Author(s) Sample StudyDesign Results ConclusionAzad,Bridgman,Becker&Kozyrskyj,2014.1

629childrenexaminedatage9and12inSAGEstudy

Secondaryanalysisofprovincialhealthcaredatabasein1995SAGEcohortstudy

Antibioticexposureinthefirstyearoflikewasmorepositivelyassociatedwiththedevelopmentofoverweightinchildhoodcomparedtounexposedgroups(P=0.002)

Antibioticexposureinfirstyearoflifesignificantlyincreasedriskofoverweightandcentraladiposityinboysages9and12.

Scottetal.,2016.12

21714childreninHealthImprovementNetwork(DatasetfromUKmedicalrecords(1995-2012)

RetrospectivecohortstudywithinHealthImprovementNetworkDataset

Antibioticexposureassociatedwithincreasedriskofobesityat4years(OR=1.21)Antibioticexposurewithinfirst2yearsoflifeisassociatedwith1.2%absoluteand25%relativeincreaseinriskofearlychildhoodobesity

Riskofchildhoodobesityheightenedwhen3ormorecoursesofantibioticswereadministeredtochildrenundertheageof2.

Turta&Rautava,2016.9

Variousstudies Literaturereview AnoutcomeofobesityisassociatedwithanincreasedabundanceofphylumFirmucutesanddecreaseinBacteriodetesHighconcentrationofintestionalbididobacteriamaybeassociatedwithlower riskofoverweight

Prolongedgutmicrobiotaalterationsmaybetheresultofrepeatedantibioticexposure.Changesingutmicrobiotacompositionassociatedwithdevelopmentofoverweightandobesity.

Edmonson&Eickhoff,2017.11

2-yearstudyinvolving607children(aged2-71months)enrolledfrom2007-2011

SecondaryanalysisofdatafromRCTInterventionforChildrenwithVesicoureteralRefluxStudy

NosignificantevidencethatprolongedexposuretoantibioticTPM/SMXaffectedweightgainoroutcomesofoverweightorobesityinhealthyinfantsandyoungchildren

Thelinkbetweenprolongedantibioticuseandweightgainremainsdoubtful.Existingstudieslackconsistencyandprecisionwithrespecttomanyvariables:age,sexandantibioticexposuredetails,etc.

Mbakwa etal.,2016.14

3030caucasianwomenpregnantwomen(34weeksgestation)recruitedTotal979childrenwereeligibleforanalysis

Cohortstudy β-lactamantibioticswereassociatedwithanincreaseinweightz-scoresduringthefollow-upperiodofthestudyChildrenexposedtoasinglecourseofantibioticsduringthefirst6monthsoflifeshowedanincreaseinweightgaincomparedtothosewhohadnoexposure.Noassociationbetweensingleexposureofantibioticsandobesitybetween6-12monthsofage

Associationtoobesitywaspresentaftersingledoseofantibioticsduringfirst6monthsoflife.

Shaoetal.,2017.15

15cohortstudiesinvolving445880participantsindevelopedcountries

Systematicreview&meta-analysis

Earlylifeantibioticexposuresignificantlyincreasedriskofchildhoodoverweight(RR=1.23)andobesity(RR=1.21)andBMI(meandifference:0.07)7%increaseinriskofoverweight(RR=1.07)and6&increaseinriskforobesity(RR=1.06)witheachadditionalcourseofantibiotics

Earlylifeantibioticexposuresignificantlyincreasedriskofchildhoodoverweightandobesity.

Cox&Blaser,2015.16

Samplesfromvariousstudies

Literaturereview Earlylifeantibioticexposurecandisruptgutmicrobiotadevelopmentandcaninfluencebodymass(weightgainorstuntedgrowth)Theseexposuresimpactbodymassinadulthood

Examiningearlylifecharacteristicsofgutmicrobiotacouldshedlightonpossibleinterventionsdirectedatmitigatingrisksassociatedwithobesity.

Pihletal.,2016.13

Samplesfromvariousstudies

Systematicliteraturereview

Arrayoffactorsinfluencethegutmicrobiotaprofile(hostgenetics,deliverymethod,diet,age,environment,antibiotics)

Establishmentofsuchfactorscanprovideabasisforobesitypreventioninitiatives.Understandingtheroleofgutmicrobiotaisparamountfortargetingchildhoodobesity.

AbstractBackground:Ithasbeenreportedthattheuseofantibioticsisassociatedwithexcessiveweightgainorobesityinhealthyinfants.Currentdatasuggestintestinalmicrobiotaperturbationcausedbyantibioticexposureintheperinatalperiodprogramsthehosttoassumeanobesity-pronemetabolicphenotype.However,thereisalackofevidenceregardingthecausalpathwaygiventhemultifactorialetiologyofobesity.Objective: Theobjectiveofthisstudywastoexplorethesignificanceoftheassociationbetweenantibioticexposureduringcriticalperiodsofinfancybeforetheageof2andthedevelopmentofobesity.Methodology:AstructuredliteraturereviewwasconductedondatabasesMedline,Scopus,CINAHLandGoogleScholarresultingin8pertinentarticles.Queries“InfantsANDObesityANDAntibioticExposureANDGutMicrobiota”weresearchedandscreened,andinfants’ageswererestrictedto1-23months.Results:Antibioticexposureduringcriticalperiodsofearlydevelopmentsignificantlyinfluencedweightgainandtheprogressionofobesity.Furthermore,markeddifferencesinthecompositionoftheirmicrobiotawereexhibitedwhencomparedtoleansubjects.Fewstudiesconcludedthatexposurewasnotconsistentlyassociatedwithincreasedbodymass,whileothersrestrictedtheassociationsolelytomaleinfants.Conclusion:Over-prescriptionofantibioticsduringinfancynotonlycausesresistancetopotentiallyharmfulorganismsintheGItract,butmayalsoleadtoalife-longriskforobesitybydestroyinghealthycolonizationofnecessarybacteria.Itisparamountthatfurtherresearchbeperformedinordertoestablishpreventivemeasuresofobesityandcounteractunfavourableeffectsonmicrobiota.

ResearchQuestionIsthereasignificantassociationbetweenantibioticexposureduringcriticalperiodsofinfancybeforetheageof2andthedevelopmentofobesity?

IntroductionChildhoodobesityisamongthemosturgentpublichealthissuesofthepediatricpopulation.1

Overthelast25years,therehasbeenaconsiderableriseinthenumberofCanadianchildrenandyouthwhoareoverweightorobese.2 BasedontheWorldHealthOrganizationguidelines,31.5%of5- to17- yearolds,anestimated1.6millionCanadianchildren,wereclassifiedasoverweight(19.8%)orobese(11.7%)from2009to2011.3 Furthermore,overweightandobesechildrenareatahighriskofbecomingobeseadultsaswellaspresentingadversehealthconsequences,whichincludecardiovasculardisease,type2diabetesandseveralcancers.4,5,6

Sincethe1940s,antibioticshavebeenessentialinreducinghumanmorbidityandmortality.7However,recentstudieshaveshownthatincreasedsusceptibilitytoobesitylaterinlifehasbeenassociatedwithearlyexposuretoantibioticsinhealthyindividuals.8 Worldwide,antibioticsareamongthemostfrequentlyusedpharmaceuticalsininfantsandchildren.9 Bytwoyearsofage,childrenhaveonaveragereceivednearlythreecoursesofantibiotics.9 Antibioticsareoftenprescribedinappropriatelydespiteasignificantnumberofexpertguidelineswhichadvocateitslimiteduse.6 Ithasbeenestimatedthat5%ofneonateshavereceivedantibiotics,althoughtheincidenceofculture-provensepsisinnewborninfantsislessthanonein1000neonates.9

Asopposedtotherelativelystablemicrobiotaofanadult,themicrobiotaofaninfantisconsiderablymorevariableandvulnerabletoantibioticperturbation.7 Thecriticalperiodofgutcolonizationappearsinearlypostnatallife.1 Thus,earlyadministrationofantibioticsmaydisruptpatternsofintestinalcolonizationandincreaseintestinalpermeability(Figure1).7 Moreover,thehostassumesanobesity-pronemetabolicphenotypewhichaltersthehost’sresponsetospecificmicrobialsignals.10 Althoughanassociationbetweenantibioticexposureandobesityinhealthyinfantsandchildrenhasbeenreported,thereisalackofevidenceregardingtheexactcausalpathwaygiventhemultifactorialetiologyofobesity.11,12

Figure1. Increasedintestinalpermeabilityresultinginhigherlevelsoflipopolysaccharidesinsystemiccirculation,leadingtoalow-gradesystemicinflammatorystate.13

MethodsMethodologyused: structuredliteraturereview

Figure2.Visualrepresentationofliteraturereviewprocess.

Keywords/SearchQueries: “Infants”AND“ObesityORWeightGain”AND“antibioticexposure”AND“gutbacteria”

The Hidden Culprit: PredispositiontoObesityasaResultofEarly-lifeAntibioticExposure

Anupallavi Sinha1,DanielleEdmonds1,RaniaBerjawi1,SoniaHajo1UniversityofOttawa1

ResultsTable1:Synthesisofmainfindingsfromeightpertinentarticlesusedforliteraturereview

DiscussionAllapartfromone,studiesdemonstratedamarked,statisticallysignificantassociationbetweenearly-lifeantibioticexposureandthedevelopmentofoverweightorobesity.AnincreasedproportionofFirmicutes toBacteroidetes isrecognizedasamarkerofobesity.10 Agreaternumberofcoursesofantibioticswasassociatedwithahigherriskofdevelopingchildhoodoverweightorobesity.Also,obesityasaresultfromantibioticexposurewasobservedinaslittleas6monthsfrombirth.Obesityduringchildhoodcanalsocarryontoadulthood.Onestudyfoundarelationshipbetweengutmicrobiotaandobesityinonlymalesonly.1 Somemechanismsestablishedinmicemodelswereexcessivecaloricintake,changesinadiposity,fattyacidmetabolism,andregulationofpeptideYYandGLP-1secretion.17 Multiplefactorsaffectthedevelopmentofgutmicrobiota,suchashostgenetics,deliverymethod,diet,age,andantibioticuse.Somepreventativefactorstoobesitythathavebeenobservedinstudiesarebreastfeeding,healthydiet,andphysicalactivity,howeverwhencoupledwithantibioticstheyhadnoprotectiveeffects.1 Thedirectmechanismifthemicrobiotaactiononadiposityalterationsremainill-detailedandpoorlyunderstood;however,mountingevidencepointstotheassociationbetweenalteredgutmicrobiotaprofilesandincreasedriskofobesity.Articlesalsoemphasizetheincreasingneedforpreventativemeasurestargetingchildhoodobesity.Withaclearerunderstandingoftheroleofgutmicrobiotainthedevelopmentofchildhoodobesitycanaidinmitigatingrisksassociatedwiththechildhoodepidemic.

Limitations:Variableswereadjustedtoaccountformaternalage,pre-gravidBMI,birthweight,sex,deliverymode,etc.12 Articlesalsoattemptedtoavoidconfoundingbyexcludingsmokingpregnantwomenfromsecondaryanalysis.12-Informationbiasesinresearchwheremedicalrecordslackedspecificinformationonantibioticexposure(use,dosage,numberofcourses,etc.)11- Recallbiaswasapparentinonestudy,asprenatalantibioticusewasdeterminedbyaquestionnaire.12- Thenatureofthestudyforcedalimitedscopeofpre-establisheddataintheformofsystematicreviews,literaturereviewsandsecondaryanalyses;performingarandomized-controlledtrialwhichadministeredantibioticstohumansforthepurposesofexperimentationisnotethicallyfeasible.

ConclusionItispresumedthattheoverprescriptionofantibioticsanditsexposureduringinfancy

significantlycontributestothemodernprevalenceofobesityduetoitspotentiallyharmfuleffectsonthemicrobiota.However,furtherstudiesareneededtoconfirmthesefindingsinordertoestablishpreventativemeasuresinthefuture.

FutureDirectionsToinvestigate• theassociationbetweenantibioticsandthehungerhormone,ghrelin18,19• theassociationbetweenantibioticsandthesatietyhormoneleptin19• theimplementationofomega-3fattyacidstocombatobesitythroughthepreventionof

antibiotic-inducedmodulationofgutmicrobiota 20

• theanti-obesityeffectsofprobiotics(Lactobacillusgenus).21• theadministrationofprebioticssuchasFOS,inulin,galacto-oligosaccharides(GOS)andlactulose

topreventandtreatchildhoodobesity.22

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InclusionCriteria: ExclusionCriteria:Infants1-23monthsofage Infantsover23monthsofage

ArticleswritteninEnglishonly Articleswritteninforeignlanguages

Peer-reviewedarticles Congenitalillnessormalformations

Articlesidentifiedondatabases:Medline,GoogleScholar,CINAHL,&

ScopusN=19

Articlesomittedbasedonaccessibilityoffulltext

onlineN=1

OmittedAfterScreeningN=10

TotalStudiesIncludedN=8