Gut Microbiome and Brain.docx

Gut Microbiome and Brain.docx

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GutMicrobiomeandBrain

GutMicrobiomeandBrain-GutAxisinAutism—AberrantDevelopmentofGut-BrainCommunicationandRewardCircuitry

ElizabethM.Sajdel-Sulkowska1 andRomualdZabielski2

[1] Dept.PsychiatryHarvardMedicalSchoolandBWH,USA

[2] DDept.PhysiologicalSciences,WarsawUniversityofLifeSciences,Poland

1.Introduction

Thefunctionofthegutmicrobiomeandthebidirectionalcommunicationbetweenthegastrointestinaltract（GIT）andthebrainisincreasinglyrecognizedinhealthanddiseaseanddisruptioninitscompositionisnotuniquetotheautisticpathology.However,thebidirectionalcommunicationbetweenthegutandthebrain,“thegut-brain/brain-gutaxis”inautismhasbeenrelativelyunderstudied.Ingeneral,thiscommunicationbetweengutandbrainoccursthroughadirectneuronalpathwayviathevagusnerve,thehormonalpathwayofseveralhormonesinvolvedintheregulationoffoodintake,suchascholecystokinin（CCK）,ghrelin,leptinandinsulin,andbytheimmunologicalsignalingpathwayinvolvingcytokines.Recentstudiesindicatethatthevagusnerveisinvolvedinimmunomodulationassuggestedbyitsabilitytoattenuatetheproductionofproinflammatorycytokinesinexperimentalmodelsofinflammation（deJongeandUllola,2007）.Furthermore,thegutmicrobiomeemergesasamajorplayernotonlyinthematurationofGITtissueandthegutbrainaxisbutalsoinbrainmaturation,throughitseffectonboththeimmuneandendocrinesystems.Manytoxins,toxicants,infectiousagents,dietorstress,affectanindividual’sgutmicrobiome,whichmaybeespeciallysensitiveduringthecriticaldevelopmentalperiod.Disruptionofthedevelopingmicrobiomemayhaveprofoundconsequencesonthedevelopinggut-brainaxisincludingthebrainaswellaslong-termeffectsonboththephysicalandpsychologicaldevelopment.

Thischapterattemptstobridgebasicanimalstudieswithclinicalfindingspertainingtothebrain-gutandgutmicrobiomeinautism,andincludesadiscussionofvariousstrategiesinmanagingautisticsymptoms.Thediscussionalsoincludespossiblechangesintherewardsystem（s）inautismasaconsequenceofalteredgutmicrobiome.Itispossiblethataberrantregulationoftherewardsystem（s）underlinesbehavioralabnormalitiesinASDthatcouldbetargetedbyfuturemicrobiome-targetingtherapies.

2.Effectofperinatalinfectionandtoxicantsonthedevelopingbrain

Inacontinuingquesttounderstandthenatureofgene-environmentinteractionsinASD,wehaverecentlycompletedtwoanimalstudiesexaminingtheeffectofperinatalexposureofthimerosal（TM）andlipopolysaccharides（LPS）onthedevelopingratcentralnervoussystem（CNS）.BothTMandinfections（modeledbyLPSexposure）havebeenimplicatedinautisticpathology.

Organicmercurycompoundsarepowerfultoxicantswitharangeofharmfulneurologicaleffectsinhumansandanimals.TM,whichismetabolizedtoethylmercury,hasbeendiscontinuedasapreservativefrominfantvaccinesbutcontinuestobeusedinseveralvaccinesincludingafluvaccineadministeredtopregnantandlactatingmothers （Sulkowskietal.,2012）.Perinatalmaternalexposureoftwostrainsofrats,SpragueDawley（SD）andspontaneouslyhypertensive（SHR）rats,tothimerosal（200ug/kgbodyweight）resultedinbothsex-andstrain-specificabnormalitiesintheneonatalrats（Sulkowskietal.,2012）.Behavioralabnormalitiesincludeddelayedstartleresponseanddecreasedmotorlearning,withtheeffectsbeingbothsex-andstrain-specific.TMexposurealsoresultedinasignificantincreaseincerebellarlevelsofanoxidativestressmarker（3-nitrotyrosine）andadecreaseincerebellartype2deiodinase,responsibleforlocalintrabrainconversionofthyroxinetotheactivehormone,3’,3,5,-triiodothyronine（T3）.TheseeffectswereassociatedwithanincreasedexpressionofseveralgenesnegativelyregulatedbyT3（Sulkowskietal.,2012）; Khanetal.,2012）suggestingthatperinatalexposuretoTMimpactsthedevelopingbrainatthegeneticlevel.AsTMexposureduringthepostnatalphasecoincidedwithlactation,someoftheTMwasdeliveredthroughthemilktotheGITandmayhavehadaneffectonthedevelopinggutmicrobiomeknowntobesensitivetoheavymetalexposure（Lapanjeetal.,2007）.Thiseffectmaybeinpartduetocompetitionwithzincresultinginadisturbanceinmetallothioneinfunctionandgeneralchelatingcapacityforothermetals.Thus,atleastpartoftheneonatalimpactofTM/mercurycouldbemediatedviaitsactiononthegutmicrobiome.

Inarelatedstudy（Xuetal.,submitted）weexaminedtheeffectofE.colilipopolysaccharides（LPS）exposureduringcriticaldevelopmentalperiodsonthedevelopingbrainemployingtheanimalmodelofinfection.Clinicalandepidemiologicaldatasuggestthatmaternalinfectionduringpregnancyandnursingincreasestheprobabilityofneonatalbraininjuryandmayhavealong-lastingimpactonbrainfunctions.Maternalinfectionduringpregnancyhasbeenlinkedtoneurologicalandneurobehavioraldisordersinhumanssuchascerebralpalsy（Schendel,2001;Schendeletal., 2002）,neonatalstrokes（Ferrieo,2004）,schizophrenia（Watsonetal.,1999; Pearce,2001）andaffectivedisorders（Watsonetal.,1999）.AnimalstudiesimplicatebacterialinfectioninthepathologyofParkinson’sdisease（Carveyetal.,2003）,andnotably,schizophreniaandautism（Patterson,2002）.Thetriggeringsignalsforcytokineproductionareendotoxins,majorcomponentsoftheoutermembraneofGram-negativebacteria.

LPSexposureisoneofthemostacceptablemodelsofinfection;LPSisasufficienttriggerforcytokineproduction.LPSadministeredtothepregnantmotheraretransferredtothefetusthroughtheplacenta（Kohmuraetal.,2000）,andresultinincreasedcytokineslevelsintheamnioticfluid（Urakaboetal.,2001; Gayleetal.,2004）andthefetalbrain（Urakaboetal.,2001）.Bacterialinfectionoflactatingmothersalsoresultsinanincreasedlevelofcytokinesinmilk（Bannermanetal.,2004）.PretreatmentofsucklingratswithLPS（10mg/kg-dayx5days–thedosewhichproducesweak,transientsignsofendotoxemia）resultsinreducedpancreaticsecretionandattenuatesacutepancreatitisatadultageduetoanincreasedconcentrationoftheantioxidativeenzymeSOinthepancreatictissue,andtothemodulationofcytokinesproduction（Jaworekatal.,2007a, b）.Thislate-effectofLPSisaccompaniedbydose-dependentreductionofmRNAsignalforCCK1receptoronpancreaticaciniaswellasmodifiedexpressionofacinarpro-apoptoticheatshockprotein-60（HSP60）andBaxproteins（Jaworeketal.,2007b,2008）.EarlypostnatalLPSexposureresultsininceasedexpressionoftoll-likereceptor4（TLR4）andcaspase-3and9-proteinsinthepancreatictissueofadultrats（Bonioretal.,2012）.ThesestudiesclearlyindicatethatperinatalexposuretoLPSmayhavelonglastingconsequencesontheGITfunction,andasexpected,thoughnotstudiedindetail,onthebrain-gutaxis.

Perinatalmaternalexposureoftwostrainsofrats,SHRorSDratdamstoLPS（200µg/kgbodyweight）resultedinincreasedrollovertime,delayedstartle,anddecreasedmotorlearning,withtheeffectsbeingbothstrain-andsex-specific.LPSchallengealsoresultedinatrendtowardsanincreaseincerebellarlevelsof3-NTandadecreaseinD2activitiesinLPS-exposedpups（Xuetal.,submitted）.SeveralgeneswereaffectedbyLPS.NotablyType2deiodinase2（DIO2）andbrainderivedneurotrophicfactor（BDNF）expressionwassignificantlyelevated,whiletransthyretin（TTR）expressionwasdecreasedfollowingLPSexposure. Invitro,acuteexposureofcerebellarculturestoLPSresultedinadecreasedsizeofthedendriticareaofPurkinjecells.Ourdatathusdemonstratethatperinatalinfectionimpactsthedevelopingcerebelluminasex-andstrain-dependentmannerviamechanismsinvolvingoxidativestress,enzymesinvolvedinmaintaininglocalTHhomeostasis,anddownstreamgeneexpression.Interestingly,genechangesobservedinthebrainsofLPS-exposedratsweredistinctfromTM-associatedgeneeffectsuggestingthattheunderlyingmacromolecularmechanismmaybetrigger-specific.

PerinatalLPSexposurecouldhaveaprofoundeffectonthegutmicrobiomesimilartotheeffectofrepeatedtreatmentwithantibiotics.ExperimentsinhealthymicehaveshownthatdisruptingthenormalbalanceofthegutmicrobiomewithantibioticscausedchangesinmicebehaviorandwasaccompaniedbychangesinBDNFwhichhasbeenlinkedtodepressionandanxiety（Berciketal.,2011; Neufeldetal.,2011）.PerinatalLPSexposuremostlikelyaffectsgutmotilityassuggestedbystudiesofirritablebowelsyndrome（IBS）,wheremildbacterialovergrowth-associatedmotilitydisordercanbereversedbyantimicrobials（ScarpignatoandPelosini,1999）.Animalstudieshavealsoshownthatstresscanchangethecompositionofthemicrobiome,wherethechangesareassociatedwithincreasedvulnerabilitytoinflammatorystimuliintheGIT.Couldgutdysbiosisbeinducedbyrecurrentinfections?

WehaveobservedanincreaseinneurotrophinlevelsinthecerebellaofratsexposedtoLPS（Sajdel-Sulkowskaetal,unpublishedobservation）andbrainregion-specificchangesinneurotrophinlevelsinASD（Sajdel-Sulkowskaetal.,2011）.Togethertheseobservationssuggestthatabacterialinfectioncouldtriggerthegutmicrobiometoinducecytokineoverproductionleadingtoanimbalanceofbrainneurotrophinsandcontributetodevelopmentalabnormalities.

3.Effectofenvironmentalperturbationsonthedevelopingcomponentsofthebrain-gutaxis:

Intestinalpermeability,inflammationandgutmicrobiome

AsindicatedabovetheperinataldevelopmentoftheCNSstructureandfunctiongreatlydependsont