Intestinal microbiotaIBS.docx

Intestinal microbiotaIBS.docx

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IntestinalmicrobiotaIBS

Nameofjournal:

WorldJournalofGastroenterology

ESPSManuscriptNO:

9351

Columns:

TOPICHIGHLIGHT

WJG20thAnniversarySpecialIssues（4）:

Irritablebowelsyndrome

Intestinalmicrobiotainpathophysiologyandmanagementofirritablebowelsyndrome

LeeKNetal.IntestinalmicrobiotainIBS

KangNyeongLee,OhYoungLee

KangNyeongLee,OhYoungLee,DepartmentofInternalMedicine,HanyangUniversityCollegeofMedicine,Seoul133-791,SouthKorea

Authorcontributions:

LeeKNperformedtheliteraturereviewanddraftedthepaper;LeeOYperformedthecriticalrevisionofthemanuscript.

Correspondenceto:

OhYoungLee,MD,PhD,DepartmentofInternalMedicine,HanyangUniversityCollegeofMedicine,222Wangsimni-ro,Seongdong-gu,Seoul133-791,SouthKorea.leeoy@hanyang.ac.kr

Telephone:

+82-2-22908343Fax:

+82-2-22988314

Received:

February9,2014Revised:

April2,2014

Accepted:

June14,2014

Publishedonline:

Abstract

Irritablebowelsyndrome（IBS）isafunctionalboweldisorderwithoutanystructuralormetabolicabnormalitiesthatsufficientlyexplainthesymptoms,whichincludeabdominalpainanddiscomfort,andbowelhabitchangessuchasdiarrheaandconstipation.Itspathogenesisismultifactorial:

visceralhypersensitivity,dysmotility,psychosocialfactors,geneticorenvironmentalfactors,dysregulationofthebrain-gutaxis,andalteredintestinalmicrobiotahaveallbeenproposedaspossiblecauses.Thehumanintestinalmicrobiotaarecomposedofmorethan1000differentbacterialspeciesand1014cells,andareessentialforthedevelopment,function,andhomeostasisoftheintestine,andforindividualhealth.TheputativemechanismsthatexplaintheroleofmicrobiotainthedevelopmentofIBSincludealteredcompositionormetabolicactivityofthemicrobiota,mucosalimmuneactivationandinflammation,increasedintestinalpermeabilityandimpairedmucosalbarrierfunction,sensory-motordisturbancesprovokedbythemicrobiota,andadisturbedgut-microbiota-brainaxis.Therefore,modulationoftheintestinalmicrobiotathroughdietarychanges,anduseofantibiotics,probiotics,andanti-inflammatoryagentshasbeensuggestedasstrategiesformanagingIBSsymptoms.ThisreviewsummarizesanddiscussestheaccumulatingevidencethatintestinalmicrobiotaplayaroleinthepathophysiologyandmanagementofIBS.

©2014BaishidengPublishingGroupInc.Allrightsreserved.

Keywords:

Immunity;Irritablebowelsyndrome;Microbiota;Permeability;Probiotics

Coretip:

Irritablebowelsyndrome（IBS）isafunctionalboweldisorderwithmultiplepathophysiology,whichisnotfullyunderstood.IntestinalmicrobiotahasrecentlybeenpostulatedtobeinvolvedinthepathophysiologyofIBS.ManystudiesofIBSfocusoninvestigatingtheefficacyofmodulatingthemicrobiotabyprobioticsandantibiotics.However,theroleoftheintestinalmicrobiotainthepathophysiologyandmanagementofIBSisnotclear.Thisreviewprovidestheaccumulatingevidenceonit.

LeeKN,LeeOY.Intestinalmicrobiotainpathophysiologyandmanagementofirritablebowelsyndrome.WorldJGastroenterol2014;Inpress

INTRODUCTION

Irritablebowelsyndrome（IBS）isafunctionalboweldisordercharacterizedbyabdominalpainordiscomfortrelievedbydefecation,andaccompaniedbychangesinbowelhabitssuchasdiarrheaorconstipation,whichcannotbeexplainedbystructural,biochemical,ormetabolicabnormalities[1].ThesymptomsofIBShavebeenaccountedforasresultingfromvisceralhypersensitivity,intestinaldysmotility,geneticorenvironmentalfactors,psychologicalfactors,oradysregulatedbrain-gutaxis[2].Inadditiontothesefactors,bacterialinfection,dysregulatedintestinalimmunefunction,andchroniclow-grademucosalinflammationhaveallbeensuggestedasputativepathogeneticmechanisms,inwhichtheintestinalmicrobiotamightplayanimportantrole,buttheirroleinIBScannotbefullyexplained（Figure1）[3,4].

Intestinalmicrobiotaisacollectivetermforacomplexecosystemofmicrobesinhabitingtheintestine[5].Inthehumanintestine,thisecosystemmayincludeanyoneofover1000microbialspecies,and1014cells（i.e.,about10timesmorethanthenumberofhumancellsinthebody[6]）,containing150-foldmoregenesthanthehumangenome[7].Themicrobiotacanbedividedintomucosalandluminalsubtypes[8],anditwaspreviouslythoughttocomprisethreepredominantenterotypes:

Bacteroides,Prevotella,andRuminococcus[9],althoughsuchastrictcategorizationisnolongerwidelyaccepted[10].

Toevaluatethecompositionandmetabolicactivityoftheintestinalmicrobiota,culture-dependentand–independenttestshavebeendeveloped[11].Ithasbeenshownthatsizeanddiversityofthemicrobiotaincreasedistallyfromtheuppertothelowergastrointestinal（GI）tract[12]andaremodulatedbygastricacid,intestinalmotility,andthefunctionoftheileocecalvalve.TheirdistributionalsovariesaccordingtotheregionoftheGItractwithgram-positivefacultativeanaerobicbacteriaintheproximalsmallintestineandgram-negativeanaerobesinthedistalsmallintestine.Althoughthecompositionanddiversityofthemicrobiotaaregeneticallycontrolledfrombirthandbecomestableafterweaningandthroughoutlife,qualitativeandquantitativechangescanoccuroverthelongitudinalandcross-sectionalaxesoftheintestine:

changesinbacterialenzymesandmetabolicactivity,aswellasinmicrobialpopulations.Thecompositionandmetabolicactivityofthemicrobiotavarybetween,butalsowithin,individualsduetomanyfactorsincludingmodeofdeliveryatbirth,diet,sanitation,antibiotics,andageing[13].Atbirth,contaminationfromthevaginalcanalprovidestheintestinewiththematernalmicrobiome,whileduringadeliverybycesarean-section,thegutcomesintocontactwithcommensalsfromtheskinandthesurgicalenvironment[14].Thecompositionofthemicrobiotacanalsobealteredbythefeedingmethod:

bifidobacteriaincreaseinbreast-fedbabies（i.e.,babiesreceivingahigh-carbohydrateandhigh-fiberdiet）,andBacteroidesspp.increaseinformula-fedbabies（babiesreceivingahigh-fatdiet）[15].Lastly,itcanvaryacrossgeographicalregions,e.g.,betweenruralAfricaandurbanEurope[16].

Theintestinalmicrobiotaisessentialformaintainingindividualhealth,includingnormalGIfunction.Inthiscontext,itsmainfunctionsaremetabolic,protective,andtrophic:

itcanhelptodigestandabsorbnutrients,andproducesavarietyofbeneficialcompoundssuchasshort-chainfattyacids（SCFA）[17],itcanactasabarrieragainstpathogensbyadheringtothemucosa,generatingimmuneresponses,andinteractingwithcomponentsoftheepitheliallayer,itcanalsoinfluencethedifferentiationandproliferationoftheintestinalepithelialcellsandthedevelopmentoftheentericimmunesystem.

Inparallelwiththebeneficialeffectsofmicrobialactivityonthegut,bacterialfermentationmaygiverisetolargeamountsofgasandthuscontributetothesymptomsofbloating,flatulence,andabdominaldistension,whicharecommonlyreportedbypatientswithIBS[18].AnassociationbetweenthemicrobiotaandIBShasbeensupportedbytheevidenceofmodulationofmucosalimmunity:

IBSsymptomswerefoundtobemorefrequentafteranepisodeofgastroenteritis,andsomeIBSsymptomswerefoundtoimproveafterantibiotictreatmenttargetingtheintestinalmicrobiota[19].Thisputativelinkwasalsodemonstratedinstudiesofprobiotics,whichmodulatedtheintestinalmicrobiotainIBSpatients.Finally,mucosalimmunity-gutmicrobiota-brainaxisisbeingsuggestedasapossiblepathwayforthedevelopmentofIBSduetoalteredintestinalmicrobiota.ThisreviewarticleexplorestheroleofthemicrobiotainthepathophysiologyandmanagementofIBS,andprovidesacomprehensivesummaryoftheevidencefortheconceptofIBSasamicrobiota-relateddisorder.

Despitethelargevolumeofstudiesoftheintestinalmicrobiota,ourunderstandingofitsroleinhealthanddiseaseisstillinitsinfancy.Instudyingthemicrobiota,culture-basedmethodsarebeingreplacedbyadvanced,culture-independent,moleculartechniques.However,thesetwoapproachesarecomplementary:

culturestudiesoffecalmatterorcolonicmucosaarevaluableforidentifyingfunctionalgroupsandforselectiveenumeration,whereasadvancedmolecularstudyareapowerfultoolformonitoringchangesinmicrobialcomposition.Themolecularmethodologyincludessequencingofthesmall-subunitribosomalRNAgenesthroughamplificationofnucleicacidsextractedfromfecalormucosalsamples,fingerprintingmethodssuchasdenaturinggradientgelelectrophoresis,targetedmethodssuchasfluorescenceinsituhybridizationandquantitativePCR,newhigh-throughputsequencing,and16SrRNA-basedmicroarraying[20]

PUTATIVEPATHOPHYSIOLOGICROLEOFINTESTINALMICROBIOTAINIBS

Alterationofthemicrobiota-gut-brainaxis

Themicrobiotainthegutcanbealteredbybrainfunction,andmicrobialalterationcan,inturn,influencebrainfunction.ItisevidencedbythefindingthatpatientswithIBSfrequentlyhaveaccompanyingpsychologicaldisorders,suchasanxietyordepression,andthosewithpsychologicalstressaremorelikelytodeveloppost-infectious（PI）-IBS.Thisconnectionbetweenthemicrobiota,thegut,andthebraininIBSpostulatestheexistenceofabidirectional,homeostaticnetwork,anditisanexcitingareaofongoingresearch.

Animalstudieshavedemonstratedtheinfluenceoftheintestinalmicrobiotaonbraindevelopment.BraindysfunctioninGerm-free（GF）micewasreported,includinganexaggeratedhypothalamic-pituitaryresponsetomildstress[21],moreexploratoryandrisk-takingbehavio