Innate Immune Response and Gut Microbiota in IBDWord格式.docx
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Innate Immune Response and Gut Microbiota in IBDWord格式.docx
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Reviews
Abstract
BACKGROUND:
Inflammatoryboweldisease(IBD)arechronic,relapsinginflammatorydisordersofthedigestivetractresultingfromalossofhomeostasisbetweentheintestinalimmunesystemandthegutmicrobiotaingenetically-predisposedindividuals.
METHODS:
Inthisreview,wediscussontheemergingnovelconceptsontheroleofinnateimmuneresponseandgutmicrobiotaincontrollingmucosalhomeostasisandchronicinflammationwithinthegastrointestinaltract.
RESULTS:
AlthoughtheetiologyofIBDremainslargelyunknown,recentevidenceshavefocusedontheinterplaybetweeninnateimmuneresponseandgutmicrobiotamodulationandhaveimplicatedthecommensalmicrobiotaasacrucialplayerintheunrestrainedinflammatoryresponsesobservedinhumanandexperimentalIBD.
CONCLUSIONS:
Theinformationderivedfromthesestudiesrevealedthatintestinalhomeostasisandinflammationaredrivenbyinnate-typecellularelementsandsolublemediatorsthattogetherwithgutmicrobiotamediatebothprocesses,withseveralcytokinesexhibitingopposingroles,dependinguponthespecificsetting.ThisnewbodyofinformationhasimportanttranslationalimplicationsforboththepreventionandtreatmentofpatientssufferingfromIBD.
INTRODUCTION
Inflammatoryboweldisease(IBD),suchasCrohn’sDisease(CD)andUlcerativeColitis(UC),arechronic,relapsinginflammatorydisordersofthedigestivetractresultingfromalossofhomeostasisbetweentheintestinalimmunesystemandthegutmicrobiotaingenetically-predisposedindividuals
1.Inappropriatemucosalimmuneresponses,duetodysregulationoftolerancetointestinalmicrobiotaordisruptionoftheepithelialbarrierseparatingmicroorganismsfromunderlyingtissues,maycontributetothedevelopmentorperpetuationofIBD.Infact,genome-wideassociationstudies(GWAS)inpatientswithIBDhaveidentifiedmorethan150associatedloci,withmanyofthegeneticvariantspointingtotheimportanceofbarrierfunctionandmicrobialdefense
2
3
4.ThenewhypothesisforIBDsummarizesinformationobtainedfromgeneticassociationstudies,animalmodelsofinflammation,aswellasclinicalstudiesandobservations.Onthebaseofthesedata,IBDareincreasinglyconsideredastateofimmunodeficiencyoftheinnatearmofimmunity,especiallyforadefectivebacterialrecognition,autophagyandantigenpresentation.
Inthiscontext,theintestinalbarrierrepresentsafunctionalunitresponsiblefortwomaintasksthatarecrucialforsurvivaloftheindividual:
allowingnutrientabsorption,anddefendingthebodyfrompenetrationofunwanted,oftendangerous,macromolecules.Thegutmucosais,infact,amulti-layeredsystemconsistingofanexternal“anatomical”barrierandaninner“functional”immunologicalbarrier.Commensalgutmicrobiota,themucouslayer,andtheintestinalepithelialmonolayerconstitutetheanatomicalbarrier.Thedeeper,innerlayerconsistsofacomplexnetworkofimmunecellsorganizedinaspecializedandcompartmentalizedsystemknownasgut-associatedlymphoidtissueorGALT.GALTrepresentsbothisolatedandaggregatedlymphoidfolliclesandisoneofthelargestlymphoidorgans,containingupto70%ofthebody’stotalnumberofimmunocytes;
moreover,itisinvolvedinresponsetopathogenicmicroorganismsandprovidesimmunetolerancetocommensalbacteria.TheabilityofGALTtointeractwithluminalantigensrestsonspecificmucosalimmunecells(i.e.,dendriticcellsandM-cells),primarilylocalizedtoPeyer’spatcheswithintheileumthatareintimatelypositionedatthemucosal-environmentalinterfaceandinternalizemicroorganismsandmacromolecules.Thesespecializedimmunecellshavetheabilitytopresentantigentonaï
veT-lymphocytes,whichsubsequentlyproducecytokinesandactivatemucosalimmuneresponses,whenneeded.Fromtheintracellularpointofview,inflammasomesareagroupofproteincomplexesthatassembleuponrecognitionofadiversesetofnoxiousstimuliandarenowconsideredthecornerstoneoftheintracellularsurveillancesystem.Inflammasomesareabletosensebothmicrobialanddamage-associatedmolecularpatterns(DAMPs)andinitiateapotentinnate,anti-microbialimmuneresponse
5.Theinteractionofthesecomponentssustainsthemaintenanceofthedelicateequilibriumneededforintestinalhomeostasis.Manyfactorssuchasalterationsinthegutmicroflora,modificationsofthemucuslayerandepithelialdamagecanalterthisbalanceleadingtoincreasedintestinalpermeabilityandtranslocationofluminalcontentstotheunderlyingmucosa
6.Theintegrityofthesestructuresisnecessaryforthemaintenanceofnormalintestinalbarrierfunction.DysregulationofanyoftheaforementionedcomponentshavebeenimplicatednotonlyinthepathogenesisofIBD,butmanyotherGIdisorders,includinginfectiousenterocolitis,irritablebowelsyndrome,smallintestinalbowelovergrowth,andallergicfoodintolerance
7
8
9.
Inparticular,severallinesofevidencehaveshownthatthemicrobialfloraiscriticalforthedevelopmentofanormalgutimmunesystem,butcanalsoplayacentralroleinthedevelopmentofIBD
10
11
12
13.Insupportofthisconcept,themajorityofgenetically-susceptiblemurinemodelsofcolitisdonotdevelopsignificantinflammationwhenraisedinagerm-freeenvironment
14
15
16
17,whileinothers,diseasecanbeattenuatedorcompletelyabolishedwithantibiotictreatment
18
19.Inthiscontext,innateimmuneresponsesthatrecognizeconservedmicrobialproducts,suchaslipopolysaccharide(LPS)andpeptidoglycan20,arelikelytobeimportantinmicrobial-hostinteractionsandintestinalhomeostasis
21
21.Criticaltothehost’ssensingofmicrobesaremembersofthetoll-likereceptors(TLR)familythat,aloneorincombination,recognizeawidearrayofmicrobe-associatedmolecularpatterns(MAMPs)oneitherpathogensorcommensals
22.Furthermore,emergingevidencesindicatethatintestinalhomeostasisandinflammationaredrivenbycellularelementsandsolublemediatorsthatmediatebothprocesses,withseveralcytokinesexhibitingopposingrolesdependinguponthespecificsetting.RelatedtothisnotionisthedogmathatchronicintestinalinflammationcharacteristicofIBDdevelopsthroughtwodistinctphases
23.Earlydiseasereferstotheinitialeventsthattakeplacewhenhomeostaticmechanismsinitiallyfailandacuteinflammatoryresponsescannotberesolved.Incontrast,latediseasereferstotheperiodwhenadaptiveimmunityhasbeenirreversiblyprimedtowardsaspecificeffectorphenotype.Duringthesedistinctstagesofdiseaseprogression,innatecytokinesplaydiverse,andoftentimes,dichotomousroles
24
25.
Inthepresentreview,wewillcomprehensivelyevaluatethenovelandemergingconceptsabouttheroleofinnateimmuneresponseandgutmicrobiotaincontrollingmucosalhomeostasisandchronicinflammationwithinthegastrointestinal(GI)tract.Onthebaseofthesedata,wespeculateaboutthepotentialimplicationsofthemodulationofthesefactorsfortreatingchronicintestinalinflammation,aswellasindesigningmoreefficaciousstrategiesforthepreventionandtreatmentofthesedevastatingGIpathologies.
GutMicrobiotainIBD:
causeorconsequence?
GIfunctionsarecarriedoutinadynamicenvironmentinhabitedby1kgofcommensalmicrobesthatincludemorethan3mlnofgenes
26
27.Theybelongtothethreedomainsoflife,
Bacteria,Archaea
and
Eukarya
28
29
30,aswellastoviralparticles
31
32.Recentadvancesinculture-independentmoleculartechniques,bytheanalysisofphylogeneticarrays,nextgeneration16SrRNAsequencingandmetagenomesequencingderivedfromhumanmucosalbiopsies,luminalcontentsandfeces,haveshownthatfourmajormicrobialphyla,(Firmicutes,Bacteroides,Proteobacteria
Actinobacteria),represent98%oftheintestinalmicrobiotaandfallintothreemaingroupsofstrictextremophileanaerobes:
Bacteroides,Clostridium
cluster
XIVa
(alsoknownastheClostridiumCoccoidesgroup),andClostridium
IV
(alsoknownastheClostridiumleptumgroup)
33
34
35
36
37,
38
39
40
41
42.
Anintricateandmutualisticsymbiosismodulatestherelationshipbetweenthehostandthegutmicrobiota
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45.Thisrelationshipisconstantlychallengedwithseveralfactorssuchasrapidturnoveroftheintestinalepitheliumandoverlayingmucus,exposuretoperistalticactivity,foodmolecules,gastric,pancreaticandbiliarysecretions,defensemolecules,drugs,pHandredoxpotentialvariations,andexposuretotransientbacteriafromtheoralcavityandesophagus,andcanleadtothecollapseofthemicrobialcommunitystructure
46.Ontheotherhand,residentmicrobesperformseveralusefulfunctions,includingmaintainingbarrierfunction,synthesisandmetabolismofnutrients,drugandtoxinmetabolism,andbehavioralconditioning
47.Gutmicrobiotaisalsoinvolvedinthedigestionofenergysubstrates,productionofvitaminsandhormones
48,protectionfrompathogenicbacteriabyconsumingnutrientsandproducingmoleculesthatinhibittheirgrowth
49
50
51,productionofnutrientsformucosalcells
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54,augmentingtotalandpathogen-specificmucosalIgAlevelsuponinfection
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56,andinmodulatingimmunesystemdevelopmentandimmunologicaltolerance
57.
Unfavorablealterationofmicrobiotacomposition,knownasdysbiosis,hasbeenimplicatedinchronicgut,andperhapsalsosystemic,immunedisorders,suchasinthepathogenesisofIBD,andothergastrointestinaldisor
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