Pulling back to the nature: A condition to fight IBD Manoj Patidar; Naveen Yadav; Sarat K. Dalai* Institute of Science, Nirma University, Ahmedabad-382481, India *Correspondence to: Sarat K. Dalai, Institute of Science, Nirma University, Ahmedabad-382481, India Chapter 1 Inflammatory Bowel Disease 1 1. Introduction Inflammatory bowel disease (IBD) grouped as autoimmune disease arises due to inflam- mation of small and large intestine. Based on the target organ IBD is classified under Ulcer- ative colitis (UC; affects the colon) and Crohn’s disease (CD; affects whole intestinal wall but mainly to the ileum) [1]. 1-1.6 million people are suffering from IBD in United States and the main target age group is between 15-30 yrs. The prevalence rate of 201/10 6 of CD and 238/10 6 of UC in adults attracts attention to the disease [2]. Abdominal cramping, weight loss, fever, sweats, fatigue, growth retardation, diarrhoea, constipation and abnormal bowel movement are the major symptoms of IBD. It is clearly noticed that IBD is not limited to just inflammation of the digestive tract, but it can lead to other complications like arthritis, thromboembolism, car- diovascular-, pulmonary-&neurological disease affecting the quality of life of an individual. It is clearly seen that IBD runs in the family, and the family members of affected individuals are at the maximum risk of IBD. In last two decades it is shown that environmental factors in the pathogenesis of IBD are playing important role in increasing the incidences of IBD cases in the countries with historically low rates of IBD. In North America and Europe 20-fold increase in IBD cases were found since World War II due to change in dietary habit and environmental factors. The environmental factors also correlates with the similar trends in IBD due to glo- balization and Westernizing East Asia [3]. Variation in microflora and disregulated immune responses are the key effectors of IBD. In this chapter we have discussed the various factors affecting the pathogenesis of IBD including genetic, environmental and immune factors. We have also discussed that the delay in IBD diagnosis and fail to control it, can result in trans-
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Pulling back to the nature: A condition to fight IBD
Manoj Patidar; Naveen Yadav; Sarat K. Dalai*
Institute of Science, Nirma University, Ahmedabad-382 481, India
*Correspondence to: Sarat K. Dalai, Institute of Science, Nirma University, Ahmedabad-382481,
Healthygutcontains10-100foldmoremicrobesthanmammaliancellsandintestinalepithelial layer hides thismicrobial line from intestinal immune systemandmaintains thepeaceornon-inflammatoryenvironment.Asthenamesuggestsinflammationisthekeytoin-ducingIBDandbysuppressinginflammationIBDcanbeameliorated.InthepathogenesisofIBD,cytokinesholdthecentralpositionasdemonstratedinmanygeneticandimmunologicalstudies(Table 1).Basedontheirnatureofevokingorsuppressingtheinflammation,theyaregroupedaspro-andanti-inflammatorycytokines.Boththeseclassesofcytokinesareinten-sivelystudiedforbetterunderstandingtheIBDbiology.Cytokinesmaintainthenormalim-munehomeostasisbytriggeringtheresponsestoinfectionsandrevertingbackinflammationtoabasallevelaftertheinfectionisresolved.Butoftendysfunctionoruncontrolledexpressionof thesecytokines triggers immunologicaldisorders.Forexample,IL-1receptorantagonist(IL-1Ra)controlstheinflammatoryresponseofIL-1cytokines,andinsteady-stateIL-1/IL-1-Rarationisfoundtobeconstant.ButanincrementintheratiowasobservedincaseofIBDduetooversecretionofIL-1bymonocytesandmacrophages.TheinvolvementofIL-1inIBDpathogenesismakesitareliablemarkerfordiagnosisofIBDandalsomakeitasuitabletargetfortherapy[4].Similarly,IL-6,-8,-12,-13,-17,-15&-21triggertheinflammationandblock-ingthesecytokinesisshowntoalleviateIBD[5,6].Anti-inflammatorycytokinesorcytokineneutralizingAbsarefoundefficaciousforIBD(Table 1).Unlikethesepro-inflammatorycy-tokines,anti-inflammatorycytokinesdownregulatetheinflammatoryconditionandhelpincuringtheIBD.ForexamplesIL-10,acrucialanti-inflammatoryplayerinCD,controlsTh17cell development andhas beneficial effects in IBD.Spontaneous development of IBDob-servedinIL-10-/-mice[7]supportthefactthatIL-10iscriticalincontrollingtheIBD.Further,useofIL-10,TGF-βandIL-4hasshowntoreverseIBD(Table1).GenomewideassociationstudiesestablishedtheimportanceofSTAT-1,-3,-4,CCR6,CCL-2,-13,IL-12R,-23R,JAK2,IL-2,-21,-10,-27andIFN-γ[8]ininductionofIBD.
AmongthecytokinesTNF-αisapotentactivatorofinflammatoryresponsesandhencedrawnattentionof researchersworking in the areaof IBD.TNF-α isnotonly involved inpathogenesisofIBDbutalsoplaysdominantroleinotherdisorderslikerheumatoidarthritis,psoriasis,psoriaticarthritis,andankylosingspondylitis[8].OverexpressionofTNF-αleadstoacascadeofinflammatoryeventswhichresultsinauto-immunediseasesincludingCDandUC.Itshowspleiotropiceffectsbyincreasingtheexpressionofadhesionmolecules,stimulat-ingfibroblastproliferation,IL-1β,IL-6,IL-33,ST2expression[Table1:Cytokinesinvolve-mentinIBD8].ElevatedlevelsofTNF-αwerefoundintheserum,mucosaandstoolofIBDpatients.Deletion ofTNF-α synthesis regulatory elements is found to evoke IBD inmice
1. IL-6 is an immunoregulatorycytokine2. Acts as both anti- and pro-inflammatory3. Signals through IL-6-sIL-6R-receptorgp130complex.4. Immune response duringinfectionandaftertrauma.
DuringIBD,inflammationisthemajorcauseforthedevelopmentofCRC[23].Asig-nificantincreaseinthelevelofinflammatorymediatorslikecyclooxygenase-2,nitricoxidesynthase-2and interferon-induciblegene 1–8Uwas found in IBDpatients leading toCRC[24].TLR4inducedCox-2andEGFRsignallingarealsoinvolvedinthepromotionofCRC[25].InactiveIBDelevatedlevelofclaudin-1,-2andBeta-cateninwasalsoobservedwhich
1. Regulate diverse host defensemechanisms from epithelial layerduringvariousinfections2.Importantformaintenanceoftheintegrityandhomeostasisoftissueepitheliallayers3. Down-regulate inflammatoryresponses and controlstissue disruptions caused byinflammation.
1.Crucialanti-inflammatoryplayerinCD.2. IL-10 controls Th17 cell development by inducing IL-1secretion.2.BlockingofIL-10leadstoIL-12andIFN-γproduction.3.LowerexpressionofIL-10wasseenininflamedmucosaandgranulomasofCDpatients[13,14].4.IL-22iselevatedinCDmucosaandserum.
2 TGF-β
1.Actsasaninhibitorycytokine2. Regulate the immunologicalhomeostasis and inflammatoryresponses
1. Use of anti-IL-4 antibody decreases Th2-type cytokineproductionandincreasesIFN-γproduction,suggestingroleofIL-4inIBDpathogenesis.2.AdministrationofIL-4resultedindown-regulationofVEGFinactiveCDandUCpatients[5,17].
Gutistheprimeentrysiteforpathogenscomingthroughfoodandorallyadministeredsubstances.GALT(gutassociatedlymphoidtissue)directstissuerestrictedandlocalizedim-muneresponseto the intestinalantigens.Tcellsprimedagainst invadingpathogenmigratefromGALT to the site of infection andprotect thegut.After resolutionof infection theseantigen-experiencedTcellsmigratetotheLP(laminapropria)andepithelialcompartmentswheretheyresideaslong-livedeffectormemoryTcellsandaccumulateovertime.Uponre-encounterwiththepathogenthesecellsrespondswiftlyandvigorouslytoeliminatethepatho-gen,preventingsystemicinfection[18,19].TheseeffectormemoryTcellsproliferateslowly,producelowamountofinflammatorycytokinesthathelpmaintainorganintegrity[20].LPisalsoenrichedwiththeTregcellsrequiredforpreventingtheexcessiveresponsesagainstthegutmicrobes,therebymaintainingthegutintegrity[21].
Hostmicrobialinteractionsandimportanceofintestinalmicrobiotaformetabolismandhostdefencearewellestablished.Humansevolvewiththesemicrobesanditisknownthataround1,800generawith15,000-36,000bacterialspeciesco-existintheintestine[43].Itisinterestingtoknowthatthebacterialload(i.e.,1014bacteria)inhumangutis100timesmorethanthehumancells(i.e.,1012cells).Mucosalimmunecellscantargetthesemicrobesandevokeimmuneresponses.Theepitheliallayerscoveringthebowelwallcontroltheentryofgutfloraandminimizetheinteractionofmicrobeswiththeimmunecells[44].Alargebodyofstudiesisfocussedonimmuneresponsesaswellasmaintenanceofimmunetolerancetotheintestinalmicrobes.TheimmuneresponsesarelargelyprovokedbyrecognitionofPAMPs(pathogenassociatedmolecularpatterns)bytoll-likereceptors(TLRs).Apartfrommicrobes,themetabolites frommicrobesare shown toplay important role in inducing inflammation.Sometimesmicrobespenetratethebowelwallandprovokeimmuneresponses[45].TherearemanyreportssuggestingtheroleofentericflorainthepathogenesisofUCandCD[46-48].Itisobservedthattheareawithhighestbacterialloadshowshighestdegreeofinflammation.LoweringthebacterialloadbyantibioticshasbeenshowntoabrogatetheprogressionofIBD.ItisworthnotingthatinoculationofbacteriasuccessfullyinducesIBDinexperimentalmice[45].Genome-wideanalysisofhealthyandIBDpatientsprovidestheclueofmicrobialcon-nectionwithIBDanditisfoundthat>160SNPsareidentifiedasmarkersofriskforIBD.Interestingly,manyofthesegenesarecriticallyinvolvedinhostresponsestothemicroflora.MutationsinNOD2,ATG16L1,IRGM,CARD9andIL23RappeartobecriticalininducingIBD[1].
The emerging cases during last two decades and severity associatedwith IBDneedfocusedeffortstodevelopsuitabletherapeutics.Thegutmicrobialcompositionanditsrela-tionshipwithimmunesystemarethekeyconsiderationsforIBD.IBDistargetedbyvariousmeansincludingantibiotics,drugsandimmunemodulators.Theseagentsshowsideeffects,highlyexpensiveandproductionisnotadequatetoreachtothelargepopulation.AlthoughthetherapeuticagentsactthroughvariousmechanismstotargetIBD,itiscriticaltomaintainthebalanceofmicroflorainthegut.AsthemodulationofTcellsshapethemicroflora,aprerequi-sitetomaintainahealthygut,weshoulduseprobiotictotreatIBD.