EXTRAGASTROINTESTINAL DISEASES.docx

EXTRAGASTROINTESTINAL DISEASES.docx

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EXTRAGASTROINTESTINALDISEASES

P.C.KONTUREK1,D.HAZIRI1,T.BRZOZOWSKI2,T.HESS1, 

S.HEYMAN1,S.KWIECIEN2,S.J.KONTUREK2,J.KOZIEL3

EMERGINGROLEOFFECALMICROBIOTATHERAPYINTHETREATMENT 

OFGASTROINTESTINALANDEXTRA-GASTROINTESTINALDISEASES

1DepartmentofInternalMedicine,Thuringia-Clinic,TeachingHospitaloftheUniversityofJena,Saalfeld,Germany, 2DepartmentofPhysiology,JagiellonianUniversityMedicalCollegeCracow,Poland, 3DepartmentofMicrobiology,FacultyofBiochemistry,Biophysics,andBiotechnology,JagiellonianUniversity,Cracow,Poland

Intherecentdecadeourunderstandingoftheroleofthehumangutmicrobiomehasbeenrevolutionizedbyadvancesindevelopmentofmolecularmethods.Approximately,upto100trillion（1014）microorganismsperhumanbodycolonizetheintestinaltractmakinganadditionalacquiredorganthatprovidesmanyvitalfunctionstothehost.Ahealthygutmicrobiomecanbedefinedbythepresenceofthevariousclassesofmicrobesthatenhancemetabolism,resistancetoinfectionandinflammation,preventionagainstcancerandautoimmunityandthatpositivelyinfluencesocalledbrain-gutaxis.Dietrepresentsoneofthemostimportantdrivingforcesthatbesidesenvironmentalandgeneticfactors,candefineandinfluencethemicrobialcompositionofthegut.Agingprocessduetodifferentchangesingutphysiology（i.e.gastrichypochlorhydria,motilitydisorders,useofdrugs,degenerativechangesinentericnervoussystem）hasaprofoundeffectonthecomposition,diversityandfunctionalfeaturesofgutmicrobiota.Aperturbedagedgutmicrobiomehasbeenassociatedwiththeincreasingnumberofgastrointestinal（e.g. Clostridiumdifficile infection-CDI）andnon-gastrointestinaldiseases（metabolicsyndrome, diabetesmellitus,fattyliverdisease,atherosclerosisetc.）.Fecalmicrobiotatransplantation（FMT）isahighlyeffectivemethodinthetreatmentofrefractoryCDI.FMTisthetermusedwhenstoolistakenfromahealthyindividualandinstilledduringendoscopy（colonoscopyorenteroscopy）intoagutofthesickpersontocurecertaindisease.FMTrepresentsaneffectivetherapyinpatientwithrecurrentCDIandtheeffectivenessofFMTinthepreventionofCDIrecurrencehadreachedapprox.90%.ThereisalsoanincreasingevidencethatthemanipulationofgutmicrobiotabyFMTrepresentsapromisingtherapeuticmethodinpatientswithinflammatoryboweldiseaseandirritablebowelsyndrome.ThereisalsoanincreasedinterestintheroleofFMTforthetreatmentofmetabolicsyndromeandobesitywhichcollectivelypresentthegreatesthealthchallengeinthedevelopedworldnowadays.TargetingofgutmicrobiotabyFMTrepresentsanexcitingnewfrontierinthepreventionandmanagementofgastrointestinalandnon-gastrointestinaldiseasesthatawaitsfurtherstudiesinpreclinicalandclinicalsettings.

Keywords:

gutmicrobiota,fecalmicrobiotatransplantation,brain-gutaxis,inflammatoryboweldisease,Clostridiumdifficile,irritablebowelsyndrome,functionalgastrointestinaldisorders

IMPORTANCEOFGUTMICROBIOTA

AccordingtothefamouswordsofHippocrates,hisstatementthat“alldiseasebeginsinthegut”seemstobeofgreatimportancenowadays.Withthesewordsthefatherofthemodernmedicinesuggestedtheessentialroleplayedbygutanddietinmanyvitalhomeostaticfunctionsofthehumanbody

（1）.Intherecentdecadeourunderstandingoftheroleofthehumangutmicrobiomehasbeenrevolutionizedbyenormousadvancesindevelopmentofmolecularmethods（especiallyhighthroughputDNAsequencing）.Basedonthisknowledge,thegutmicrobiomeisconcernedasthemostdenselypopulatedanddiversemicrobialcommunities

（2）.Approximately,morethan500differentmicrobialspeciesconstitutingupto100trillion（1014）microorganismsperhumanthatcancolonizetheintestinaltractmakinganadditionalacquiredorganweighingca.1.5–2kg（Fig.1）.Thehumangutmicrobiotaisremarkablydiverse.Thecolonizationofgutbymicrobesbeginsafterdeliveryandthebabyearlylifeenvironmentplaysacrucialroleinthedevelopmentofhealthymicrobiome.Oncefullydeveloped,gutmicrobiomebecomestheessentialacquiredorganthatprovidesmanyvitalfunctionstothehost.Currentlyithasbeensuggestedthat4differentPhyla（Bacteroidetes,Actinobacteria,Firmicutes andProteobacteria）consistingofthousandsofmostlyanaerobicspeciesinhabitthehumangutwithasteep,stomachacid-drivenproximal-distalgradient（Fig.1）.Thenumberofgenesinmicrobiotaoutnumberhumangenesbyonehundredfold（3）.Thegeneralhumanpopulationcanbestratifiedonthesolebasisofthreedominantbacteria（i.e.theconceptofenterotypes）,orsubjectscategorizationaccordingtotheirmicrobiomegenerichness.Bothaspectshavebeenstrengthenedbyrecentstudiesinvestigatingtheimpactofnutrients（e.g.,dietaryfibers,fatfeeding）anddietaryhabits（i.e.,vegansversus omnivores）ofdifferentpopulations（4）.

Fig.1. Spatialandlongitudinalvariationsinmicrobialnumbersandcompositionacrossthelengthofthegastrointestinaltract.Thehumanmicrobiotacontainsasmanyas1014 bacterialcells,whosenumberthatis10timesgreaterthanthenumberofhumancellspresentinthebodies.Thenumberofbacterialcellspresentinthemammaliangutshowsacontinuumthatgoesfrom102 to103 bacteriapergramofcontentsinthestomachandduodenum,progressingto104 to107 bacteriapergraminthejejunumandileumandculminatingin109 to1012 cellspergraminthecolon.

Fromtheclinicalpointofviewthemostofthemicrobialspeciescanbedetectedbycultureindependentmethodssuchas16sribosomalRNAsequencingmethod.Importantly,eachindividualhasitsownuniquemicrobiota,sothegutmicrobiomeofeachindividualislikeafingerprint.Thecompositionofthegutmicrobiotaremainsrelativelystablefromlatechildhoodtooldage,whenchangesoccuragainduetoagingprocess（5,6）.Morerecently,groupsofbacterialfamilieshavebeenclassifiedintoenterotypesonthebasisoftheirfunctions.Thisclassificationisbasedonmetabolismofdietarycomponentsandabilitytotolerateandmetabolizedrugswhichshouldhelptofurtherunderstandingoftheroleofentericmicrobiotainhealthanddisease.Agingisassociatedwithchangesindiversityofnon-culturedspecies,withagreaterproportionof Bacteroides species,adistinctabundanceof Clostridiumclusters,anincreasedenterobacteriapopulation,andalowernumberofBifidobacteria （7,8）.

Thehumanbeingslifestyle,dietandmedicalinterventionsincludingpharmacologicaltherapyincludinguseofantibioticsandprotonpumpinhibitorshaveprofoundimpactonthecomposition（diversity）ofthegutmicrobiota（9）.Theimpairmentofhomeostasisbydysbiosismayincreasesusceptibilitytoinflammatoryboweldiseases（IBD）（9）.Theenvironment,genetics,andhostimmunityformahighlyinteractiveregulatorytriadthathavebeenshowntoregulatetolllikereceptor（TLR）function.ImbalancedrelationshipswithinthistriadmaypromoteaberrantTLRsignaling,criticallycontributingtoformationofinflammasomeresultinginacuteandchronicintestinalinflammatoryprocesses,suchasinIBDconsistingofCrohndiseaseandulcerativecolitis,andcolorectalcancer（10）.Inparticular,IBDarecharacterizedbyidiopathicintestinalinflammationthatcanarisefrompredisposinggenetic（genesencodingproteinsrelevanttobothinnateandadaptiveimmunity:

NOD2,STAT3,IL-23receptor,etc.）andenvironmentalfactors（specificTLRsligands,andantigensderivedfromcommensalbacteria）actingontheimmunoregulatorysystem.ItisgenerallyacceptedthatIBDmayberesultofanimbalanceofproinflammatory-andregulatory-T-cellsresponses（11,12）.

The“lasthumanorgan“playsacentralroleinthedevelopmentofimmunesystem,alterationsinintestinalfunctionsanddefenseagainstpathogensandmetabolism（13）（Fig.2）.Beyondthemicrobialrichness（diversity）,ahealthygutmicrobiomeischaracterizedbythepresenceofthemicrobesthatenhancemetabolism,resiliencetoinfectionandinflammation,resistancetocancerandautoimmunityandthepositiveinfluenceonbrain-gutaxis（14,15）.Importantly,thegutmicrobiotaaffectstheintestinalmucosa via interactionwithepithelialcells,entericnervoussystemleadingtochangesingutmotility,sensoryfunctionsandpainperception（microbiota-brain-gutaxis）（16）（Fig.2）.Microbiota-braininteractionsconstituteanexcitingareaofresearchwhichmaycontributetothenewinsightsintoindividualpredispositionsincognition,personality,mood,sleep,andeatingbehavior（17）.Moreover,thisinteractioncanhelpinunderstandingofawiderangeofneuropsychiatricdiseasesrangingfromaffectivedisorderstoautism,depressionandschizophrenia（Fig.2）.Gutmicrobesaffectthefunctionsofintestinalbarrier,especiallyitspermeabilityaswellascellproliferationandproductionofIgAanddefensins（18）.

Fig.2. Physiologicroleofgutmicrobiotainfluencedbydiet:

thebidirectionaleffectofgutmicrobiotaonthebrain-gutaxis,defenseagainstpathogens,effectonmetabolism via microbiota-liveraxisandalterationsofintestinalfunctionsincludinganimpactonintestinalpermeability,sensoryandmotilityfunctions.

Themechanismbywhichmicrobiotamaycontributetothefunctionofbrain-gutaxisremainsunknownbutmicrobesreleasemanybiologicallyactivesubstancessuchasentericshortchainfattyacids（SCFA）thatshowstrongimmunomodulatoryandsensoryeffects.AmongtheSCFAs,theaceticacid（AA）,butyricacid（BA）,andpropionicacid（PPA）arethemostaboundant（19）.TheSCFAsconsistofthemajorclassofsignalingmoleculesproducedfrombacterialfermentationo