Cell-Host-Remodeling-of-the-Gut-Microbiome-and-Met

1、HostRemodelingoftheGutMicrobiomeandMetabolicChangesduringPregnancyOmryKoren,1JuliaK.Goodrich,1TylerC.Cullender,1Ayme´Spor,1,11KirsiLaitinen,3,4HeleneKlingBa¨ckhed,6,7AntonioGonzalez,8JeffreyJ.Werner,2,12LargusT.Angenent,2RobKnight,9,10FredrikBa¨ckhed,6,7ErikaIsolauri,5SeppoSalminen,4andRuthE.Ley1,*1DepartmentofMicrobiologyandDepartmentofMolecularBiologyandGenetics2DepartmentofBiologicalandEnvironmentalEngineeringCornellUniversity,Ithaca,NY14853,USA3InstituteofBiomedicine4FunctionalFoodsForumUni。

2、versityofTurku,20610Turku,Finland5DepartmentofPediatrics,TurkuUniversityHospital,20521Turku,Finland6SahlgrenskaCenterforCardiovascularandMetabolicResearch/WallenbergLaboratory,SE-41345Gothenburg,Sweden7DepartmentofMolecularandClinicalMedicine,UniversityofGothenburg,SE-40530Gothenburg,Sweden8DepartmentofComputerScience9DepartmentofChemistryandBiochemistry10HowardHughesMedicalInstituteUniversityofColorado,Boulder,Boulder,CO80309,USA11Presentaddress:INRA,UMR1347Agroe´cologie,21000Dijon,France12Pres。

3、entaddress:DepartmentofChemistry,SUNYCortland,Cortland,NY13045,USA*Correspondence:[e-mail]’sage,andtheinfantmicrobiotawasunaffectedbymother’shealthstatus.Gutmicrobiotachangeddramaticallyfromfirst(T1)tothird(T3)trimesters,withvastexpansionofdiversitybetweenmothers,anoverallincreaseinProteobacteriaandActinobacteria,andreducedrichness.T3stoolshowedstrongestsignsofinflam-mationandenergyloss;however,microbiomegenerepertoireswereconstantbetweentrimesters.Whentransferredtogerm-freemice,T3microb。

4、iotainducedgreateradiposityandinsulininsensitivitycomparedtoT1.Ourfindingsindicatethathost-microbialinteractionsthatimpacthostmetabolismcanoccurandmaybebeneficialinpregnancy.INTRODUCTIONOverthecourseofanormal,healthypregnancy,thebodyundergoessubstantialhormonal,immunological,andmetabolicchanges(MorandCardenas,2010;NewbernandFreemark,2011).Bodyfatincreasesearlyinpregnancy,followedbyreducedinsulinsensitivitylateringestation(Barbouretal.,2007).Reducedinsulinsensitivityhasbeencorrelatedwithchangesinim。

5、munestatusinpregnancy,includingelevatedlevelsofcirculatingcytokines(e.g.,TNF-aandIL-6;Kirwanetal.,2002)thatarethoughttodriveobesity-associatedmeta-bolicinflammation(GregorandHotamisligil,2011).Incontrasttotheobesestatewheretheyaredetrimentaltolong-termhealth,excessadiposityandlossofinsulinsensitivityarebene-ficialinthecontextofanormalpregnancy,astheysupportgrowthofthefetusandpreparethebodyfortheenergeticdemandsoflactation(DiCiannietal.,2003;LainandCatalano,2007;Nelsonetal.,2010).Thecauseofreducedi。

6、nsulinsensitivityinpregnancyremainsunclear.Inthecontextofnonpregnantobesity,recentworksuggestsaroleforgutmicrobiotaindrivingmetabolicdisease,includinginflammation,weightgain,andreducedinsulinsensi-tivity(Canietal.,2007;Vijay-Kumaretal.,2010).Thegutmicro-biotaisshapedbyenvironmentalfactors,suchasdiet(Wuetal.,2011),hostgenetics(Sporetal.,2011),andtheimmunesystem,which,inparticular,canhaveprofoundeffectsonthecomposi-tionofthegutmicrobiota(Salzmanetal.,2010;Slacketal.,2009;Vijay-Kumaretal.,2010).Inpr。

7、egnancy,immunologicalchangesoccurattheplacentalinterfacetoinhibitrejectionofthefetus,whileatthemother’smucosalsurfaces,elevatedinflammatoryresponsesoftenresultinexacerbatedbacteriallymediateddiseases,suchasvaginosisandgingivitis(Beigietal.,2007;Straka,2011).Inthegut,bacterialloadisreportedtoincreaseoverthecourseofgestation(Colladoetal.,2008),butacompre-hensiveviewofhowmicrobialdiversitychangesoverthecourse470Cell150,470–480,August3,2012ª2012ElsevierInc.ofnormalpregnancyislacking.Thecontributionof。

8、intestinalhost-microbialinteractionsinpromotingweightgainandothermetabolicchangesinthecontextofpregnancyremainstobeevaluated.Inthepresentstudy,wehavecharacterizedthechangesinthegutmicrobiotathatoccurfromthefirst(T1)tothethird(T3)trimesterofpregnancyandhaveassessedthepotentialofT1andT3microbiotatoinducemetabolicchangesusinggerm-free(GF)mousetransfers.Weprovideevidencethatthegutmicrobialcommunitycompositionandstructureareprofoundlyalteredoverthecourseofpregnancy.Furthermore,theT3micro-biotainducesm。

9、etabolicchangesinGFrecipientmicethataresimilartoaspectsofmetabolicsyndrome.Thesechangesareassociatedwithmetabolicdiseaseinnonpregnantwomenandmenbutmaybebeneficialinthecontextofanormalpregnancy.RESULTSTheGutMicrobiotaIsProfoundlyAlteredduringPregnancyToaddresshowpregnancyaltersthegutmicrobiome,weob-tainedstoolsamples,dietinformation,andclinicaldatafor91pregnantwomenwhowerepreviouslyrecruitedforaprospec-tive,randomizedmother-infantnutritionstudyinFinland(seeSupplementalInformationavailableonlinefor。

10、details;Colladoetal.,2008,2010;Laitinenetal.,2009).Eachpregnantwomandonat。