the gastrointestinal (gi) system and gut microbiome in ... · outline • historical link between...
TRANSCRIPT
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CalliopeHolingue,MPH,PhDCandidate
DepartmentMentalHealth,JohnsHopkinsBloombergSchoolofPublicHealth
DepartmentalSeminar,WednesdayMarch28,2018
Thegastrointestinal(GI)systemandgutmicrobiomeinAutismSpectrumDisorders(ASD)
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Outline
• HistoricallinkbetweenASDandgut,possibleconnections
• EvidenceforroleofgutmicrobiomeinASD• MeasurementChallenges• FutureDirections
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‘Alldiseasestartsinthegut’Hippocrates~460-370BC
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AutismSpectrumDisorder
DSM-5APA2013
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“Autisms”
EytanNisinzweig,ayoungmanwithautism ©EytanArt.com2010
5
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GILinkwithAutism
• LeoKanner1943:6ofthe10childrenwithautism“presentedseverefeedingdifficultyfromthebeginningoflife”
Kanner1943;Goodwinetal1971;D’Eufemiaetal1996;Chaidezetal2014
> >
ASD DD TD
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GISymptoms• MostcommonGIissues(medianacross144autismstudies)– Constipation(22%)– Diarrhea(23%)– Abdominalpain/discomfort(14%)– Bloating/flatulence(13%)– Nausea/vomiting(6%)– Anysymptom(47%)
• Foodsensitivities,preferences,mealtimebehaviors,toiletingproblemsarecommon
Holingueetal2017
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Whystudythegutinautism?
• ComplementaryandAlternativeTreatments/Medicine(CAMs)
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Complementary/AlternativeTreatments/Medicine(CAMs)
• DevelopedoutsideofWesternmainstreammedicine
• Manyaimto‘healthegut’toprevent/treatASDsymptoms
• Over70%familiesreportone+CAMs
• Verylittledataonsafetyorefficacy
Christonetal2010
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Whystudythegutinautism?
• CAMs• Treatingcomorbidities,improvingqualityoflife
• Gutasariskfactorfor– ExacerbationofASDsymptoms– IncidenceofASD
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PossibleConceptualDiagram
ASD GIissues
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PossibleConceptualDiagram
ASD
Co-occurringconditions
Medications
GIissues
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PossibleConceptualDiagram
ASD
Co-occurringconditions
Medications
Diet
GIissues
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PossibleConceptualDiagram
Gut ASD
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PossibleConceptualDiagram
Gut ASD
DiscomfortDistressPain
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PossibleConceptualDiagram
Gut ASD
DiscomfortDistressPain
“Biology”
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EvidenceforroleofgutmicrobiomeinASD
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TheHumanMicrobiome
“Themicrobiomeisdefinedasthecollectivegenomesofthemicrobes(composedof
bacteria,bacteriophage,fungi,protozoaandviruses)thatliveinsideandonthehuman
body.”
Yang,Joy."TheHumanMicrobiomeProject:Extendingthedefinitionofwhatconstitutesahuman."NationalHumanGenomeResearchInstitute(2012).
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Microbe:Microorganisms[e.g.bacteria,virus]Microbiota:MicroorganismsinparticularsiteMicrobiome:Combinedgeneticmaterialofmicroorganismsinparticularenvironment
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Thediversityofmicrobesvariesbyanatomicsite
TheHumanMicrobiome
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TheHumanMicrobiome
Health,diet,hygiene,genotype… àComposition,complexity,andfunctionofour
microbialcommunities
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Rolesofgutmicrobiome
• Bacteriacommunicatewitheachotherandwithhost(Us!)
• Producevitaminsandnutrients• Influencehostgeneexpression,immunecellresponses
• Regulategutmotility,intestinalbarrierhomeostasis,nutrientabsorption,fatdistribution
• Gut-braincommunication,brainfunction,behavior
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SynergisticRelationship
“Microbiotanormallyhasabalanced
compositionalsignaturethatconfershealthbenefits...
disruptionofthisbalanceconfersdiseasesusceptibility”
Cryan,JohnF.,andTimothyG.Dinan."Mind-alteringmicroorganisms:theimpactofthegutmicrobiotaonbrainandbehaviour."Naturereviewsneuroscience13.10(2012):701-712.
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MicrobiomeisDynamic
“…Themicrobiomeisafluctuatingcollectionofgenesandgeneproducts;environmentalperturbations,suchasantibiotictreatmentandinfection,canreadilyalter
themicrobialcompositionandfunctionofeachcommunity…Thehumanmetagenomeisrelatively
plasticormalleable,whichmakesthemicrobiomeanattractivetargetformanipulationbycellorgene
therapy”
Pflughoeft,KathrynJ.,andJamesVersalovic."Humanmicrobiomeinhealthanddisease."AnnualReviewofPathology:MechanismsofDisease7(2012):99-122.
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MeasuringtheGutMicrobiome
• Collectingsamplesoftheactualgutisoftennotfeasibleorethical
• Moststudiesexaminethefecalmicrobiome
• DNAisextracted,sequencedtodeterminewhichmicrobesarepresent
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EvidenceforroleofgutmicrobiomeinASD
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MaternalImmuneActivation
BehavioralAbnormalitiesCorticalpatches
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MaternalImmuneActivation
Healthypups
Antibiotic
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• GutbacteriathatinduceTh17cells✔• Pro-inflammatorystimulus✔• Pregnancy✔AllrequiredforincreaseinIL-17awhichpromotesMIA-inducedneurodevelopmentalabnormalities
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MaternalImmuneActivation
+
SpecificBacteriainMom’sGut
ASDinchild
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MaternalImmuneActivation
+
SpecificBacteriainMom’sGut
ASDinchild
?
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DissertationAim
AntibioticExposureInPregnantWomen
ASDinoffspring
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DissertationAim
AntibioticExposureInPregnantWomen
ASDinoffspringX
MaternalImmuneActivation
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ASDhumanmicrobiomestudiesFindingsInconsistent
Clostridium,Sutterella,Lactobacillus,Desulfovibrio
Prevotella,Coprococcus,andVeillonellaceae
Bacteroidetes/Firmicutesratio
Parrachoetal2005;Vuongetal2016;Kangetal2013;Finegoldetal2002;Songetal2004;Williamsetal2012;Wangetal2013;Tomovaetal2014;Williamsetal2011
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Reasonsforinconsistenciesacrossstudies
• Differencesinhowmicrobiomedatawascollected,stored,analyzed
• Unadjustedconfounding• HeterogeneityofASD
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DissertationAim
ToestimateassociationsofgutmicrobiomesignaturesincludingdiversitymetricsandrelativeabundanceoftaxawithASDco-occurringconditions.
GutmicrobiomeASDco-occurringconditions
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• Recruit30boys3-6yearswithASDfromKennedyKriegerInstitute,CenterforAutismandRelatedDisorders
• Stoolkit:OmnigeneGut• Questionnaires:
• Childbehaviorchecklist• Theshortsensoryprofile• GIquestionnaire• BristolStoolScale
• SampleswillbeprocessedandsequencedatJHUwith16srRNAtechnology
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StatisticalAnalysis
Estimateassociationsbetweenco-occurringissues/behaviorandmicrobialprofiles,withinASD
ExemplarHypotheses:Anxiety~PrevotellawithinASDSomaticComplaints~PrevotellawithinASDSleepproblems~PrevotellawithinASD
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MeasurementIssues
• AssessingGIsymptoms/conditionsinASDischallenging
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DissertationAim
Todevelopareliableandvalidquestionnairethatassessesgastrointestinal(GI)symptomsinchildrenwithautismspectrumdisorderforuseinepidemiologicstudies.
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StudyPopulation
• RegistryofparentsofchildwithASDatKennedyKriegerInstitute
• Havepreviouslyconsentedtobecontactedforresearchpurposes
• Ages3-18years• Recruitment,consent,datacollectionwillallhappenonline
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Methods• BaseoffofAutismTreatmentNetworkGI
InventoryandBriefAutismMealtimeBehaviorInventory
• Focusgroupsandexpertpanel
• Administerourquestionnaire+childbehaviorchecklist
• Assesspsychometricperformanceandrevise• Administertoindependentsample,assess
psychometricperformance
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KeyTakeaways
• GIsymptomsareelevatedinASD• GIsymptoms/disordersmaybeduetohavingASD
• GutmayplayaroleincausingASD• Bothdirectionsarelikelyoccurring,dependsontheindividual
• Accurate,reliableassessment,diagnosis,treatmentofGIsymptomsinASDiscritical
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ImpactandImplications
• Etiologyofautismandmentalillness
• Targetforpreventionandtreatment
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Futurework
• Measurementandassessment• Latentclassesapproachestoidentifying‘subgroups’ofASD
• Incorporatingmultipledatatypes• Animalandhumanstudiesshouldinformeachother,informmechanisticwork
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Thankyou!!
ThesiscommitteeDaniFallin(Adviser)Li-ChingLeeNoelMuellerSarahMurrayRashelleMusciJayPasricha
FundingPsychiatricEpidemiologyTrainingProgram(PI:PeterZandi)WendyKlagCenterforAutismandDevelopmentalDisabilities
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ShamelessPlugs
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References(1)• Kanner,Leo."Autisticdisturbancesofaffectivecontact."Nervouschild2.3(1943):217-250.• Goodwin,MaryStewart,T.CampbellGoodwin,andMurrayA.Cowen."Malabsorptionandcerebral
dysfunction:amultivariateandcomparativestudyofautisticchildren."JournalofAutismandchildhoodSchizophrenia1.1(1971):48-62.
• d'Eufemia,P.,etal."Abnormalintestinalpermeabilityinchildrenwithautism."ActaPaediatrica85.9(1996):1076-1079.
• Chaidez,Virginia,RobinL.Hansen,andIrvaHertz-Picciotto."Gastrointestinalproblemsinchildrenwithautism,developmentaldelaysortypicaldevelopment."Journalofautismanddevelopmentaldisorders44.5(2014):1117-1127.
• Holingue,Calliope,etal."Gastrointestinalsymptomsinautismspectrumdisorder:Areviewoftheliteratureonascertainmentandprevalence."AutismResearch(2017).
• Christon,LillianM.,VirginiaH.Mackintosh,andBarbaraJ.Myers."Useofcomplementaryandalternativemedicine(CAM)treatmentsbyparentsofchildrenwithautismspectrumdisorders."ResearchinAutismSpectrumDisorders4.2(2010):249-259.
• Yang,Joy."TheHumanMicrobiomeProject:Extendingthedefinitionofwhatconstitutesahuman."NationalHumanGenomeResearchInstitute(2012).
• Cryan,JohnF.,andTimothyG.Dinan."Mind-alteringmicroorganisms:theimpactofthegutmicrobiotaonbrainandbehaviour."Naturereviewsneuroscience13.10(2012):701-712.
• Pflughoeft,KathrynJ.,andJamesVersalovic."Humanmicrobiomeinhealthanddisease."AnnualReviewofPathology:MechanismsofDisease7(2012):99-122.
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References(2)• Kim,Sangdoo,etal."Maternalgutbacteriapromoteneurodevelopmentalabnormalitiesinmouseoffspring."Nature
549.7673(2017):528.• ParrachoHMRT,BinghamMO,GibsonGR,McCartneyAL.Differencesbetweenthegutmicrofloraofchildrenwithautistic
spectrumdisordersandthatofhealthychildren.JMedMicrobiol.2005;54(10):987–91.• VuongHE,HsiaoEY.Emergingrolesforthegutmicrobiomeinautismspectrumdisorder.BiolPsychiatry.Elsevier;2016;• KangDW,ParkJG,IlhanZE,WallstromG,LaBaerJ,AdamsJB,etal.ReducedIncidenceofPrevotellaandOtherFermentersin
IntestinalMicrofloraofAutisticChildren.PLoSOne.2013;8(7).• FinegoldSM,MolitorisD,SongY,LiuC,VaisanenM-L,BolteE,etal.Gastrointestinalmicroflorastudiesinlate-onsetautism.
ClinInfectDis.OxfordUniversityPress;2002;35(Supplement1):S6–16.• SongY,LiuC,FinegoldSM.Real-TimePCRQuantitationofClostridiainFecesofAutisticChildrenReal-TimePCRQuantitation
ofClostridiainFecesofAutisticChildren.ApplEnviromentalMicrobiol.2004;70(11):6459–6465.• WilliamsBL,HornigM,ParekhT,LipkinWI.ApplicationofnovelPCR-basedmethodsfordetection,quantitation,and
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