Gut Microbiota The Neglected Endocrine Organ.docx

Gut Microbiota The Neglected Endocrine Organ.docx

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GutMicrobiotaTheNeglectedEndocrineOrgan

Minireview:

GutMicrobiota:

TheNeglectedEndocrineOrgan

GerardClarke, RomanM.Stilling, PaulJ.Kennedy, CatherineStanton, JohnF.Cryan,and TimothyG.Dinan

Addressallcorrespondenceandrequestsforreprintsto:

ProfTedDinan,

DepartmentofPsychiatry,CorkUniversityHospital,Wilton,Cork,Ireland.

E-mail:

.

Received:

April06,2014

Accepted:

May29,2014

PublishedOnline:

June03,2014

窗体底端

Theconceptthatthegutmicrobiotaservesasavirtualendocrineorganarisesfromanumberofimportantobservations.Evidenceforadirectrolearisesfromitsmetaboliccapacitytoproduceandregulatemultiplecompoundsthatreachthecirculationandacttoinfluencethefunctionofdistalorgansandsystems.Forexample,metabolismofcarbohydratesresultsintheproductionofshort-chainfattyacids,suchasbutyrateandpropionate,whichprovideanimportantsourceofnutrientsaswellasregulatorycontrolofthehostdigestivesystem.Thisinfluenceoverhostmetabolismisalsoseenintheabilityoftheprebioticinulintoinfluenceproductionofrelevanthormonessuchasglucagon-likepeptide-1,peptideYY,ghrelin,andleptin.Moreover,theprobiotic Lactobacillusrhamnosus PL60,whichproducesconjugatedlinoleicacid,hasbeenshowntoreducebody-weightgainandwhiteadiposetissuewithouteffectsonfoodintake.Manipulatingthemicrobialcompositionofthegastrointestinaltractmodulatesplasmaconcentrationsoftryptophan,anessentialaminoacidandprecursortoserotonin,akeyneurotransmitterwithinboththeentericandcentralnervoussystems.Indirectlyandthroughasyetunknownmechanisms,thegutmicrobiotaexertscontroloverthehypothalamic-pituitary-adrenalaxis.Thisisclearfromstudiesonanimalsraisedinagerm-freeenvironment,whoshowexaggeratedresponsestopsychologicalstress,whichnormalizesaftermonocolonizationbycertainbacterialspeciesincluding Bifidobacteriuminfantis.Itistemptingtospeculatethattherapeutictargetingofthegutmicrobiotamaybeusefulintreatingstress-relateddisordersandmetabolicdiseases.

Microbiomesciencehasprosperedinrecentyears,andtheexcitingdiscoveriesarisingfromthissurgeininteresthaveforcedareevaluationofourperceptionofthetrillionsofmicroorganismswhichresideinthehumangastrointestinal（GI）tractinparticular.Thegutmicrobiotaperformsanumberofessentialprotective,structural,andmetabolicfunctionsforhosthealth,includingfoodprocessing,digestionofcomplexhost-indigestiblepolysaccharides,pathogendisplacement,andsynthesisofvitamins（1–3）.Aswellasadirectactiononthegutmucosaandtheentericnervoussystem（ENS）,themetabolicoutputofthegutmicrobiotagivesitareachwellbeyondthelocalGIcompartment.Thus,consideringtheabilitytoinfluencethefunctionofdistalorgansandsystems,inmanyrespects,thegutmicrobiotaresemblesanendocrineorgan（4, 5）.

Throughthislens,themicrobiotaproducesnumerouschemicalsofahormonalnaturethatarereleasedintothebloodstreamandactatdistalsites（see Table1）.ThetargetsforthesesubstancesarenotjustthelocalENSbutmanyotherorgansincludingthebrain.Itreleasesitshormonalproductsintointerstitialtissuetobepickedupbybloodandlymphcapillaries,andthesesecretionsareusuallyeffectiveinlowconcentrationsontargetorgansortissuesremotefromtheentericmicrobiota.Aswellasprovidinganimportantdirectsourceofhumoralagents,bothactivecompoundsandprecursors,whichactatdistalsites（see Figure1）,themicrobiotaalsoplaysanindirectroleinregulatingcomplexendocrinenetworks.Moreover,specificmembersoftheoverallmicrobialcommunitycanrespondtohormonessecretedbythehost（6, 7）.Takentogetherwiththespecializedfunctionsperformedbythegutmicrobiotaanddespitetheobviousphysicaldissimilarity,itsabilitytofunctionasacollectivetoinfluenceotherorganswithinthehostand,inturn,toberesponsivetothesecretionsofotherhostorganssatisfiesthemostimportantconditionsofanyconceptualdefinitionofanorgan（8）.Itisthesequalitiesthathaveseentheterm“virtualorgan”assignedtothegutmicrobiota（5）.

Table1. CandidateHormonesoftheGutMicrobiota

Table1.CandidateHormonesoftheGutMicrobiota

Class

Examples

Functions

Comment

Reference

SCFAs

Acetate

Energysource

Directlyproducedbybacteria;epigeneticandreceptor-mediatedeffects;CNSeffectslinkedtoautism-likebehaviors

63, 84, 94

Butyrate

Hostmetabolism

Propionate

Signalingmolecules

Neurotransmitters

Serotonin

Dopamine

Noradrenaline

GABA

Mood,emotion,cognition,reward（CNS）

Motility/secretion（ENS）

Canbedirectlyproducedbybacteria（see Table2）orindirectlyregulated

61, 188,200

Precursorstoneuroactivecompounds

Tryptophan

Precursorto:

5-HT

Kynurenineisitselfametaboliteoftryptophan,productionsubjecttoregulationbymicrobiota

135, 137,138, 194

Kynurenine

l-Dopa

Kynurenicacid,quinolinicacid,Dopamine

Bileacids

Secondarybileacids

Antimicrobial

Someeffectsmediatedbybileacidreceptors

5, 101

Hostmetabolism

Cholinemetabolites

Trimethylamine

Lipidmetabolism（choline）

Metabolizedinthelivertotrimethylamine-N-oxide,linkedtocardiovasculardisease

37, 102,103

HPAhormones

Cortisol

Stressresponse

Indirectregulation;HPAendocrineabnormalitiesprominentinstress-relatedpsychiatricdisorders

177

Hostmetabolism

Anti-inflammatory

Woundhealing

GIhormones

Ghrelin

Hostmetabolism

Indirectregulation;possiblymediatedbySCFAsviaenteroendocrinecells

70, 128

Leptin

Appetiteregulation

Glucagon-likepeptide-1

PYY

GImotility/secretion

Figure1. Hormone-likemetabolitesproducedorregulatedbythegutmicrobiota.MicrobialmetabolitessuchasSCFAswithsignalingfunctionsaresecretedintothegutlumen,transportedacrosstheepithelialbarrier,andtransportedtotheeffectororgans,includingthebrain,viathebloodstream.Thegutmicrobiotaisalsocapableofproducingorreleasingneurotransmitterssuchasserotoninorregulatingtheavailabilityofprecursorssuchastryptophan.Themicrobiotaalsoregulatesthebioavailabilityofcholineanditsmetabolites.

Inthisreview,weconsiderthemainfeaturesofthegutmicrobiotathatenablethisendocrinecapacityandrenderitsusceptibletomodification,focusingondevelopment,structure,andfunctionaswellasthekeyhormonalmediatorsproduced.Usingspecificexamples,weexploretheregulationofglucosemetabolismandobesitytogetherwiththeimpactonthestresssystem,especiallyonthehypothalamic-pituitary-adrenal（HPA）axis,andtheinfluenceonbrainandbehavior.Havingexaminedthekeyendocrinefunctionsthiscollectionofmicroorganismsregulatesinthehost,wealsoconsidertheimplicationsforhealthanddisease.

TheDiverseGutMicrobiome:

AComplexEndocrineOrgan

窗体顶端

窗体底端

Unlikeotherendocrinesystemsororgans（see Figure2）,whichsecreteasingleoratmostasmallnumberofhumoralagents,thegutmicrobiotahasthepotentialtoproducehundredsofproducts.Fromamorphologicalandbiochemicalperspective,itisfarlargerandmorebiochemicallyheterogeneousthananyotherendocrineorganinman（9）.Infact,thebiochemicalcomplexityofthegutmicrobiotaevenexceedsthatofthebrain,andmanyofthehormonesproducedbythemicrobiotaarealsoneurotransmitterswithinthecentralnervoussystem（CNS）.Forexample,γ-aminobutyricacid（GABA）,themostimportantinhibitorytransmitterinthebrainisproducedbyseverallactobacilli（10）,whereasmonoaminessuchasnoradrenaline,dopamine,andserotoninarealsoproducedbycertainstrainsofbacteria（11,12）（See Table2）.

Table2. ExamplesofNeurotransmitter-Producingor-ReleasingBacterialStrains

Table2.ExamplesofNeurotransmitter-Producingor-ReleasingBacterialStrains

Neurotransmitter

BacterialStrain

Reference

Serotonin

Lactococcuslactis subsp.cremoris （MG1363）

201

L.lactissubsp. lactis（IL1403）

201

Lactobacillusplantarum（FI8595）

201

Streptococcusthermophilus（NCFB2392）

201

Escherichiacoli K-12

156

Morganellamorganii（NCIMB,10466）

202

Klebsiellapneumoniae（NCIMB,673）

202

Hafniaalvei（NCIMB,11999）

202

Dopamine

Bacilluscereus

33

B.mycoides

33

B.subtilis

33

Proteusvulgaris

33

Serratiamarcescens

33

S.aureus

33

E.coli

33

E.coliK-12

156

M.morganii（NCIMB,10466）

202

K.pneumoniae（NCIMB,673）

202

H.alvei（NCIMB,11999）

202

Noradrenaline

B.mycoides

33

B.subtilis,

33

P.vulgaris

33

S.marcescens

33

E.coliK-12

156

GABA

L.brevisDPC6108

10

B.adolescentisDPC6044

10

B.dentiumDPC6333

10

B.dentiumNFBC2243

10

B.infantisUCC35624

10

L.rhamnosusYS9

71

Acetylcholine

L.plantarum

122

Histamine

L.lactissubsp.cremoris （MG1363）

201

L.lactissubsp.lactis（IL1403）

201

L.plantarum（FI8595）

201

S.thermophiles（NCFB2392）

201

M.morganii（NCIMB,10466）

202

K.pneumoniae（NCIMB,673）

202

H.alvei（NCIMB,11999）

202

Figure2. Thegutmicrobiotaasanendocrineorgan.Theendocrinesystemisprimarilycomposedofglandsthateachproduceasingleoratmostasmallnumberofhumoralagents.However,themicrobiotaproducesnumerouschemicalsofahormonalnaturethatarereleasedintothebloodstreamandactatdistalsites.Thisbiochemicalcapacityarisesfromthevastanddiversearrayofmicrobialcellsthatconstitutethegutmicrobiota.

Thisbiochemicalcapacityarisesfromthevastanddiversearrayofmicrobialcells,withanapproximateweightof1to2kginanaverageadult（13）.Thenumberofcellsisfargreaterthanthenumb