Intestinal Microbiota Distinguish Gout Patients from Healthy ...

Intestinal microbiota of gout are more similar to those of type-2 diabetes than to liver cirrhosis, whereas depletion of Faecalibacterium ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature scientificreports articles article IntestinalMicrobiotaDistinguishGoutPatientsfromHealthyHumans DownloadPDF Subjects BacterialgenesMetagenomicsRheumaticdiseases AbstractCurrentblood-basedapproachforgoutdiagnosiscanbeoflowsensitivityandhysteretic.Hereviaa68-membercohortof33healthyand35diseasedindividuals,wereportedthattheintestinalmicrobiotaofgoutpatientsarehighlydistinctfromhealthyindividualsinbothorganismalandfunctionalstructures.Ingout,BacteroidescaccaeandBacteroidesxylanisolvensareenrichedyetFaecalibacteriumprausnitziiandBifidobacteriumpseudocatenulatumdepleted.Theestablishedreferencemicrobialgenecatalogueforgoutrevealeddisorderinpurinedegradationandbutyricacidbiosynthesisingoutpatients.Inanadditional15-membervalidation-group,adiagnosismodelvia17gout-associatedbacteriareached88.9%accuracy,higherthantheblood-uric-acidbasedapproach.Intestinalmicrobiotaofgoutaremoresimilartothoseoftype-2diabetesthantolivercirrhosis,whereasdepletionofFaecalibacteriumprausnitziiandreducedbutyratebiosynthesisaresharedineachofthemetabolicsyndromes.ThustheMicrobialIndexofGoutwasproposedasanovel,sensitiveandnon-invasivestrategyfordiagnosinggoutviafecalmicrobiota. DownloadPDF IntroductionGoutisanauto-inflammatorydiseasecausedbyadisorderinpurinemetabolismandtheresultedchronicelevationofblooduricacid(i.e.,hyperuricemia)1.Withincreasedintakeofhighproteinfoodinmanysocieties,incidentsofgouthasbeenexpandingatanalarmrateworldwide2.In2011,prevalenceofgoutinUSadultsisabout3.9%,andthatofhyperuricemiawhichisapreconditionfordevelopinggoutreachedupto21%3.InUK,prevalenceofgouthasrisento2.5%ofthegeneralpopulationin2012,anincreaseof63.9%since19974.InChina,goutwaspreviouslyextremelyrare,yetthenumberofconfirmedcaseshasreached75millionbytheendof20105.Despitetheexpandingprevalenceofthedisease,accuratediagnosisremainsachallenge.Pathogenesisofgoutiscloselyrelatedtotheincreasedaccumulationandthereducedexcretionofuricacid(theendproductofpurinemetabolism).Theresulteddepositionofuricacidsaltcrystalsinjointsandthesurroundingtissuesleadtoacutejointpain6.Therefore,thetwosymptomsof(i)depositionofuricacidsaltcombinedwithacutepaininandaroundjointsand(ii)increaseinuricacidlevelinblood,arepresentlytheclinicaldiagnosticcriteriaforgout7.Thelatter,termedtheblooduricacidvalue,isconsideredasthemajordiagnosticcriteriaincurrentclinicalpractice,asitisquantifiable.Howevertheblooduricacidindexseemstobehystereticinalargepartandnotsufficientlysensitive8.Individualssufferedfromgoutarefrequentlyinastressedstate,whichcausesreflectivesecretionofadrenocorticotrophichormonetocompelthedischargeofuricacidbykidney9.Consequently,therecanbenosignificantriseofuricacidformostearly-onsetgoutpatients8.Thereforemethoddevelopmentforearlydiagnosisofgouthasbeenofhighpriority.Healthyhumansexcreteuricacidintwomainways,with70%excretedthroughthekidneyandtheremaining30%viatheintestine10.Humanintestinehomesahugenumberofmicrobescollectivelyknownasintestinalmicrobiota,whoseactivitiesarelinkedtonumeroushostfunctions11,12,13,14,15.Theintestinalmicrobiotaareknowntoparticipateinmetabolismofpurineanduricacid.Forexample,intheoxidativemetabolismofpurine,theresponsibleenzymexanthinedehydrogenasecanbesecretedbytheEscherichiacoligroupofhumanintestinalbacteria16,17.Inuricacidcatabolism,uricase,allantoinaseandallantoicaseactivitiescansequentiallydegradeuricacidto5-hydroxyisourate,allantoin,allantoateandeventuallytourea.SynthesisoftheseenzymeswasfoundvigorousinLactobacillusandPseudomonas,bothcommonmembersofhumanintestinalmicrobiota18.Moreovertransportproteinofuricacidwerefoundsecretedbyvariousindigenousmicrobesinhumangut19.Therefore,wehypothesizethattheintestinalmicrobiotacanpotentiallyserveasproxytoprobeuricacidmetabolisminthehostforthepurposeofdiagnosisorprognosis.Totestthishypothesis,herewedesignedacross-sectionalstudyinan83-memberChinesecohortthatconsistsofbothgoutpatientsandhealthyindividuals.Thetaxonomicstructureoftheirintestinalmicrobiotawasdeterminedby16SrRNAgenepyrosequencing,andthefunctionalprofileofthecorrespondingmicrobiomewasdeterminedbyshotgunmetagenomicsequencing.Profounddifferenceinmicrobialtaxonomicandfunctionalfeatureswasdiscoveredbetweengoutpatientsandhealthyindividuals.Amicrobiota-basedmodelbasedonsuchdifferencewasestablishedandshowntodiagnosegoutat88.9%accuracy.ResultsIntestinalmicrobiotaalteredprofoundlyingoutpatientsThestudycohortincludes83Chineseadults(Table1,SupplementaryTable1).Thegoutgroupconsistsof35adultpatientswhowereclinicallydiagnosedbyendocrinologistsasgoutbasedonblooduricacids,claimofjointpainsandotherparameters.Thehealthygroupwhichservesascontrolconsistsof33healthyadults.Anadditional,15-membergroupformodelvalidationpurposeconsistsof6goutpatientsand9healthyindividuals.Foreachofthecollectively83subjects,organismalstructureofintestinalmicrobiotawasanalyzedbysequencing16SrRNAgeneamplicons,whichrevealedforeachmicrobiotaonaverage202operationaltaxonomicunits(OTUs)fromaveragely6402reads(SupplementaryTable2).Tocharacterizethefunctionalprofilesofmicrobiota,16fromthegoutgroup,18fromthehealthygroupand5fromthevalidationgroupwererandomlyselectedforwhole-metagenomeshotgunsequencing,yielding371.2 Gigabase(Gb)ofpair-endreads(averagely59,681,612high-qualityreadsforeachmicrobiota;SupplementaryTable3).Table1Sampleinformationandbloodindex.FullsizetableBetweenthegoutgroupandthehealthygroup,nosignificantdifferencewasfoundforthefactorsofage,genderorBMI.However,amongthearrayofbloodindices,significantdifferences(P