于肠道，易暴露于肠道细菌及其代谢产物•肝脏通过分泌胆汁酸等调节肠道菌群；肠道菌群调控胆汁酸合成与代谢•脂肪肝、肝硬化患者肠道菌群均发生改变炎症细胞肠菌代谢物胆汁酸肝脏原发性硬化性胆管炎LazaridisKN,etal.NEnglJMed2016;375:1161-70.PSC&IBD50-80%PSC合并UC5%的UC合并PSCKarlsonTH,etal.JournalofHepatology2013;59:571–582Thegut–liverrelationshipinPSCO’HaraSP,etal.Gut2017.ThegutmicrobiotacontributestoamousemodelofspontaneousbileductinflammationSchrumpfE,etal.JHepatol2017;66:382-389.GermfreeNOD.c3c4micehavelessCD3,Ly6GandMac-2positivecellsaroundtheirbileductscomparedwithconventionallyraisedNOD.c3c4mice.GermfreeNOD.c3c4micehavereducedinflammatoryportalinfiltratescomparedwithconventionallyraisedNOD.c3c4miceat18weeksofage.AbsenceoftheintestinalmicrobiotaexacerbateshepatobiliarydiseaseinPSCmodal.TabibianJH,etal.Hepatology.2016;63:185-96.ConceptualframeworkfortheroleofthemicrobiotaintheetiopathogenesisofPSCTabibianJH,etal.Hepatology.2016;63:185-96.原发性硬化性胆管炎、炎症性肠病、健康人群的肠道微生物差异SabinoJ,etal.Gut2016.PSC患者肠道菌群组成与健康对照、IBD患者均有显著差别；无论有无IBD，PSC的肠道菌群相似PSC-UC患者菌群多样性显著降低52PSC,52HC,13UC,30CD16SrRNA基因测序SabinoJ,etal.Gut2016.肠球菌属，链球菌属，乳杆菌属的比例在PSC患者中特异性上升，与患者是否合并IBD及服用UDCA无关梭菌属在PSC和IBD患者中都有显著上升PSC肠菌标记物原发性硬化性胆管炎、炎症性肠病、健康人群的肠道微生物差异ThegutmicrobialprofileinPSCisdistinctfromulcerativecolitiswithoutbiliarydiseaseandhealthycontrolsKummenM,etal.Gut.2017;66:611-619.BetadiversityAUROCanalysisusingtherelativeabundanceoftheVeillonellagenusorall9generadifferingbetweenPSCandHCorUCCountryNorwayBelgiumGerman(letter)Japan(letter)PSCpatients85667313Healthycontrols263668823IBDcontrols36439815Alpha-diversityPSCvs.HC↓↓↓PSCvs.IBD-↑Taxa↑PSCvs.HCVeillonellaEnterococcusLactobacillusFusobacteriumVeillonellaVeillonellasp.3_1_44StreptococcusparasanguinisEnterococcusfaeciumEnterococcussp.NBRC107345Taxa↓PSCvs.HCSuccinivbrio,DesulfovibrioPhascolarctobacteriumCoprococcusLachnospiraceaeChristensenellaceaeClostridiales…AnaerostipeshadrusParabacteroidesdistasonisBlautiaobeumKummenM,etal.Gut2017;66:611-619.Sabi