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CalliopeHolingue,MPH,PhDCandidate
DepartmentMentalHealth,JohnsHopkinsBloombergSchoolofPublicHealth
DepartmentalSeminar,WednesdayMarch28,2018
Thegastrointestinal(GI)systemandgutmicrobiomeinAutismSpectrumDisorders(ASD)
Outline
• HistoricallinkbetweenASDandgut,possibleconnections
• EvidenceforroleofgutmicrobiomeinASD• MeasurementChallenges• FutureDirections
‘Alldiseasestartsinthegut’Hippocrates~460-370BC
AutismSpectrumDisorder
DSM-5APA2013
“Autisms”
EytanNisinzweig,ayoungmanwithautism ©EytanArt.com2010
5
GILinkwithAutism
• LeoKanner1943:6ofthe10childrenwithautism“presentedseverefeedingdifficultyfromthebeginningoflife”
Kanner1943;Goodwinetal1971;D’Eufemiaetal1996;Chaidezetal2014
> >
ASD DD TD
GISymptoms• MostcommonGIissues(medianacross144autismstudies)– Constipation(22%)– Diarrhea(23%)– Abdominalpain/discomfort(14%)– Bloating/flatulence(13%)– Nausea/vomiting(6%)– Anysymptom(47%)
• Foodsensitivities,preferences,mealtimebehaviors,toiletingproblemsarecommon
Holingueetal2017
Whystudythegutinautism?
• ComplementaryandAlternativeTreatments/Medicine(CAMs)
Complementary/AlternativeTreatments/Medicine(CAMs)
• DevelopedoutsideofWesternmainstreammedicine
• Manyaimto‘healthegut’toprevent/treatASDsymptoms
• Over70%familiesreportone+CAMs
• Verylittledataonsafetyorefficacy
Christonetal2010
Whystudythegutinautism?
• CAMs• Treatingcomorbidities,improvingqualityoflife
• Gutasariskfactorfor– ExacerbationofASDsymptoms– IncidenceofASD
PossibleConceptualDiagram
ASD GIissues
PossibleConceptualDiagram
ASD
Co-occurringconditions
Medications
GIissues
PossibleConceptualDiagram
ASD
Co-occurringconditions
Medications
Diet
GIissues
PossibleConceptualDiagram
Gut ASD
PossibleConceptualDiagram
Gut ASD
DiscomfortDistressPain
PossibleConceptualDiagram
Gut ASD
DiscomfortDistressPain
“Biology”
EvidenceforroleofgutmicrobiomeinASD
TheHumanMicrobiome
“Themicrobiomeisdefinedasthecollectivegenomesofthemicrobes(composedof
bacteria,bacteriophage,fungi,protozoaandviruses)thatliveinsideandonthehuman
body.”
Yang,Joy."TheHumanMicrobiomeProject:Extendingthedefinitionofwhatconstitutesahuman."NationalHumanGenomeResearchInstitute(2012).
Microbe:Microorganisms[e.g.bacteria,virus]Microbiota:MicroorganismsinparticularsiteMicrobiome:Combinedgeneticmaterialofmicroorganismsinparticularenvironment
Thediversityofmicrobesvariesbyanatomicsite
TheHumanMicrobiome
TheHumanMicrobiome
Health,diet,hygiene,genotype… àComposition,complexity,andfunctionofour
microbialcommunities
Rolesofgutmicrobiome
• Bacteriacommunicatewitheachotherandwithhost(Us!)
• Producevitaminsandnutrients• Influencehostgeneexpression,immunecellresponses
• Regulategutmotility,intestinalbarrierhomeostasis,nutrientabsorption,fatdistribution
• Gut-braincommunication,brainfunction,behavior
SynergisticRelationship
“Microbiotanormallyhasabalanced
compositionalsignaturethatconfershealthbenefits...
disruptionofthisbalanceconfersdiseasesusceptibility”
Cryan,JohnF.,andTimothyG.Dinan."Mind-alteringmicroorganisms:theimpactofthegutmicrobiotaonbrainandbehaviour."Naturereviewsneuroscience13.10(2012):701-712.
MicrobiomeisDynamic
“…Themicrobiomeisafluctuatingcollectionofgenesandgeneproducts;environmentalperturbations,suchasantibiotictreatmentandinfection,canreadilyalter
themicrobialcompositionandfunctionofeachcommunity…Thehumanmetagenomeisrelatively
plasticormalleable,whichmakesthemicrobiomeanattractivetargetformanipulationbycellorgene
therapy”
Pflughoeft,KathrynJ.,andJamesVersalovic."Humanmicrobiomeinhealthanddisease."AnnualReviewofPathology:MechanismsofDisease7(2012):99-122.
MeasuringtheGutMicrobiome
• Collectingsamplesoftheactualgutisoftennotfeasibleorethical
• Moststudiesexaminethefecalmicrobiome
• DNAisextracted,sequencedtodeterminewhichmicrobesarepresent
EvidenceforroleofgutmicrobiomeinASD
MaternalImmuneActivation
BehavioralAbnormalitiesCorticalpatches
MaternalImmuneActivation
Healthypups
Antibiotic
• GutbacteriathatinduceTh17cells✔• Pro-inflammatorystimulus✔• Pregnancy✔AllrequiredforincreaseinIL-17awhichpromotesMIA-inducedneurodevelopmentalabnormalities
MaternalImmuneActivation
+
SpecificBacteriainMom’sGut
ASDinchild
MaternalImmuneActivation
+
SpecificBacteriainMom’sGut
ASDinchild
?
DissertationAim
AntibioticExposureInPregnantWomen
ASDinoffspring
DissertationAim
AntibioticExposureInPregnantWomen
ASDinoffspringX
MaternalImmuneActivation
ASDhumanmicrobiomestudiesFindingsInconsistent
Clostridium,Sutterella,Lactobacillus,Desulfovibrio
Prevotella,Coprococcus,andVeillonellaceae
Bacteroidetes/Firmicutesratio
Parrachoetal2005;Vuongetal2016;Kangetal2013;Finegoldetal2002;Songetal2004;Williamsetal2012;Wangetal2013;Tomovaetal2014;Williamsetal2011
Reasonsforinconsistenciesacrossstudies
• Differencesinhowmicrobiomedatawascollected,stored,analyzed
• Unadjustedconfounding• HeterogeneityofASD
DissertationAim
ToestimateassociationsofgutmicrobiomesignaturesincludingdiversitymetricsandrelativeabundanceoftaxawithASDco-occurringconditions.
GutmicrobiomeASDco-occurringconditions
• Recruit30boys3-6yearswithASDfromKennedyKriegerInstitute,CenterforAutismandRelatedDisorders
• Stoolkit:OmnigeneGut• Questionnaires:
• Childbehaviorchecklist• Theshortsensoryprofile• GIquestionnaire• BristolStoolScale
• SampleswillbeprocessedandsequencedatJHUwith16srRNAtechnology
StatisticalAnalysis
Estimateassociationsbetweenco-occurringissues/behaviorandmicrobialprofiles,withinASD
ExemplarHypotheses:Anxiety~PrevotellawithinASDSomaticComplaints~PrevotellawithinASDSleepproblems~PrevotellawithinASD
MeasurementIssues
• AssessingGIsymptoms/conditionsinASDischallenging
DissertationAim
Todevelopareliableandvalidquestionnairethatassessesgastrointestinal(GI)symptomsinchildrenwithautismspectrumdisorderforuseinepidemiologicstudies.
StudyPopulation
• RegistryofparentsofchildwithASDatKennedyKriegerInstitute
• Havepreviouslyconsentedtobecontactedforresearchpurposes
• Ages3-18years• Recruitment,consent,datacollectionwillallhappenonline
Methods• BaseoffofAutismTreatmentNetworkGI
InventoryandBriefAutismMealtimeBehaviorInventory
• Focusgroupsandexpertpanel
• Administerourquestionnaire+childbehaviorchecklist
• Assesspsychometricperformanceandrevise• Administertoindependentsample,assess
psychometricperformance
KeyTakeaways
• GIsymptomsareelevatedinASD• GIsymptoms/disordersmaybeduetohavingASD
• GutmayplayaroleincausingASD• Bothdirectionsarelikelyoccurring,dependsontheindividual
• Accurate,reliableassessment,diagnosis,treatmentofGIsymptomsinASDiscritical
ImpactandImplications
• Etiologyofautismandmentalillness
• Targetforpreventionandtreatment
Futurework
• Measurementandassessment• Latentclassesapproachestoidentifying‘subgroups’ofASD
• Incorporatingmultipledatatypes• Animalandhumanstudiesshouldinformeachother,informmechanisticwork
Thankyou!!
ThesiscommitteeDaniFallin(Adviser)Li-ChingLeeNoelMuellerSarahMurrayRashelleMusciJayPasricha
FundingPsychiatricEpidemiologyTrainingProgram(PI:PeterZandi)WendyKlagCenterforAutismandDevelopmentalDisabilities
ShamelessPlugs
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.
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• 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.
References(2)• Kim,Sangdoo,etal."Maternalgutbacteriapromoteneurodevelopmentalabnormalitiesinmouseoffspring."Nature
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