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InfantGutMicrobiomeAssociatedWithCognitiveDevelopment婴儿（2岁时）的认知发育与（特定种类的）肠道微生物有关BiologicalPsychiatry,June2017（online）IF:10.577Yaoxing,2018-01-02ContensBackgroundObjectivesMethodsResultsStrengthsandlimitationsConclusionsWordsrodents（啮齿动物）Gutcolonization（肠道微生物定植）MSEL:MullenScalesofEarlyLearning（马伦早期学习量表）16SribosomalRNAampliconsequencing（16srRNA扩增子测序）alphadiversity（α多样性：α多样性高，肠道菌群比较成熟）theUniversityofNorthCarolinaatChapelHill（北卡罗来纳大学教堂山分校）Co-occurrenceNetworks（共线/同现网络）MetagenomePrediction（宏基因组学预测，利用基因组学的研究策略研究样品所包含的全部微生物的遗传组成及其群落功能）Faecalibacterium（普氏菌）Bacteroides（拟杆菌）Ruminococcaceae（瘤胃球菌/疣微菌科）Background1.Thegutmicrobiomeisacomplexmicrobialecosystemthatvariesbetweenindividualsandmaybeakeymodulatorofneurodevelopmentthroughthemicrobiome-gut-brainaxis（肠脑轴）.2.Inrodents,experimentalmanipulationsthataltertheintestinalmicrobiotaimpactanxietyanddepression-relatedbehaviors.3.Inhumans,alteredmicrobialcompositionoftheguthasbeenreportedinchildrenwithautismandadultswithdepressionandislinkedtochildhoodtemperamentandadultcognition.4.Nostudieshaveaddressedwhentheserelationshipsemergeordirectlyexaminedwhichbrainregionsmaybeinvolved.5.Arelationshipmayexistbetweenconcurrent(同时发生的)gutcolonizationandbraindevelopmentprocesses.Objectives1.Inthisprospective,longitudinalstudy,theresearcherstestedwhetherthe1-year-oldgutmicrobiomewasassociatedwithcognitiveoutcomesat1and2yearsofage.2.Theyhypothesizedthatinfantgutmicrobiomesampleswouldclusterintogroupsofcommunitysimilarityandthatcognitiveabilitywoulddifferbetweenclusters.根据群落相似性，肠道菌群样本可以聚类为不同的组，而聚类到不同组的婴儿可能具有不同的认知能力Methods1.StudyPopulationRecruited891-year-oldinfants(twinsandsingletons)fromtwoprospectivelongitudinalstudiesofearlybraindevelopmentattheUniversityofNorthCarolinaatChapelHill.两项关于早期大脑发育的前瞻性、纵向研究Exclusioncriteriafortheparentstudiesincludedfetalultrasoundabnormalitiesandmajormedicalillnessofthemother.2.MicrobiomeAnalysis（微生物群分析方法）Parentscollectedapproximately200mgoffecalmaterialfromasinglediaper,placeditinatubefilledwithAllprotectreagent（试剂）andreturneditthroughovernightshipping（连夜运送）.Oncereceived,sampleswerestoredat-80°Cuntilanalysis.MiSeqplatform（用于对细菌种类进行鉴别和量化）,QuantitativeInsightsIntoMicrobialEcologysoftware（用于获取生物学信息、多样性测定）,denovoalgorithm（用于最优分类单位选取）,ChimeraSlayer（用于嵌合测序）.Clusteringanalysiswascompletedwithdistancemetrics，Clusterscoringmethodswereusedtoassesstheoptimalnumberofclusters.3.GeneraAnalysisandCo-occurrenceNetworksTobetterunderstandtheuniquecommunitydynamicsofeachcluster,weusedonerepresentativegenerafromeachclusterasaseedtogenerateco-occurrencenetworksviaSpearmancorrelations.4.CognitiveTestingTheMullenconsistsoffiveseparatescales,withtheirownage-groupstandardizednormativeTscoresandpercentiles,andanEarlyLearning(Cognitive)Composite(ELC).Thefivescalesmeasuregrossmotor,finemotor,visualreception,expressivelanguage,andreceptivelanguageskills.ThestandardizedTscoresoffourscales(grossmotornotincluded)arecombinedtocreatetheELC.Thisprovidedcognitivedatafor86subjectsat1yearofageand69subjectsat2yearsofage.5.StructuralImageAcquisitionSiemenshead-only3TTIM-TrioscannerDuringunsedatednaturalsleep婴儿在自然睡眠状态下的大脑成像Magnetizationpreparedrapidacquisitiongradient-echoscanswereobtainedatyears1and2Atotalof38infantsatyear1didnotgotosleeporwokeupinthescanner(successrate=57%).Atotalof61infantsatyear2didnotgotosleep,wokeupinthescanner,orwerelosttofollow-up(successrate=31%).6.ImageAnalysisBraintissuewasclassifiedasgraymatter,whitematter,andcerebrospinalfluid.ITK-SNAPsoftwareObtainedmeasuresofintracranialvolume,totalgraymatter,totalwhitematter,totalcerebrospinalfluid,lateralventriclevolume,and90-regiongraymattervolumesat1yearofagefor46subjectsandat2yearsofagefor27subjects.扫描结果提供了颅内容量、总灰质、总白质、总脑脊液、侧脑室体积和90区域灰质体积等信息7.AssociationofCognitiveandBrainOutcomesWithClusterMembershipandAlphaDiversityLinearmixedeffectmodelswereusedtotestforeffectsof：1.cognitiveperformanceandbrainvolumes2.clustermembershiponalphadiversityLikelihoodratiotestswereusedtotestthesignificanceofthecoefficientofeachclusterandalphadiversitymeasure.Secondaryanalyseswereadjustedformultiplecomparisons7.AssociationofCognitiveandBrainOutcomesWithClusterMembershipandAlphaDiversitySensitivityanalysesRawscoresTscoresDemographicandmedicalvariablesassociatedwithclustermembershiporalphadiversityandneuroimagingorcognitiveoutcomeswereincludedascovariates8.MetagenomePredictionFromPhylogeneticInvestigationofCommunitiesbyReconstructionofUnobservedStatesPICRUSt（生物信息软件）wasusedtopredictmeta-genomefunctionalcontentfromthe16SribosomalRNAsequencingdata.Results1.InfantMicrobiotaClusterIntoThreeGroupsCluster1(C1)characterizedbyarelativelyhighabundanceofFaecalibacterium;第一组的普氏菌属细菌丰度较高Cluster2(C2)byarelativelyhighabundanceofBacteroides;第二组的拟杆菌属细菌丰度较高Cluster3(C3)byarelativelyhighabundanceofanunnamedgenusinthefamilyRuminococcaceae.第三组以瘤胃球菌菌科一种未命名的细菌属的相对丰度较高为主要特征2.IdentificationofPredictorCovariatesC2组（拟杆菌丰度高）的婴儿在1岁时更少的是通过剖腹产出生、更多的是母乳喂养。2.IdentificationofPredictorCovariatesPaternalethnicityinC2was90%whitecomparedwi