Metabolic Interaction.docx

Metabolic Interaction.docx

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MetabolicInteraction

Microorganisms 2016, 4

（1）,15;doi:

10.3390/microorganisms4010015

Review

MetabolicInteractionof Helicobacterpylori InfectionandGutMicrobiota

Yao-JongYang 1,2 andBor-ShyangSheu 2,3,*

1

DepartmentsofPediatrics,NationalChengKungUniversityHospital,MedicalCollege,NationalChengKungUniversity,#138ShengLiRoad,Tainan70428,Taiwan

2

InstituteofClinicalMedicine,MedicalCollege,NationalChengKungUniversity,Tainan70428,Taiwan

3

DepartmentofInternalMedicine,NationalChengKungUniversityHospital,CollegeofMedicine,NationalChengKungUniversity,#138ShengLiRoad,Tainan70428,Taiwan

*

Correspondence:

Tel.:

+886-6-235-3535（ext.5368）

AcademicEditor:

CarlGordonJohnston

Received:

6August2015/Accepted:

5February2016/Published:

16February2016

Abstract

:

 Asabarrier,gutcommensalmicrobiotacanprotectagainstpotentialpathogenicmicrobesinthegastrointestinaltract.Crosstalkbetweengutmicrobesandimmunecellspromoteshumanintestinalhomeostasis.Dysbiosisofgutmicrobiotahasbeenimplicatedinthedevelopmentofmanyhumanmetabolicdisorderslikeobesity,hepaticsteatohepatitis,andinsulinresistanceintype2diabetes（T2D）.Certainmicrobes,suchasbutyrate-producingbacteria,arelowerinT2Dpatients.Thetransferofintestinalmicrobiotafromleandonorsincreasesinsulinsensitivityinindividualswithmetabolicsyndrome,buttheexactpathogenesisremainsunclear. H.pylori inthehumanstomachcausechronicgastritis,pepticulcers,andgastriccancers. H.pylori infectionalsoinducesinsulinresistanceandhasbeendefinedasapredisposingfactortoT2Ddevelopment.GastricandfecalmicrobiotamayhavebeenchangedinH.pylori-infectedpersonsandmicetopromotegastricinflammationandspecificdiseases.However,theinteractionof H.pylori andgutmicrobiotainregulatinghostmetabolismalsoremainsunknown.Furtherstudiesaimtoidentifythe H.pylori-microbiota-hostmetabolismaxisandtotestif H.pylori eradicationormodificationofgutmicrobiotacanimprovethecontrolofhumanmetabolicdisorders.

Keywords:

 H.pylori;microbiota;metabolicinteraction;insulinresistant;diabetes

1.Introduction

Thehumangut,includingthestomachandintestine,isinhabitedbyavastnumberofmicroorganismsthathostmicrobiota[1].Gutmicrobiotastartsafterbirththroughcontactwiththemother’svaginal,skin,andfecalmicroorganisms[2,3]anditsecologyisinfluencedbythedeliverytype,maternaldiet,gestationalage,andantibioticexposure[4,5,6].Usingnewmetagenomicstechniques,researchershavedemonstratedthatgutmicrobiotaregulatethehostimmunehomeostasisandarerelatedtomanyhumanmetabolicdisorders[7].Inananimalstudy,thegutmicrobiomeincreasedthecapacityofobesemicetoharvestenergyfromtheirdiet[8].Moreover,thetransmissionofmicrobiotafromobesemicetogerm-freemiceledtoincreasedtotalbodyfat[8].Thus,theintegrityandbalanceofgutmicrobiotaplayamajorroleinthemetabolicinteractionbetweenthehostandthemicrobialcommunity.

H.pylori canpersistentlycolonizethegastricepitheliumbyinteractingwithbacterialadhesionmoleculesandgastricreceptors[9,10].Themetabolicconsequencesof H.pylori infectionhavebeenreportedtochangethemicrobial-originfattyacidandlipidprofilesinhostblood[11].InananimalstudythatusedNMR-basedmetabolicanalysis, H.pyloriinfectionwasshowntodisturbthecarbohydrateandaminoacidmetabolismofthehost[12].Inaddition,metabolicchangesareassociatedwiththediversityofgutmicrobiota.Takentogether,thesestudiesindicatethatthehomeostasisandsystemicmetabolismbetweengutmicrobiotaandthehostmaybealteredby H.pylori.However,theexactmechanismremainsunclear.Thisreviewarticlefocusedonthemetabolicinteractionbetweengutmicrobiotaand H.pylori,aswellastherelatedconsequencesofsuchinteractiononthehost’shealth.

2.CrosstalkbetweenMicrobiotaandIntestines

Gutmicrobialcommunitiesareknowntobeinheritedfromthemother[2,3].Severalstudieshaveshownthathumanhealthissusceptibletointeractionsbetweengutmicrobiotadiversityorcompositionandintestinalcells[1,3].Mucosalandimmunehomeostasiscanbeestablishedbyabalancedinteractionbetweenmicrobialsignalsandhostimmunecells[2,13].Inmicestudies,Ivanov etal.demonstratedthatasinglesegmentedfilamentousbacteriumcaninduceeffectorTcelldifferentiationinthelaminapropria[14].OtherreportsshowthatcertaincommensalbacteriamodulateintestinalinflammatoryresponsesbyinducingregulatoryT（Treg）cellsandthedownstreamproductionoftransforminggrowthfactor-β（TGF-β）andinterleukin-10（IL-10）[15,16].Mortha etal. reportedthatintestinalmacrophagescouldsensemicrobialsignalstoinducetheRORγt+ innatelymphoidcells（ILCs）toproducecolony-stimulatingfactor2（CSF2）,therebypromotingintestinalhomeostasis[13].Allofthesesuggestthatautoimmunediseasescausedbytheinnate-adaptiveimmuneactivationarelikelytobeaffectedbythemicrobialenvironment[17].

3.MetabolicRolesofGutMicrobiota

Crosstalkandsignalingbetweenthehostandmicrobiotaoccuratboththecellularandmetaboliclevels.Ktsoyan etal.showedthatsignificantconcentrationsofmicrobiallongchainfattyacids（LCFAs）werepresentinhumanbloodandcorrespondedtospecificmicrobialcompounds[11].Furthermore,theprofileoftheseLCFAsisdistinguishedbetweenhealthyandpathologicstates.Commensalmicrobiotacanbreakdownindigestiblepolysaccharidesinthediet,therebyservingas70%oftheenergysource.Usinggenomicanalysis,studiesrevealedthathumancolonicmicrobeslikeBacteroides and Bifidobacterium possessedabundantpolysaccharidesandstarchbreakdowngenes[18,19,20].

Theotherimportantenergysourceofbacterialcolonizersoftheepithelium,especiallybutyratefermentingbacteria,isshortchainfattyacids（SCFA）[21].Microbe-producingbutyratemayserveasnutrientsforcellgrowthbutalsoasaugmentationofthebarrierfunctiontopreventcarcinogenesisofthecolonicepithelium[22,23].Usingthe16SrRNAsequencingmethod,Pryde etal. demonstratedthatthemostcommonbutyrate-producingbacteriawere Clostridium spp.,particularinclustersXIVaandIVinthehumanfeces[21].DecreasedproductionofSCFAscanalsobecorrelatedtocolonicinflammationandclinicaldiseases.Kelly etal. revealedthatmicrobe-derivedSCFAs,particularlybutyrate,stimulatedepithelialmetabolismanddecreasedintracellularO2,resultinginthestabilizationofthetranscriptionfactorhypoxia-induciblefactor-1（HIF-1）andepithelialbarrierfunction[22].Inaratmodelofcoloncancer,Mclntyre etal.reportedthatratsfedahighbutyrate-producingfiberdiet（wheatbran）hadsignificantlyfewertumorsandlesstumormassthanthosegivenlowbutyrate-productionfiberdiet[23].Theseresultsimplythatgutmicrobiotainfluenceslocalandsystemicmetabolites,andcloselydeterminatesimmunityandotherprotectivemechanismsinhumans（Figure1）.

Figure1. Themetabolicandimmunologicrolesofgutmicrobiotaand H.pyloriinfectiononhumanmetabolicdisorders.IPS,indigestiblepolysaccharides;SCFA,short-chainfattyacid;LDL,low-densitylipoprotein;HDL,high-densitylipoprotein.

4.GutDysbiosisandHumanMetabolicDisorders

Analteredbalancebetweengutmicrobiotaandthehostcontributestoaspectrumofimmune,inflammatory,andmetabolicdisorders.Ametagenome-wideassociationstudyusingdeepshotgunsequencingofthegutmicrobialDNAdemonstratedthattype2diabetes（T2D）inChinesepatientshadmoderatedegreesofgutmicrobiotadysbiosis,particularlydecreasedbutyrate-producingbacteria[24].Basedonthecloseassociationbetweenmicrobiotaanddiabetes,Vrieze etal.transferredintestinalmicrobiotafromleandonorstorecipientmaleswithmetabolicsyndrome.Sixweekslater,theinsulinsensitivityoftherecipientsincreasedalongwithlevelsofbutyrate-producingintestinalmicrobiota[25].

Wen etal. usedatype1diabetes（T1D）non-obesediabetic（NOD）micemodeltosuggestthatsignalingthroughtheMyD88adaptorwascriticalforT1Ddevelopment.Thiseffectdependedoncommensalmicrobesbecausegerm-freeMyD88-negativeNODmicedevelopedrobustdiabetes[26].Moreover,thetransplantationofmicrobiotafromspecificpathogen-freeMyD88-negativeNODdonorstogerm-freeNODrecipientsattenuatedtheT1D.Takentogether,alterationsinintestinalmicrobiotaareassociatedwithinsulinresistanceanddiabetes.Therestorationof“healthymicrobiota”（microbiotainhealthycondition）maybeapromisingtherapeuticstrategyforcontrollingmetabolicsyndrome.

5. H.pylori InfectionandMetabolicDiseases

IdentifiedbyMarshallandWarrenin1984, H.pylori cancausechronicgastritisandpepticulcerdisease[27,28].TheWorldHealthOrganization（WHO）hascategorized H.pylori asagroupIcarcinogen,emphasizingitsassociationwithgastriccancer[29]. H.pylori havealsobeenassociatedwithseveralextra-gastricdiseaseslikeirondeficiencyanemia,idiopathicthrombocytopenicpurpura,andchildhoodgrowth[30,31,32].Althoughtheexactrelationshipbetween H.pylori anddiseasesisstillbeingdebated,bacterialeradicationresultsinlong-termbenefits[33,34].Recently,studiesdemonstratedthat H.pylori infectionwasalsorelatedtolipidandglucosemetabolism[35,36].Alarge-scalecross-sectionalstudyrevealedthatmaleswhowere H.pylori-seropositiveexhibitedsignificantlyhigherlow-densitylipoprotein（LDL）cholesterollevelsandsignificantlylowerhigh-densitylipoprotein（HDL）cholesterollevelsthan H.pylori-seronegativesubjects[37].Jia etal. suggestedtha