Human Gut Microbiome and Body Metabolism.docx

Human Gut Microbiome and Body Metabolism.docx

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HumanGutMicrobiomeandBodyMetabolism

TheHumanGutMicrobiomeandBodyMetabolism:

ImplicationsforObesityandDiabetes

SrideviDevaraj,1,2 PeeraHemarajata,1,2 and JamesVersalovic1,2,*

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Thepublisher'sfinaleditedversionofthisarticleisavailablefreeat ClinChem

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Abstract

BACKGROUND

Obesity,metabolicsyndrome,andtype2diabetesaremajorpublichealthchallenges.Recently,interesthassurgedregardingthepossibleroleoftheintestinalmicrobiotaaspotentialnovelcontributorstotheincreasedprevalenceofthese3disorders.

CONTENT

RecentadvancesinmicrobialDNAsequencingtechnologieshaveresultedinthewidespreadapplicationofwhole-genomesequencingtechnologiesformetagenomicDNAanalysisofcomplexecosystemssuchasthehumangut.Currentevidencesuggeststhatthegutmicrobiotaaffectnutrientacquisition,energyharvest,andamyriadofhostmetabolicpathways.

CONCLUSION

AdvancesintheHumanMicrobiomeProjectandhumanmetagenomicsresearchwillleadthewaytowardagreaterunderstandingoftheimportanceandroleofthegutmicrobiomeinmetabolicdisorderssuchasobesity,metabolicsyndrome,anddiabetes.

Obesity,metabolicsyndrome,andtype2diabetesaremajorpublichealthchallenges,affectingapproximately26millionchildrenandadultsintheUS.Morethan8%oftheUSpopulationhasdiabetes,ofwhich17.9millionpeoplehavethemetabolicsyndrome 

（1）.Duringthepast20years,obesityhasdramaticallyincreasedinprevalenceintheUS.Morethan1in3USadults（36%）areobese,andapproximately12.5million（17%）ofchildrenandadolescents（age2–19years）areobese 

（2）.IntheUSin2010 

（2）,allofthestateshadaprevalenceofobesityofover20%.Theheterogeneityofthesedisordershasbeendemonstratedthroughbothanthropometricandgeneticstudies.Thesemetabolicdisordersarebelievedtobecausedbyacombinationofgeneticsusceptibilitiesandlifestylechanges.Recently,interesthassurgedinthepossibleroleoftheintestinalmicrobiomeasapotentialcontributortotherapidlyincreasedprevalenceofobesity （3–5）.Thisreviewfocusesonrecentadvancesintheunderstandingofthegutmicrobiomeandtechniquestoassessthemicrobiomeanditsrelationshiptohumanbodymetabolism,obesity,metabolicsyndrome,andtype2diabetes （Fig.1）.

Hyperglycemia（HG）andincreasedfreefattyacids（FFA）,whicharehallmarksofobesity,metabolicsyndrome,anddiabetes,combinedwithahigh-fat,high–glycemicloaddiet,couldresultinincreasedactivationoftheinflammasomecomplexaswell ...

TheHumanGutMicrobiome:

TheToolkitbehindtheScience

Thewidespreadapplicationof16SrRNAgenesequencingfordetectionofbacterialpathogensandmicrobialecologyhasprovidedarobusttechnicalplatformfortheevaluationofthebacterialcompositionofthehumanmicrobiome.Sequencingof2primarytargetswithinbacterial16SrRNAgenesyieldedvaluablecompositionaldatapertainingtothehumanfecalmicrobiomeof242healthyadults （6, 7）.IntheHumanMicrobiomeProject,18differentbodysitesweresampledandsequenced.Stoolspecimenswerethesinglespecimentypeusedtostudytheintestinalmicrobiome.Previouslypublishedstudiesdemonstratedthevariationincompositionofthegutmicrobiomeamonglocationswithinthegastrointestinaltractindifferentmammalianspecies.Forexample,16SrRNAgenesequencinghasbeendeployedtostudythematurationofmurinececalmicrobiota,andthesestudiesdemonstratedtheexistenceofalargenumberofyet-unidentifiedbacteriathatinhabitthemammalianintestine （6）.Suchsequencingstrategies,whicharecultureindependent,areessentialfordeterminingbacterialcompositionofthemicrobiomeanditsrelativestabilityanddiversityovertime.Thus,itisessentialtodeveloprobustexperimentalmodelsofthehumanmicrobiometodelineateimportantmechanisticprocessesinthedevelopmentofhumandiseasestates.

Advancesinsequencingtechnologieshaveresultedinthewidespreadapplicationofwhole-genome（WG）3sequencingtechnologiesformetagenomicDNAanalysisofcomplexecosystemssuchasthehumanintestine （7）.WGsequencingstrategiesprovidemicrobialcompositionalaswellasfunctionalinformation.WGdatacanbeusedtoinferbacterialcomposition,andthesedatayieldinformationsimilartothatgeneratedby16SrRNAgenesequencing.Thegenomesequencesofhighlyabundantspeciesarewellrepresentedinasetofrandomshotgunreads,whereaslessabundantspeciesarerepresentedbyfewersequencesgeneratedinanext-generationsequencingrun.Thisrelativerichnesspermitsthecomprehensivemeasurementofthecompositionalresponsesofanecosystemtodietarychanges,drugtherapy,epigeneticalterations,andenvironmentalperturbations.Alternatively,mostgenes（usuallyapproximately2000genesperbacterium）inthemicrobiomearesequencedsothatmetabolicandotherfunctionalpathwayscanbeevaluatedineachindividual’smetagenome.FunctionalWGdataprovideopportunitiestofindoutwhichmetabolicpathwaysareaffectedandhowthemicrobiomemaycontributemechanisticallytohealthanddiseasestates.Thistechnologycreatestheformidablechallengeofmanagingvastdatasets.Advancesinnext-generationDNAsequencingyielded576.7GbofmicrobialDNAsequencedata,whichweregeneratedwithanIllumina™genomeanalyzer（Illumina）fromtotalDNAfromthestoolsamplesof124Europeanadults （8）.Therelationshipbetweenthecommensalmicrobiotathatcomprisethegutmicrobiotaandthosethatareintheintestinalbarrieriscomplexanddiffersspatiallythroughoutdifferentareasofthegastrointestinaltract.Fecalmetagenomicsmeasuresecosystemchangesinstoolorthedistalintestine,butitdoesnotcomparethemicrobiomesindifferentregionsoftheintestine.Itisalsoimportanttonotethatmetagenomicanalysisoffecalsamplesdoesnotincludeallimportantmolecularinteractionswithinthegastrointestinaltract.Turnbaughetal.haveproposedtheideaofacoresetoffunctionswithinthemicrobiome,andthetoolsofproteomicsandmetabolomicsmayberequiredformorein-depthfunctionalanalyses （7, 9）.Fromasystemsperspective,metagenomicanalysesmayprovidefurtherdetailsonspecificintraindividualchangesandthushavemajorimplicationsforpersonalizedmedicinestrategies.

Metatranscriptomics,metaproteomics,andmetabonomicswillbeusefultoexplorethefunctionalaspectsofthegutmicrobiomefromthetopdown.Realtimeanalysisoftheintestinalmicrobiomeisausefultoolinthedevelopmentofpersonalizedapproachestotargetedtherapies.Metabonomicscanbedescribedasthestudyofmetabolicresponsestochemicals,theenvironment,anddiseasesandinvolvesthecomputationalanalysisofspectralmetabolicdatathatprovideinformationontemporalchangestospecificmetabolites.Inaddition,metabonomicsprovidesglobalmetabolicprofilingofanindividualinrealtime.Itispossible,withsuchapproaches,toelucidatecomplexpathwaysandnetworksthatarealteredinspecificdiseasestates.Thecombinationofmetabolicprofilingandmetagenomicstudiesofgutmicrobiotapermitsthestudyofhostandmicrobialmetabolismingreatdetail.Suchanalysisoffunctionalcomponentsofthemicrobiomethataffectmetabolismandhumanhealthisreferredtoasfunctionalmetagenomics.

Metagenomicsandthescienceofthehumanmicrobiomehavearrivedattheforefrontofbiologyprimarilybecauseofmajortechnicalandconceptualdevelopments.Themajortechnicaldevelopmentwasthedeploymentinmanycentersofnext-generationDNAsequencingtechnologieswithgreatlyenhancedcapabilitiesforsequencingcollectionsofmicrobialgenomesinthemetagenome.Technologicaladvanceshavecreatednewopportunitiesforthepursuitoflarge-scalesequencingprojectsthatweredifficulttoimagineadecadeago.Thekeyconceptualdevelopmentwastheemergingparadigmoftheessentialnatureofcomplexmicrobialcommunitiesandtheirimportancetomammalianbiologyandhumanhealthanddisease.TheHumanMicrobiomeProjectwasapprovedinMay2007as1of2majorcomponents（inadditiontothehumanepigenomicsprogram）ofNIHRoadMapversion1.5（nowknownastheCommonFund）.Recently,2seminalreportsfromtheHumanMicrobiomeProjectconsortium （10, 11） describedinvestigationsinwhichapopulationof242healthyadultsweresampledat15or18bodysitesupto3times,5177microbialtaxonomicprofilesweregeneratedfrom16SrRNAgenes,andmorethan3.5Tbasesofmetagenomicsequencesweregenerated.Inaddition,inparallel,theHumanMicrobiomeProjectconsortiumhassequencedapproximately800human-associatedreferencegenomes.Thisresourcewillprovideaframeworkforfuturestudiesofdiseasestatesandareferencecollectionofhealthyhumanmicrobiomedata.Thedatasetwillenablefutureinvestigationsintotheepidemiologyandecologyofthehumanmicrobiomeinvariousdiseasestates,andtreatmentstrategieswillevolvefromthesestudies.Usingcompositionalandfunctionalapproaches,therelationshipsbetweenpathologicalvariationsinthegutmicrobiomeandseveraldiseasestateshavebeendelineated.

Urinemetabolomicsprovidesanopportunityforstudiesofthemicrobiome’simpactonwhole-bodymetabolism.Theadvantagesofusingurinarysamplesincluderelativelylargesamplevolumesandtheconvenienceofnoninvasivecollection.Inaddition,urinesamplescanbeusedfortheinvestigationofthechronologyofmetabolicchangesandthusareavaluabletoolforinvestigationsrelatedtothepathogenesisorprogressionofdiseaseandforscreeninganddiagnosisaswellasprognosticevaluat