Articles850VOLUME23|NUMBER7|JULY2017nAturemedicineMetforministhemostprescribedpharmacotherapyforthetreatmentofindividualswithtype2diabetes(T2D)becauseofitsrelativesafety,lowcost,andbeneficialeffectsonbloodglucoseandcardiovascu-larmortality1,2.However,itsmechanismofactionremainsunclear.Althoughmetforminisgenerallyconsideredtomediateitsantihyper-glycemiceffectsbysuppressinghepaticglucoseoutputthroughtheactivationofAMP-activatedproteinkinase(AMPK)-dependent3–5andAMPK-independentpathways6–8intheliver,accumulatingevi-denceindicatesthatitmightalsoactthroughpathwaysinthegut9,10.Forexample,itsglucose-loweringeffectismorepronouncedwhengivenorallythanwhenadministeredintravenously11.Inaddition,astudycomparingmetforminformulationswithreducedandnormalplasmaexposureprovidedevidencetoindicatethatthelowerbowelisamajorsiteofactionformetformin12.Furthermore,recentstud-iesinbothrodents13–15andhumans16–18suggestthatgutmicrobialchangesmightcontributetotheantidiabeticeffectofmetformin.Sofar,however,itisnotknownhowmetforminaffectsthegutmicro-biotaofindividualswithtreatment-naiveT2D,norhowmetformininteractswithgutbacteria.Hereweperformedarandomized,placebo-controlled,double-blindstudyinindividualswithnewlydiagnosedT2Donacalorie-restricteddiet,andwecombinedmetagenomicsandtargetedmetabolomicstoinvestigatetheeffectofmetforminonthecompositionandfunctionofthegutmicrobiota.Wealsotransferredhumanfecalsamplestogerm-freemicetostudytheeffectsofmetformin-alteredmicrobiotaonhostglucosemetabolism,andweusedaninvitrogutsimulatortoinvestigatemetformin–microbiotainteractionsdirectly.RESULTSMetforminaltersthegutmicrobiotacompositionToinvestigatehowmetforminaffectsthecompositionofthegutmicrobiota,werandomizedtreatment-naiveindividualswithrecentlydiagnosedT2Dtoreceiveeitherplacebo(n=18)or1,700mg/dofmetformin(n=22)for4monthsinadouble-blindstudy.ClinicalcharacteristicsoftheseindividualsbeforeandaftertreatmentarepresentedinTable1.Bothgroupswererecommendedtoconsumeacalorie-restricteddietforthe4-monthstudy...
