Gastrointestinal function development and microbiota

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Gastrointestinal function development and microbiota
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Mauro, Antonio Di
Neu, Josef
Riezzo, Giuseppe
Raimondi, Francesco
Martinelli, Domenico
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BioMed Central (Italian Journal of Pediatrics)

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Abstract:
The intestinal microbiota plays an important role in the development of post-natal gastrointestinal functions of the host. Recent advances in our capability to identify microbes and their function offer exciting opportunities to evaluate the complex cross talk between microbiota, intestinal barrier, immune system and the gut-brain axis. This review summarizes these interactions in the early colonization of gastrointestinal tract with a major focus on the role of intestinal microbiota in the pathogenesis of feeding intolerance in preterm newborn. The potential benefit of early probiotic supplementation opens new perspectives in case of altered intestinal colonization at birth as preventive and therapeutic agents. Keywords: Intestinal microbiota, Feeding intolerance, Microbial effect on gastrointestinal function development
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Publication of this article was funded in part by the University of Florida Open-Access publishing Fund. In addition, requestors receiving funding through the UFOAP project are expected to submit a post-review, final draft of the article to UF's institutional repository, IR@UF, (www.uflib.ufl.edu/UFir) at the time of funding. The institutional Repository at the University of Florida community, with research, news, outreach, and educational materials.
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Di Mauro et al. Italian Journal of Pediatrics 2013, 39:15 http://www.ijponline.net/content/39/1/15; Pages 1-7
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doi:10.1186/1824-7288-39-15 Cite this article as: Di Mauro et al.: Gastrointestinal function development and microbiota. Italian Journal of Pediatrics 2013 39:15.

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REVIEWOpenAccessGastrointestinalfunctiondevelopmentand microbiotaAntonioDiMauro1,JosefNeu2,GiuseppeRiezzo3,FrancescoRaimondi4,DomenicoMartinelli1, RuggieroFrancavilla1andFlaviaIndrio1*AbstractTheintestinalmicrobiotaplaysanimportantroleinthedevelopmentofpost-natalgastrointestinalfunctionsofthe host.Recentadvancesinourcapabilitytoidentifymicrobesandtheirfunctionofferexcitingopportunitiesto evaluatethecomplexcrosstalkbetweenmicrobiota,intestinalbarrier,immunesystemandthegut-brainaxis.This reviewsummarizestheseinteractionsintheearlycolonizationofgastrointestinaltractwithamajorfocusonthe roleofintestinalmicrobiotainthepathogenesisoffeedingintoleranceinpretermnewborn.Thepotentialbenefit ofearlyprobioticsupplementationopensnewperspectivesincaseofalteredintestinalcolonizationatbirthas preventiveandtherapeuticagents. Keywords: Intestinalmicrobiota,Feedingintolerance,MicrobialeffectongastrointestinalfunctiondevelopmentIntroductionInthehumangutresidesthe microbiota ,alargeanddiversecommunityofmicroorganism,dominatedbybacteria,knowntohaveacriticalroleintheevolutionofthe intestinalfunctionsandinoverallhealthofthehost[1]. Thebacterialcellsfaroutnumberthehumancellsofthe hostthatharborsthemandthetotalamountofgenesin thevariousspeciesrepresentedinourindigenousmicrobialcommunitiesisestimatedabout2 – 4million,exceedingthenumberofourhumangenes>100-fold[2]. Throughexpressionofthisexceptionalquantityofgenes, whosetotalityistermedthe “ microbiome ” ,intestinalbacteriacanexecutenumerousenzymaticreactionsthatthe mammalianhostisnotabletocatalyze.Thisisthereason whythemicrobiotaisnowconsideredasan “ organwithin anorgan ” ,withitsownfunctions:itmodulatesexpression ofgenesinvolvedinmucosalbarrierfortification,angiogenesisandpostnatalintestinalmaturation.Italsohasa criticalroleinsupportingnormaldigestionandaffectsenergyharvestfromthedietandenergystorageinthehost, fermentingunusedenergysubstratestoshortchainfatty acids(SCFAs)[3]. Microbialfunctionsareintimatelystrain-relatedand evendifferentstrainsofasinglespeciesmaydifferinthe effectstheyproduce. Primarycolonizationofthegutcanberegardedasan importantstageofdevelopmentofintestinalfunctions andthetransferenceofthemicrobiotaatbirthfrommaternalvaginalandintestinalfloracomprisesahereditary successionofaparallelgenome[4]. Alargeinterfacebetweentheexternalenvironmentand themammalianhostisrepresentedbytheintestinalepithelium.Thecomplexcross-talkbetweenthegutandits microbialcontentisanormalpartofdevelopmentand playsadeterminantroleinthecapacitytodistinguishpotentiallydangerousfromharmlessbacterialandfoodantigens.Thisfunctionrequiressophisticatedsensorsystems toberesponsivetoawidevarietyofmicrobialandfood antigensthattransitsorpopulatestheGItract[5]. Theintestinalmicrobiotapossessesanimmunomodulatorycapacity,affectingavarietyofsignalingpathways withmodulationofproperimmune,inflammatoryand allergicresponses.Animbalanceofnormalintestinal microbiota,orthehostresponsetosuchanimbalance areconsideredtobeinvolvedinthepathogenesisofa varietyofintestinaldisorders[6]. *Correspondence: f.indrio@neonatologia.uniba.it1DepartmentofPediatrics,UniversityofBari,Policlinico,PiazzaGCesare, Bari,Italy Fulllistofauthorinformationisavailableattheendofthearticle ITALIAN JOURNAL OF PEDIATRICS 2013DiMauroetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.DiMauro etal.ItalianJournalofPediatrics 2013, 39 :15 http://www.ijponline.net/content/39/1/15

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IntestinalcolonizationNewborninfantsexittheuterusandenteranextrauterine environmentfilledwithmicrobes.Thegastrointestinal tractofanormalfetusisgenerallythoughttobesterile. However,recentstudiesusingmoleculartechniquesare suggestingthatthefetalintestinemaybeexposedtomicrobesviaswallowingofcolonizedamnioticfluid[7,8]. Occultmicrobesinamnioticfluidmaybeassociatedwith pretermlaborandprematureruptureofmembranes. Despiteongoingstudiestodeterminethequalitative andthequantitativestateofmicroorganismsinamniotic fluid,thisnewaspectoffetalgutcolonizationremainsa largelyunexploredarea.ThefindingofmicrobialDNA inmeconiumofpreterminfantsofferstheopportunity tofurtherexploretheintraamnioticmicrobialmilieuof newlyborninfants[9]. Duringdelivery,bacteriafrommaternalvaginalandintestinalmicrobiotainvaginalbirthorfrommaternalskin surfaceandthesurroundingenvironmentincesarean section,colonizethegutofthenewbornwithdifferentmicrobialstrains[10].Agreatnumberofbacteria,bothbeneficialandharmful,cancolonizethegastrointestinaltract. Somebacteriafamilyarecommonpathogens,suchas Clostridiacea,Pseudomonadaceae and Staphylococcaceae Otherscanbeeitherpathogenicorbeneficialsuchas Bacterioidaceae and Enterobacteriaceae .Stillothersare thoughttobeprimarilybeneficial,mostcommonly Lactobacillaceae and Bifidobacteriaceae Althoughvarystudieshavebeenperformedtosample thegeneralcompositionoftheinfantgut,therealmicrobialbiodiversitystillremaincontroversialandunknown; cautionmustbeappliedintheinterpretationofthedifferentresultsobtainedbybothculture-dependentandmetagenomictechniques,duetotechnicalbiases[11]. Accordingtodeliverymode,caesareansectiondeliverednewborns,thataredeprivedofcontactwith maternalvaginalmicrobiota,haveadeficiencyofstrict anaerobeswithlowernumbersof E.coli Bacteroides andBifidobacteriaandanhigherpresenceoffacultative anaerobessuchas Clostridium species,comparedwith vaginallyborninfants[12]. Alsoinfant ’ sgestationalageatbirthseemtohavesignificanteffectsontheintestinalmicrobiota[13].It ’ snowclear thatthepatternofbacterialcolonizationinthepreterm neonatalgutdiffersfromthatinthehealthy,full-term neonatalgut.Thisaberrantcolonization,mostlydueto theroutineuseofsterileformulaandantibioticsinneonatalintensivecareunit(NICU),couldhaveacentralrole infeedingintoleranceandindevelopmentofnecrotizing enterocolitis(NEC),adevastingdiseaseaffectingprimarily prematureinfants[14]. Afterwards,intheearlystageoflife,thecomposition oftheintestinalmicrobiotaundergoesmajormodifications,mostlyinfluencedbythefeedingpattern[10]. Gastrointestinalfloracompositiondifferssubstantiallyin breast-fedinfantsandformula-fedinfantsbecauseofthe differencesincompositionbetweenhumanmilkand standardinfantformula.Forexample,breastmilk-fedinfantmicrobiotaiscomposedbyanincreasednumberof bifidobacteriaand lactobacilli ,whereasformula-fedinfant microbiotahasmore enterococci and enterobacteria .This differenceisthoughttobeduetothebreastmilkcompositionofmoleculeswithantimi crobialactivityandprebiotic oligosaccharides,thoughttohaveabeneficialroleforthe infant[15,16].Furthermore,thereisaccumulatingevidence thathumanmilkisnotsterilebutcontainsmaternalderivedbacterialmolecularmotifsthatarethoughttoinfluencethenewborn ’ simmunesystemdevelopment.This procedureiscalled “ bacterialimprinting ” ,anditsoverall biologicaleffectrequiresfurtherstudy[17,18]. Theinitialbacterialcolonizationafterbirth,andits changeaccordingtoenvironment,nursing,weaningand drugs,playsacrucialfunctioninthefinaldevelopmentof thegutwithlargeshiftsintherelativeabundancesoftaxonomicgroups.Thecompositionofmicrobiotaundergoes significantchangesininfancy.Someauthorsobserveda gradualincreaseindiversityovertime,withadiscretesteps ofbacterialsuccessionaccordingtosimilarlifeevents[19]. Thegutinteractswithintestinalbacteriatomature protectivemechanismsagainstharmfulmolecules(via improvingbarriergutfunctions,motilityandimmune stimulation)andappropriate,non-exaggeratedresponses versuscommensalbacteriaandnutrients(viaimmunemodulationandimmune-tolerance)[20].Themechanismsofthisinteractionbetweenhostandbacteriaare increasinglybeingunrevealed.Anaberrantbacterial colonizationmaybeacoexistingfactorinfeedingintoleranceinnewborn.Theexacteffectsofbacterialcolonizationinpathophysiologyoffeedingintoleranceisbased onthepost-nataluncorrectontogenesisoftheintestinal barrier,oftheimmuneresponsesandofsensori-motor functionsofthegut[21]Figure1.Microbiotamodulationondevelopmentof gastrointestinalfunctions MicrobiotaandintestinalbarrierfunctionMicrobialintestinalcontentplaysanimportantpartin theevolutionofgastrointestinalstructureviadirect interactionwithmucosalcell,immunecellsandneuronalendings.Tosupportthisstatement,somestudies haveshownstructuralaberrationaffectingfree-germ mice:greatlyenlargedcecum,reducedintestinalsurface area,decreasedepithelialcellturnover,smallerPeyer ’ s Patchesanddisorderedgut-associatedlymphoidtissue andsmallervillousthickness[22,23].Thismorphological consequencesofgrowingupgerm-freeresultingastrointestinalfunctionaldisorders.DiMauro etal.ItalianJournalofPediatrics 2013, 39 :15 Page2of7 http://www.ijponline.net/content/39/1/15

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Thus,bacteriaregulatedevelopmentoftheintestinalbarrierand,consequently,itsfunctions.Studieshaveshown thatcertainbacteria( E.coli,Bifidobacterium,Lactobacillis ) increaseintestinalepithelialcellsurvivalbyinhibitingthe activationoftheepithelialcellpro-apoptoticpathwayassociatedwithpathogenicbacteria[24].Thecommensal microbiotaisalsoinvolvedinmaintenanceofbarrierfunctioninducinganincreasedepithelialcellproliferationand enhancingintestinalepithelialintegrity,throughtranslocationofthetightjunctionproteinsandup-regulationof genesinvolvedindesmosomemaintenance[25].Finally, commensalbacteriaregulatedevelopmentofintestinalvillusvasculararchitecture[26]. Surfaceenterocytescanrecognizebacterialproductsvia ahighlyconservedfamilyofpathogen-associatedmolecularpattern(PAMP)receptorscalledToll-likereceptors (TLR).Eachofthesereceptorsrecognizesaspecificbacterialproduct. Bindingofanyofthisreceptorsleadstoactivationof nuclearfactorB(NFB),agroupofproteinsthatstart thetranscriptionalprocessofawideamountofgenes. Despitecommensalbacteriainterferencewithpathogenicinfectionsthrougheffectsonintestinalmucosa structure,thepreventionofcolonizationbypathogensis achievedinlargepartbycompetingfornutrientsandreceptors,byproductionofanti-microbialcompoundsand bytriggeringtheexpressionofmultiplecell-signaling processthatcanlimitthereleaseofvirulencefactors. Theintestinalmucosabarrieriscomposedbybothnonspecificdefensivemechanisms,suchasintestinalmotility, mucussecretion,gastricacidsandpancreaticenzymes, andspecificimmunemechanismsthatpreventthetransit ofexternalandunprocessedantigensacrossthegastrointestinalbarrier[27]. Thegut-barrierfacesimportantchallenges:toprevent pathogensandharmfulelementsofthegutlumenfrom Figure1 Intestinalfunctionandmicrobiota. Commensalbacteriainhabitingthehumanintestineparticipateinthedevelopmentand maintenanceofgutimmunologic,sensoryandmotorfunctions.Undernormalconditions,thegastrointestinaltractprovidesastablehabitatfor commensalbacteriathatsupportsitsstructuralandfunctionalintegrity.TheENSinfluencethegutdirectlywiththeactivityrelatedtothe contractionandindirectlyinfluencingthecellsofthegutimmunesystem.Thefunctionalbidirectionalinteractionactvianeuroimmunepeptide receptoronimmunecellsandonseveralreceptorforimmunemediatorsexpressedonentericnerves.Immunecellsreleasemediatorsin responsetoneuralstimuli. DiMauro etal.ItalianJournalofPediatrics 2013, 39 :15 Page3of7 http://www.ijponline.net/content/39/1/15

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enteringintotheinternalenvironmentofthehost;to allowtheabsorptionofnutrients;andfinallytopromote passageofmoleculesandinformationbetweengutlumen andthecomponentsoftheendocrinal,neuronal,immunal routesimplicatedinmaintenanceofhomeostasis. Exposedtotrillionsofmicrobesandcountlessfood antigensofthegutlumen,theintestinalmucosaisincessantlytastingluminalelementsandpromotingmolecularmodificationatitsfrontiertorespondindifferent waytocommensalbacterialortopathogens. Theearlymicrobialcompositionofthehumangastrointestinaltracthaslong-lastingfunctionaleffects,affectingthepostnatalimmunesystemdevelopmentandan aberrantearlycolonizationthatmayprovokedifficulty inthecapacitytodistinguishpotentiallydangerousfrom harmlessantigens.Areducedoraabnormalmicrobial colonizationduringfirstmonthsoflifewouldalsoprovokeaslowerpostnatalmaturationofepithelialcellbarrierfunctionswithaconsequentialalteredpermeability thatfacilitatestheinvasionofpathogensandforeignor harmfulantigens[28]. Anabnormalmicrobialcolonizationcouldfinallylead tomucosalinflammationthatplaysapivotalfunctionin thedevelopmentoffeedingintolerance[29].MicrobiotaandgastrointestinalmucosalimmunologyThehumanimmunesystemincludestheinnateimmunity,thathasastandardizedresponsetoalladverseagents, andtheadaptativeimmunity,thatrecognizespecifically eachmicroorganismandhaveaspecificresponseand memory.Withregardstonewborns,wehavealsotomentiontheimmunitypassivelyacquiredbytrans-placental transportofmaternalimmunoglobulinGinuteroand fromhumanmilksecretoryIgAantibodyafterbirth.Since theintestinalmucosaconstantlyexposedtoantigenic stimulation,theprotectivefunctionofthegutrequires differentfactorstostimulateeitherinnateandadaptive immuneresponse,inacomplexandwellregulatednetof tolerance-inducingmechanismsresidingintheGALT (gutassociatedlymphoidtissue),themostextensive lymphoidsystemofthehumanbody. GALTisformedbybothinductive(Peyer ’ spatches)and effectorsites(laminapropriaandsub-epithelialcells).It worksasacontainmentsystemthatpreventsthetransit ofexternalandunprocessed,potentiallyharmful,antigens acrosstheintestinalbarrierbutisalsoconstantlyincontactwiththemicrobiotaandwithfoodantigens. Germfreestudieshaverevealedthatthemicrobiotais oneofthemostimportantfactorforthedevelopmentof theGALT[30].GALTpreventspotentiallyharmfulintestinalantigensthroughpolymericimmunoglobulinA(IgA) secretionandmodulatesthetoleranceversusluminalantigensthroughprocessesthatinvolvespecificcytokineand peculiarpopulationofcells.Thisfundamentalenteric function,knownas oraltolerance ,isbasedontheinteractionbetweentheluminalcontent,theintestinalepitheliumandthetolerogenicdendriticcells(DCs)from mesentericlymphonodesoftheGALT[31].Oraltolerance isabletoavoidinflammatoryresponseagainstfoodproteinsandselfaggressionagainstthehost ’ sownresident intestinalbacterialmicrobiotathroughtheestablishment ofatolerogenicmechanismonCD4+Tcellnavethat suppresstheexpressionofTeffectorcells(Th1andTh2) andstimulatetheexpansionofregulatoryTcells(Tregs) bysecretingcytokinessuchasIL-10andTGF .Mcells andDCsoftheGALTcaninfactsamplethemicrobial milieu:Mcellsefficientlytakeupinlumenandtransport inthelaminapropriaavarietyofmicroorganismsand antigensviaactivevesiculartransportacrosstheepithelium.LaminapropriaDCsprocessantigensfromintestinallumenbysendingdendritesbetweenenterocytesand presentthemtoTnavecells. Inthelaminapropria,isolatedandepithelium-associated lymphoidfolliclesareproposedtobelocalsitesingutfor interactionbetweensubepithelialantigen-presentingcells, antigensandlymphocytes.Inthissetting,DCsmodulate immuneresponsesthroughactivationofsignalingevents leadingtoimproveexpressionoffactors,suchascytokines andchemokinethatrecruitandregulatethephenotype andfunctionsofimmuneTcells[32].AntigensarepresentedbydendriticcellsinthecontestofMHCclassII moleculestonaveTlymphocytes.Intestinalresponsesof thenaveTcellstotheseeitherfoodorbacterialsignalsare generallydescribedintermsoftwoclassesofCD4+Tcells, definedbytheircytokineproduction:Thelpertype1that modulatecell-mediatedimmunitybysecretingINF and TNF ;andThelpertype2thatmodulatehumoralimmunitybysecretingIL-4andIL-6.Inanon-diseasedstate thereisatightregulationofthesecytokines. Theimmatureimmunesystemofnewbornisknownto haveaTh2bias.Thepostnatalgutcolonizationmakesan appropriateshifttowardsaTh1responsethatresultsina balanceofthesystem.Microbialcolonizationinfluences toll-likereceptorsongutimmunecellsthatrecognize PAMPsandmodulatebothintestinalinnateandanappropriateadaptiveimmuneresponse,accordingtothecharacteristicsofmicrobialstrain(commensalorpathogen). Differentlacticacidbacteriaas Lactobacillus and Bifidobacterium havebeenshowntodetermineaproportionedThelpercellresponse,forbiddingaTcellunbalance(Th2>Th1orTh1>Th2)thatmayconduceto clinicaldisease[33]. Thesefindingsdemonstratethattheintestinalmicrofloraanditsqualitativedifferencesincompositionmight affectimmunologichomeostasis.Thebalancebetween microbiota,immuneresponseandtolerancemechanisms isfundamentalforahealthyintestine,andinappropriate relationshipduetoanabnormalcolonizationmayresultDiMauro etal.ItalianJournalofPediatrics 2013, 39 :15 Page4of7 http://www.ijponline.net/content/39/1/15

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infeedingintoleranceinearlypostnatallifeandin gastrointestinaldiseaseinchildhood.Microbiota-gut-brain-axisInthepastfewyears,growingevidencesupportstheimportanceofmicrobiotainthematurationandmodulationofgutsensorimotorfunctions.Gutsensoryand motorfunctionareundercontrolofthegut-brainaxis,a complexbidirectionalcommunicationsystemthatexists betweenthecentralnervoussystemandthegastrointestinaltract.Microbiotacaninteractwiththisaxisemittingandreceivingamultiplicityofsignalstoandfrom thebrain.Thishasbeenreflectedintheformofarevised nomenclaturetothemoreinclusivebrain-gut-microbiota axisandasustainedresearchefforttoestablishhowcommunicationalongthisaxiscontributestobothnormaland pathologicalcondition[34]. Thebraincaninfluencemicrobiotacompositionindirectlythroughmodificationsingastrointestinalmotility,secretion,andintestinalpermeab ility,ordirectly,viacitokines releasedintothegutlumenfromenterochromaffincells, neuronsandimmunecellsoflaminapropria.Throughthe removalofexuberantbacteriafromthelumen,intestinal motilityisconsideredoneof themostimportantcontrol systemsoftheintestinalmi crobiota,Ontheotherhand, entericmicrobiotaalsoplayaroleinthedevelopmentand sustenanceofbothsensoryandmotorgutfunctions, throughcommunicationwiththebrainthatoccursindirectlythroughinteractionwithepithelial-cellandreceptormediatedsignalinganddirectlythroughstimulationof neuronalcellsinthelaminapr opria,whenintestinalpermeabilityisincreased[35]. Integraltothesecommunicationsareenterochromaffin cells,whichserveasbidirectionaltransducersthatmodulateinterrelationshipbetweenthegastrointestinallumen andthenervoussystem[36].Enterochromaffincellsare innervatedbythesensoryfiberofvagusnerve.Gutmicrobiotainfluenceonenterochromaffincellssuggestarolein theregulationofvisceralpain.Thecorrectmechanismsof actionofsucheffectcurrentlyremainunclear.Furthermore,evidenceforcombinationofneural,immuneand endocrineeffectsemergesfromstudies[37]. Animmatureontogenesisofthebidirectionalinterrelationbetweentheentericmicrobiotaandthenervous system,duetoanaberrantcolonizationafterbirth,could affectthepathophysiologyoffeedingintoleranceinpretermnewbornandofdifferentchildhoodfunctional gastrointestinaldiseaselaterinlife[38].MicrobiotaandfeedingintoleranceinpretermnewbornDisturbanceofnormalgastrointestinalontogenesis,early postnatalstress,differentpatternofgastrointestinal colonization,changesinthemicrobiotainducedbyinfectionorearlyuseofantibioticsinNeonatalIntensive CareUnit(NICU),orotherevents,perturbphysiologic inflammationandgutphysiology,resultinginanaberrantactivationofintestinalperistalsisandgut-brainaxis [39].Aberrantintestinalfunctionsdevelopmentarethe majordeterminantforfeedingintolerance(FI),amajor probleminNICU.FIisdefinedastheinabilitytodigest enteralfeedingsandmaybeconsideredasapredictive valueforadevelopingNEC[40].FIoccursmostcommonlyinverylowbirthweight(VLBW)infants,indicating adeficiencyinthedevelopmentalpatternofgastrointestinaltractwithdecreasinggestationalage(GA).Newborns requirestructuralandfunctionalmaturationofgastrointestinaltractforthedigestionandabsorptionofthe nutrientelementsfromcolostrumandbreastmilk.A completeintestinalmotorfunctiondevelopmentincludes suck-swallowcoordination,gastroesophagealsphincter tonecontinence,adequategastricemptyingandintestinal peristalsis.Termnewbornsareabletoacquireadequate quantitiesofnutrientstopromotetherapidgrowththat occursshortlyafterbirth.However,halfofpreterminfants aredelayedinachievingfullenteralfeedingvolumesand presentreflux,gastricresidualandconstipationdueto delayedgastricemptying,prolongedintestinaltransit, abdominaldistension,anddelayedpassageofmeconium, allofwhichreflexgastrointestinalfunctionsimmaturity [41].Therearefewstudiesavailableaboutthefetalontogenesisandtheneonatalearlyadaptationofmotilityand mucosalbarrierfunctionsofthehumangut[42-44].Functionalcomponentsofthehumangastrointestinaltractdo notevolvesimultaneously:infacts,althoughtanatomical differentiationofhumangutisusuallyachievedwithin20weeksofgestation,thefunctionalmaturationispostponed overtimeandrequireanorganizedperistalsisandacoordinatedsuckingandswallowingreflexes,thatarenot extabished,respectively,until29 – 30weeksand32 – 34weeksofgestations[45].Asillustratedbefore,theearly compositionoftheintestinalmicrobiotaatbirthcaninfluencethecorrectontogenesisofgutbarrier,motorand immunefunctionsthroughacomplexneuroendocrine cross-talk[46].Thus,anappropriatecolonizationofthe gastrointestinaltractafterbirthislikelytoplayanimportantroleinthefinaldevelopmentofgutfunctions.Prematureinfantshaveanabnormalcolonization,tendto colonizewithfewerbacteria,areroutinelyadministered antibiotics,areoftenbornviacaesariansection,andare exposedtohighlypathogenicinstitutionalorganisms [47,48].Examiningtheintestinalbacteriapresentinprematureinfantsmaybeanimportantdeterminantinthe pathogenesisoffeedingintoleranceandnecrotizingenterocolitis(NEC)[49].Usingadvancedtechnologiesand stoolsamplesstudieshaveshownthatinfantswhodevelop NEChavesignificantlylessbacterialdiversityintheirintestinalmicrobiotawithpresenceofcertainpathogenic bacteriaandthelackofprotectivebacteria[50,51].DiMauro etal.ItalianJournalofPediatrics 2013, 39 :15 Page5of7 http://www.ijponline.net/content/39/1/15

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Exposureto “ non-beneficial ” microorganismsandantibioticsearlyinlifemayresultinimmunedysregulation, aberrantbarrierfunctions,andalteratedgutsensorimotorfunctionsthat,insusceptibleindividuals,may leadtosomediseasestatesafterbirthorlaterinlife.Effortstooptimizetheintestinalmicrobiotacolonization atbirthinneonateswhoarebornbycaesareandelivery, bornpreterm,exposedtoantibioticsand/orfedwith infant-sterile-formulas,haveincreasedtheinterestin earlyprobioticssupplementation.Introducingprobiotic topreterminfantshasbeenpostulatedtoenhanceenteralfeeding,preventNECandavoidovergrowthof pathogenicorganism.Probioticsarelivemicrobesthat providehealthbenefitstothehostwhendispensedinadequatedoses.Manystrainsthatarepartofthehuman intestinalmicrobiotacouldbeconsideredaspotential probioticsbutmicroorganismsusedinpreventionand treatmentofpediatricclinicaldiseasesaretypicallymembersofthegenera lactobacillus and bifidobacterium ,followingthenaturalevolutionofthemicrobialcolonization inahealtytermbreast-fedbaby.ConclusionTheintestineservesasavastinterfacebetweenourinternalmilieuandexternalenvironments.Evidenceis rapidlyaccumulatingthatthemicrobesresidingwithin theintestinaltractplaymajorrolesintheontogenesisof theimmunesystem,andinteractwiththegutaswellas thecentralnervoussystems. Anaberrantmicrobialcolonizationwithconsequential immaturityindevelopmentofimmuneandneuronalpatternofgastrointestinaltractmaybeacoexistingcauseof feedingintolerance.Abnormalcolonizationshouldconstantlybekeptinmindasanimportantenvironmental factorthatpredisposestodiseasealsolaterinlife. Itisemphasizedthattheperinatalperiodmostprobably correspondstoacriticaltimeatwhich “ setpoints ” are imprinted.Moreneedstobeknownaboutnormaland healthycolonizationpatternsinnewbornstopromote thesepatternsandtoavoidperturbationsthatresultin lifelongdisease.Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authors ’ contributions Alltheauthorscontributedtothereviewandwereinvolvedinwriting, revisingandapprovingthefinaldraftofthemanuscript. Authordetails1DepartmentofPediatrics,UniversityofBari,Policlinico,PiazzaGCesare, Bari,Italy.2UniversityofFlorida,Gainesville,FL,USA.3LabofExperimental Pathophysiology,IRCCSCastellanaGrotte,CastellanaGrotte,Italy.4University FedericoII,Naples,Italy. 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