RESEARCHARTICLESUMMARY◥MICROBIOMEGutmicrobiome–mediatedbileacidmetabolismregulateslivercancerviaNKTcellsChiMa,MiaojunHan,BerndHeinrich,QiongFu,QianfeiZhang,MilanSandhu,DavidAgdashian,MasakiTerabe,JayA.Berzofsky,ValerieFako,ThomasRitz,ThomasLongerich,CaseyM.Theriot,JohnA.McCulloch,SoumenRoy,WuxingYuan,VishalThovarai,ShurjoK.Sen,MathurosRuchirawat,FirouzehKorangy,XinWeiWang,GiorgioTrinchieri,TimF.Greten*INTRODUCTION:Primarylivertumorsandlivermetastasiscurrentlyrepresentthelead-ingcauseofcancer-relateddeaths.Theliverintimatelycross-talkswiththegutandper-formsmanyessentialfunctionsrelatedtodigestion,metabolismofnutrients,andclear-anceofbacterialmetabolites.Diseasedliversareoftenassociatedwithalteredgutbacterialcomposition,ordysbiosis,andithasbeensug-gestedthatgutbacterialproductscontributetomalignanttransformationofhepatocytes.Theliverisexposedtothegutmicrobiomethroughtheportalveinandisanimmuno-logicalorganthatisheavilypopulatedbyim-munecells.Emergingstudieshaveshownthatgutcommensalbacteriaareimportantregulatorsofantitumorimmunity.Althoughithasbeenestablishedthatthegutmicrobiomeinfluencestheefficacyofcancerimmuno-therapy,theroleofgutbacteriainantitumorsurveillanceintheliverispoorlyunderstood.RATIONALE:Theliverisexposedtogutbac-terialmetabolitesandproductsbywayofbloodfromtheintestine,whichcomprises70%ofthewholeliverbloodsupply.Changesinthegutmicrobiomemayaffectimmunecellfunctionintheliver,andcommensalbacteriacanmediatethemetabolismofprimaryintosecondarybileacids,whichrecirculatebackintotheliverthroughtheenterohepaticcirculation.Giventhatbileacidsareknowntobeinvolvedinlivercancerdevelopment,wefocusedontheroleofbileacidsinimmunosurveillanceoftumorsgrowingintheliver.Wealteredgutbacteriaandexaminedchangesofhepaticim-munecellsandantitumorimmunitydirectedagainstlivertumors.Uncoveringhowthegutmicrobiomeusesbileacidstoshapeimmunitytolivercancermayhavefuturetherapeuticapplications.RESULTS:Usingoneprimarylivermodelandthreelivermetastasismodels,wefoundthatalteringcommensalgutb...
