GutmicrobiomeinHCC–Mechanisms,diagnosisandtherapyRobertF.Schwabe1,2,⇑,TimF.Greten3,4,⇑SummaryThemicrobiomeexertsessentialfunctionsinhealthanddisease,modulatingkeyprocessesinmetabo-lism,inflammationandimmunity.Recentevidencehasrevealedakeyroleofthemicrobiomeincarcino-genesisaswellasanti-cancerimmuneresponsesinmousemodelsandpatients.Herein,wewillreviewfunctionsofthegutmicrobiomeinhepatocellularcarcinoma(HCC),thethirdleadingcauseofworld-widecancermortality.ThemajorityofHCCdevelopsinpatientswithchronicliverdisease,causedbyviralhepatitis,non-alcoholicfattyliverdisease(NAFLD)andalcohol-relatedfattyliverdisease.Inthisreview,wewilldiscussmechanismsbywhichthegut-liveraxispromotesthedevelopmentofHCCinmousemodelsandpatients,includingdysbiosis,theleakygutandbacterialmetabolites,withapartic-ularfocusonNAFLDasthefastestgrowingcauseofHCCdevelopment.Moreover,wewillreviewrecentprogressinharnessingthegutmicrobiomeasapotentialdiagnostictoolandnoveltherapeutictargetinpatientswithHCC,inparticularinthesettingofimmunotherapy.PublishedbyElsevierB.V.onbehalfofEuropeanAssociationfortheStudyoftheLiver.IntroductionInaworlddominatedbymicrobes–notonlyintermsofpurebiomass,butalsodiversityandgenepool–ourorganismhasdevelopedmechanismstoengageinmutualrelationshipswithmicrobes,whicharepresentatitssurfacesincludingthegut.Moreover,thepresenceofefficientbarriersrestrictcontacttosurfaceareasandpreventthemicrobiotafrominvadingourorganism.Theseprinciplesallowhumanstobenefitfromthemicrobiotainmanyways,includingmetabolismandimmunity,whileavoidingpathogenicinfec-tions.Whiletheliverisnotindirectcontactwithmicrobiota,ithastightanatomiclinkstothegut.1,2Thephysiologictransportofnutrient-richbloodfromtheintestinetotheliverisaccompa-nied–despitethehighlyefficientmulti-levelintestinalbarrier–bylow-gradeexposuretogutmicrobiota-derivedmetabolitesandproducts,1,2oftentermedmicrobiota-associatedmolecularpatterns(MAMPs).Intheliver,Kupffercellsserveasanefficient‘‘bacterialfirewall”protectingfrombacterialinfect...
