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Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878Colonicbacterialmetabolitesandhumanhealth1WendyR.
Russell1#,LesleyHoyles2#,HarryJ.
Flint1*andMarc-‐EmmanuelDumas2*21.
RowettInstituteofNutritionandHealth,UniversityofAberdeen,GreenburnRoad,Bucksburn,3AberdeenAB219SB,UK42.
ComputationalandSystemsMedicine,DepartmentofSurgeryandCancer,FacultyofMedicine,5ImperialCollegeLondon,ExhibitionRoad,LondonSW72AZ,UK67#WRRandLHmadeequalcontributionstothisreview.
8*jointcorrespondingauthors(emailaddresses):9Marc-‐EmmanuelDumas(m.
dumas@imperial.
ac.
uk)10HarryJFlint(h.
flint@abdn.
ac.
uk)1112Abstract(100-‐120words)13Theinfluenceofthemicrobial–mammalianmetabolicaxisisbecomingincreasinglyimportantfor14humanhealth.
Bacterialfermentationofcarbohydratesandproteinsproducesshort-‐chainfatty15acids(SCFA)andarangeofothermetabolitesincludingthosefromaromaticaminoacid(AAA)16fermentation.
SCFAinfluencehosthealthasenergysourcesandviamultiplesignallingmechanisms.
17Bacterialtransformationoffibre-‐relatedphytochemicalsisassociatedwithareducedincidenceof18severalchronicdiseases.
The'gut–liveraxis'isanemergingareaofstudy.
Microbialdeconjugationof19xenobioticsandreleaseofaromaticmoietiesintothecoloncanhaveawiderangeofphysiological20consequences.
Inaddition,theroleofthegutmicrobiotaincholinedeficiencyinnon-‐alcoholicfatty21liverdiseaseandinsulinresistanceisreceivingincreasedattention.
222324Highlights:25-‐Diet-‐drivenchangesinmicrobially-‐producedSCFAcaninfluencehealthviasignalling26-‐Gutmicrobiotamediatesthereleaseandtransformationofmanybioactivephenolics27-‐Gutmicrobiotadegradesdietarycholinetomethylamines28-‐Interactionsbetweenthemicrobiota,inflammasomesandhostinfluenceliverdisease293031Abbreviations:SCFA,short-‐chainfattyacids;CHO,carbohydrate;FFAR,freefattyacidreceptor;WL,32weightloss;NSP,non-‐starchpolysaccharide'fibre';AAA,aromaticaminoacids;NAFLD,non-‐alcoholic33fattyliverdisease;NASH,non-‐alcoholicsteatohepatitis;HMS,hepaticmacrovesicularsteatosis;PC,34Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878phosphatidylcholine;PEMT,phosphatidylethanolamine-‐N-‐methyltransferase;SNP,singlenucleotide35polymorphism;TMA,trimethylamine;TMAO,trimethylamine-‐N-‐oxide.
36Introduction37Thehumanlargeintestineiscolonisedbydensemicrobialcommunitiesthatutilisebothdiet-‐and38host-‐derivedenergysourcesforgrowth,predominantlythroughfermentativemetabolism.
This39highlydiversecommunityhasthecapacitytoperformanextraordinaryrangeofbiochemical40transformationsthatgowellbeyondthoseencodedbythehostgenome,andtheseactivitiesexert41animportantinfluenceuponmanyaspectsofhumanhealth.
Metabolitesformedbythegut42microbiotaarelargelydeterminedbythecompositionofthedietandthepatternoffoodintake,and43itisnowclearthatthespeciescompositionofthecolonicmicrobiotaisitselfalteredbythediet44[1*,2,3**].
Thisreviewwillconsiderselectedexampleswhererecentprogresshasbeenmadein45understandingthelinksbetweendiet,gutmicrobialactivityandmetabolitesrelevanttohealth.
4647Bacterialmetabolitesderivedfromthefermentationofplant-‐derived48carbohydratesandtheirimpactonthehost4950Manycarbohydrates(CHOs)presentinplant-‐derivedfoodsaredigestedslowly,ifatall,inthesmall51intestine,makingthemavailableformicrobialfermentationinthelargeintestine.
Intakeofstarch52thatisresistanttodigestioninthesmallintestine(resistantstarch)canhavebenefitsformetabolic53health[4]andresultsinchangesinthegutmicrobiota[1*].
Recentworkalsoshowsabeneficial54influenceofwholegrainintakeuponinflammation,againwithconcomitantchangesinthegut55microbiota[5*].
Diet-‐inducedchangesinthemetabolicactivityofthegutmicrobiotaarethought56likelytomediatetheseeffects.
5758Hexoseandpentosesugarsarefermentedbyisolatedhumancolonicbacteriaviapathwaysleading59totheformationofacetate,succinate,propionate,butyrate,formate,lactate,ethanol,hydrogen60andCO2,dependingonthestrainandspecies.
ButyrateformationoccursincertainFirmicutes61bacteria,eitherviabutyratekinase(inmanyClostridiumandCoprococcusspecies)orviabutyryl62CoA:acetateCoAtransferase[6].
Thelatterpathwayisfoundinthenumericallypredominant63butyrate-‐producingspeciesofRoseburia,Eubacteriumrectale,E.
halliiandFaecalibacterium64prausnitzii,andinvolvesthenetuptakeofexternalacetate[7].
Acetateisproducedbymost65anaerobes,includingacetogensthatareabletoperformreductiveacetogenesisfromformateor66hydrogenplusCO2.
Producersofsuccinateandpropionatelargelybelongtothephylum67Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878Bacteroidetes,butalsoincludesomeFirmicutes.
Lactatecanbeformedbymanygroups,butis68generallyconvertedintoacetate,propionateorbutyratebyasubsetoflactate-‐utilizingspecies[8].
69FormationofthegaseshydrogenandCO2varieswidelybetweenspeciesinpureculture;inthe70mixedcommunitytheseproductsarepartiallyconvertedtoacetate,methaneorhydrogensulfide71[9].
Thenetoutcomeofallofthesecomplexcross-‐feedinginteractionsforatypicalhealthy72microbiotaisthat,infaecalsamples,acetateisthedominantshort-‐chainfattyacid(SCFA)detected73(typically4070mM)followedbypropionateandbutyrate(each1030mM)[10].
While74alternativeproductssuchasethanol,succinateandlactatearenormallyfoundatlower75concentrations,theycanaccumulateinsomecircumstancesandalinkhasbeenproposedbetween76endogenousalcoholformationandnon-‐alcoholicsteatohepatitis[11].
7778Attheseconcentrations,SCFAhaveamajorimpactonthelargeintestinalenvironmentandon79absorptionfromthelumen.
Whilebutyrateislargelyutilisedbythegutepithelium,andpropionate80islargelymetabolisedintheliver,acetateistheSCFAthatreachesthehighestconcentrationsin81plasma[10].
Thereisincreasingevidencethatacetateplaysanimportantroleincontrolling82inflammationandincombatingpathogeninvasion[12,13].
Acetateandlactatewerealsofound83recentlytoinfluencecyclingeneexpressionandepithelialcellproliferationinapH-‐dependent84mannerinvitro[14].
Theimportanceofbutyrateasanenergysourceforepithelialcellshaslong85beenrecognised,butitsroleinregulatinginflammation,cellulardifferentiationandapoptosis,and86inhelpingtopreventcolorectalcancer,isstillemerging[15].
Interestingly,butyratewasrecently87foundtobethemostpotentSCFAinactivatingtheAP-‐1signallingpathwayinepithelialcelllines88[16].
InteractionshavebeenrecognisedbetweenSCFAandthehostcellreceptorsFFAR2andFFAR389thatmightinfluencesatiety,protectagainstdiet-‐inducedobesityandimproveinsulinsensitivity,90withpropionateconsideredtohaveapotentiallyimportantrole17,18].
Inviewofthisitis91importanttounderstandhowdietandmicrobiotacompositioncaninfluencerelative,aswellas92total,SCFAproduction.
Studiesinobesesubjectsonweightlossdietsdemonstratethatdietary93intakeofCHOhasamajorimpactonfaecalSCFAconcentrations[19,20**]presumablyreflecting94decreasedfermentationinthecolon(Fig.
1).
Moresurprising,however,isthatbutyratepercent95respondeddisproportionately,aneffectthatcorrelateswithamarkeddecreaseintheRoseburia-‐E.
96rectalegroupofbutyrate-‐producingbacteria[19].
Thismaybeexplainedbythegreaterdependence97ofthisgroup,comparedwithothermembersofthemicrobiota,onintakeofresistantdietaryCHOs,98andprovidesevidencethatSCFArelativeproductionratesareresponsivetodietcomposition.
An99inverserelationshiphasbeennotedbetweenfaecalpHandbutyrateconcentrationinvivo[21];this100Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
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com/science/article/pii/S1369527413000878islikelytoreflectthegreatcompetitiveabilityofsomebutyrate-‐producersatthereducedpHarising101fromactivefermentationintheproximalcolon[22].
102Decreasednumbersofbutyrate-‐producingbacteria,especiallyFaecalibacteriumprausnitzii,have103beennotedinpatientssufferingfromCrohn'sdisease.
Thisspeciesexertsanti-‐inflammatoryeffects104thatappeartoinvolvesolublefactorsinadditiontobutyrate[23].
Interestingly,F.
prausnitziiwas105recentlyshowntodiminishtheimpactoftheacetate-‐producingspeciesBthetaiotaomicronon106mucusproductionandgobletcelldevelopmentinagnotobioticrodentmodel[24].
107108Formationandmetabolismofaromaticcompounds109110Fibre-‐relatedphytochemicals111Itissuggestedthattheinverserelationshipbetweentheintakeoffibre-‐richdietsandtheincidence112ofseveralchronicdiseasesismediatedinpartbythegutmicrobiota.
Microbialreleaseof113phytochemicalmetabolitesmaybeacontributingfactorandmostwidelystudiedfordisease114preventionarethearomaticmetabolitesproducedbythephenylpropanoidpathway[25,26].
115Increasingthefibrecontentofthedietfrom8.
8to14gday-‐1inahumanvolunteerstudyresultedin116significantlyincreasingcertainphenolicacidsandtheirderivativesinthegut,specificallyferulicacid,1174-‐hydroxy-‐3-‐methoxyphenylpropionicacidand3-‐hydroxyphenylpropionicacid[20].
Ferulicacid,118whichisfoundextensivelyboundtoplantpolysaccharides,canbereleasedandmetabolisedbythe119gutmicrobiota[20,27](Fig.
2).
Indeed,themajorestersofotherphenolicacidssuchascaffeicacid120(chlorogenicandcaftaricacid)arealsorapidlyde-‐esterifiedbyhumanfaecalmicrobiota[28].
It121appearsthatthegutmicrobiotacaneffectivelyde-‐esterifycompounds,whethertheconjugateis122quinicacid,tartaricacidorasugarmoietytoreleasetheaglyconeforfurthermetabolism.
Gut123bacteriacanalsoeffectivelyhydrogenatetheα,β-‐unsaturatedbondpresentonthesidechainof124phenolicacids[27]andtheextenttowhichthisoccursappearstobedependentonadditional125dietaryfactors,withhigh-‐proteindietsdecreasingtheefficiencyofthistransformation[20].
Site-‐126specificdehydroxylationanddemethylationofthephenolichydroxylpresentinphenolicacidshas127alsobeenobserved[20,27].
Theresultantmicrobialproductsofferulicacidmetabolismhad128differingeffectsonprostanoidproductioninvitrosuggestingthatthemicrobialtransformationof129dietarycompoundswillhaveimportantconsequencesforinflammation[27,29].
130131Aromaticaminoacidmetabolites132Proteinmetabolismisamajoralternativemechanismforproductionofaromaticmetabolites[30]as133observedinrecenthumandietaryinterventionsinvolvingcarefullycontrolledintakesofCHOand134Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
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com/science/article/pii/S1369527413000878protein[20].
Untilrecently,themajormetabolitesofaromaticaminoacid(AAA)fermentationwere135consideredtobephenol,p-‐cresolandindole,withp-‐cresolsuggestedtobeaproductofphenol136catabolism.
Ithasnowbeendemonstratedthatamuchwidermetabolicpathwayofmetabolism137existsforallthreeAAAs[31].
Inparticular,phenylaceticacid,4-‐hydroxyphenylaceticacidandindole-‐1383-‐aceticacidwerefoundtobemajor(de-‐aminatedandchain-‐shortened)productsofphenylalanine,139tyrosineandtryptophan,respectively[31].
Bacteriacapableofproducingtheseproductscould140effectivelymetaboliseallthreeAAAsubstrates.
TheseincludedBacteroidesthetaiotaomicron,B.
141eggerthii,B.
ovatus,B.
fragilis,ParabacteroidesdistasonisandtheGram-‐positivebacteria142ClostridiumbartlettiiandEubacteriumhallii.
Bacterialspeciesthatdidnotsubstantiallyproduce143thesede-‐aminatedandchain-‐shortenedproductswereidentified.
TheseincludedMegamonas144hypermegale,Roseburiaintestinalis,Ruminococcusobeum,Eubacteriumrectaleand145Faecalibacteriumprausnitzii,butstrainsofthesespeciesoftenproducedhigheramountsofbenzoic146acid,4-‐hydroxybenzoicacidandindole-‐3-‐carboxylicacidandoxidationproductsincluding147phenylpyruvicacid,phenyllacticacid,4-‐hydroxyphenyllacticacid,indole-‐3-‐pyruvicacidandindole-‐3-‐148lacticacid.
GiventhatcertainspeciesofgutbacteriacanmetaboliseallthreeAAAsbyspecific149mechanisms,itislikelythatotherstructuralformsofaminoacidscanundergothesemolecular150transformations.
Thiswillgiverisetoarangeofnovelmetabolites,whichrequiretobeinvestigated151toassesstheirpotentialtoaffecthumanhealth.
152153Itisclearthatmacronutrientbalanceinfluencesnotonlythecompositionofthegutmicrobiotabut154alsotheavailabilityofaromaticmetabolites.
CertainmetabolitessuchasSCFAandphenyl155metabolitescanbeproducedbybacterialmetabolismofbothCHOandproteininthelargeintestine,156whereascertainbranched-‐chainfattyacidsandnitrogen-‐containingmetabolitesareconsideredto157bederivedfromproteinmetabolismalone.
Thereisapositiveassociationbetweenanimalprotein158consumption(specificallyredandprocessedmeat)andcolorectalcancer[32].
Evidenceisalso159beginningtoemergethattheconcentrationsofaromaticgutmetabolitesinthesystemiccirculation160playsaroleinvascularhealthand[33].
161162Enterohepaticcirculationandβ-‐glucuronidase163Manydiet-‐derivedaromaticcompounds,includingdrugs,aretreatedasxenobioticsandare164conjugatedintheliverfollowedbyreleaseintotheintestineviathebile.
Oneofthemain165mechanismsforconjugationisglucuronidation,butithasbeenknownforsometimethatbacterial166β-‐glucuronidasesinthelargeintestinetendtocleavetheseconjugates,thusreleasingthearomatic167moietyandmakingitavailableagainforre-‐absorption.
ThegusgenefromEscherichiacoliwas168originallyidentifiedasencodingthisactivity.
Arecentsurveyuseddegenerategusprimerstodetect169Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878relatedgenesamongthefaecalmicrobiotafrom10healthyvolunteers;thisshowedahighlyuneven170distributionwith60ofsequencesaccountedforbyonly4operationaltaxonomicunits,whilein171total96ofsequencescamefromFirmicutesand3fromE.
coli[34].
Itseemslikelythatthis172activityisassociatedwithenzymesinvolvedindegradingplantpolysaccharides.
Thecontributionof173asecondputativeβ-‐glucuronidasegeneidentifiedfrommetagenomiclibraries[35]hasstilltobe174fullyestablished[34].
175176The'gut–liver'axis,dietaryamines,theintestinalmicrobiotaandthe177methylamines'pathway178The'gut–liver'axis179Giventheexposureofthelivertointestinal-‐derivedcatabolitesandthemicrobiotatobiliary/waste180products,the'gut–liveraxis'isreceivinggreatattentionwithrespecttohosthealthanditspotential181toaffectsystemichostprocesses[36].
Arecentstudyhasnicelydemonstratedthedirect182involvementofthegutmicrobiotainthedevelopmentofobesity-‐independentnon-‐alcoholicfatty183liverdisease(NAFLD),andthemicrobiota'sinfluenceonwholebodyglucosehomeostasisandliver184lipidmetabolism[37**].
Germ-‐freemiceinoculatedwithintestinalmicrobiotafromamousethat185developedhyperglycaemiaandhadahighplasmaconcentrationofpro-‐inflammatorycytokinesafter186beingfedahigh-‐fatdietdevelopedhepaticmacrovesicularsteatosis(HMS)afterhigh-‐fatfeeding,187withincreasedexpressionofhepaticgenesinvolvedinde-‐novolipogenesisandlipiduptake(SREBP,188ChREBP,acetyl-‐CoAcarboxylase1andCD36)observed.
Incomparison,germ-‐freemiceinoculated189withfaecesfromamousethatwasnormoglycaemicandhadalowerlevelofsystemicinflammation190afterbeingfedahigh-‐fatdietdevelopedlow-‐levelsteatosisonthesamediet[37**].
Differences191wereobservedinthefaecalmicrobiotaofthetwogroupsofmice:LachnospiraceaeandBarnesiella192(Porphyromonadaceae)sequencesweresignificantlyoverrepresentedintheHMSmice,whilethe193low-‐levelsteatosismicehadanincreasednumberofsequencesrelatedtoBacteroidesvulgatus.
194Concentrationsofisobutyrateandisovalerate,branched-‐chainaminoacidsresultingfromthe195bacterialfermentationofvalineandleucine,respectively,weresignificantlyhigherinthecaecumof196theHMSmice.
Inaddition,theseanimalshadsignificantlyhigherfastingglycaemia,fasting197insulinaemia,homeostasismodelassessment—insulinresistanceindexandleptinaemia,andhigher198plasmaconcentrationsofaspartateaminotransferasethantheanimalsthatdevelopedlow-‐level199steatosis.
Takentogether,theseresultsdemonstratethatthegutmicrobiotaconstitutesan200environmentalfactordrivingtheprogressionofNAFLD[37**].
201202Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
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com/science/article/pii/S1369527413000878AlthoughbothgroupsofanimalswerefedthesamedietintheLeRoystudy[37**],itiswellknown203thattheintestinalmicrobiotacaninfluencethe'gut–liveraxis'andthedevelopmentofNAFLD(and204otherdiseases)bymicrobialutilizationofdietarymethylamines.
205206CholinedeficiencyandNAFLD207CholineisanessentialnutrientofthevitaminBcomplexwithnumerousrolesinthebody:actingas208amethyldonorinbiochemicalreactions,asaprecursorforthebiosynthesisofphospholipids209[phosphatidylcholine(PC),lysophosphatidylcholine,cholineplasmalogenandsphingomyelin],of210acetylcholineandoflipoproteins,andinhomocysteinereduction[38,39,40].
Themainfateof211cholineinthebodyisitsincorporationintoPCviatheKennedypathway[41].
212213Exogenouscholineisderivedfromeitherdietarycholineor,morecommonly,PCfromplantand214animalmaterial[38,39,42].
Foodshighincholineincludemeatanddairyproducts,fish,soybeans,215nutsandwholegrains,withPCaddedtoanumberoffoodsasanemulsifier[43].
Endogenous216sourcesofcholine,intheformofPC,includebiliarylipids,exfoliatedepithelialcellsandintestinal217bacteria[44,45].
Denovosynthesisofcholineoccursviaareactioncatalysedby218phosphatidylethanolamine-‐N-‐methyltransferase(PEMT)[41].
219220Theintestinalmicrobiotaplaysaroleinthecatabolismofcholineinhumansandrodents221[46,47,48,49,],withtrimethylamine(TMA),acetateandethanoltheproductsoffermentation[50].
222Cholinedegradationbythehumanintestinalmicrobiotaistemporallystable[47].
TMAproducedby223intestinalbacteriafromcholineisabsorbedbycoloniccellsandconvertedtotrimethylamine-‐N-‐224oxide(TMAO)byflavinmono-‐oxygenaseenzymes[51],demethylatedintodimethylamineand225(mono)methylamineintheliver,orexcretedintheurine.
Themethylaminepathwayisatypical226exampleofmicrobial–mammalianco-‐metabolism[52,53](Figure3).
227228KnowledgepertainingtothosemembersoftheintestinalmicrobiotaresponsibleforproducingTMA229fromcholineissparse.
Insilicopredictionshavesuggestedthatseveralmembersofthehuman230intestinalmicrobiota(includingClostridium,Anaerococcus,Collinsella,Desulfitobacterium,Klebsiella,231Escherichia,Providencia,YokenellaandProteusspp.
)havetheabilitytodegradecholinetoTMAvia232cholineTMA-‐lyase[54**].
Inadditiontotheaforementionedspecies,manymoremembersofthe233humanintestinalmicrobiotamaybeabletodegradecholinetoTMAusingthesamemechanism234and/orviaanalternativepathway(s).
235236Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
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com/science/article/pii/S1369527413000878237Choline-‐deficientdietsinhumans(≤50mgday-‐1)androdentsareknowntoleadtoNAFLD,non-‐238alcoholicsteatohepatitis(NASH)andhepaticdamage[39,55].
Tocombattheseandother239complications(e.
g.
infertility,renalhaemorrhageandhypertension),theFoodandNutritionBoardof240theInstituteofMedicineofAmericarecommendsanadequateintakeofcholineformenis550mg241perdayandforwomen425mgperday[38,43].
Reducedordelayedurinaryexcretionof242TMAO/TMAisspecifictohepaticdisease,andithasbeensuggesteddysbiosisoftheintestinal243microbiotainpatientswithhepatobiliarydiseasesmaydelay/decreaseconversionofcholinetoTMA244andsubsequenturinaryexcretionofTMAO/TMA[47,48].
Analysesofurinarymetabolitesproduced245bymicefedhigh-‐fatdietsledtotheproposalsthatmicrobialutilization,andsubsequentreduced246availability,ofdietarycholinecontributestothedevelopmentofNAFLD[56]andinsulinresistance247[57].
TheonlystudytodatecomparingthefaecalmicrobiotasofhealthyandNAFLDindividuals248foundnodifferenceintheircompositions[58].
However,studiesinrodentshaveshownthat249probiotic[59]andantibioticadministration[60**]canofferprotectionagainsttheonsetofNAFLD.
250TherolefordietarycholineinNAFLDcanbeexplainedbythebioavailabilityoffreecholinetoform251lipoproteinsintheliver(inparticular,VLDL),whichallowstheexportoffreefattyacidsfromthis252organ.
IfthegutmicrobiomeconvertsexcessiveamountsofdietarycholineintoTMA,thisleadsto253reducedcholinebioavailabilityand,therefore,NAFLD[57].
254255Recentworkhasdemonstratedthatchangesincholinelevelsinastandardizeddietmodulatethe256faecalmicrobiotaandcanleadtothedevelopmentoffattyliverinhumansubjects[61**].
Fifteen257females(BMI15–34)ona2-‐weekin-‐patientstudywerefedastandardizeddietinwhichcholine258levelsweremanipulated.
Gammaproteobacteriawereseeminglyinhibitedbyhighlevelsofdietary259choline,andnegativelycorrelatedwiththepercentchangeinliverfat/spleenfatratios.
260Erysipelotrichisequencenumberswerepositivelycorrelatedwiththepercentchangeinliver261fat/spleenfatratios.
Thisledtothesuggestionthatbaselinelevelsofthesetaxamaypredictthe262susceptibilityofanindividualtofattyliverdiseasefromacholine-‐deficientdiet[61**].
Combining263PEMTpromoterSNPrs12325817phenotype,GammaproteobacteriaandErysipelotrichidataproved264apowerfulmethodforpredictingthephysiologicaleffectsofcholinedeficiency,andledthe265researcherstohypothesizethatthosewiththewild-‐typeversionSNPinthePEMTgenewerebetter266abletoproducePCendogenouslyandwerelessaffectedbythecompositionoftheirintestinal267microbiotainrelationtotheeffectsofcholinedeficiency.
268269Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878Interactionsbetweentheintestinalmicrobiota,inflammasomesandNAFLDareknowntooccur.
270DeficienciesoftheNLRP3andNLRP6inflammasomespositivelyregulatedNAFLDprogressioninmice271harbouringacolitogenicintestinalmicrobiota[60**].
Switchingtheanimalstoacholine-‐deficient272dietmodulatedthefaecalmicrobiota,particularlyrepresentationofmembersofthefamilies273Porphyromondaceae,ErysipelotrichaceaeandPrevotellaceae.
Modulationoftheintestinal274microbiotabythecholine-‐deficientdietwasthoughttopromoteaTLR4/TLR9signallingcascadein275theliverthatledtoenhancedhepatictumournecrosisfactorexpressionthatdroveprogressionto276NASHinsusceptibleanimals.
277278MicrobialmetabolismofphosphatidylcholineandL-‐carnitineisassociatedwithcardiovascular279disease280CholinepresentindietaryPCisdegradedbyintestinalbacteria,butismoreresistanttodegradation281thanfreecholine[49,62].
Theintestinalmicrobiotaofmiceisabletocatabolisecholinefromdietary282PCviaanunknownmechanism,whichledtotheproposalofalinearpathwayPCcholineTMA283→TMAO[63*].
Itisknownthathumanintestinalbacteria(bacteroides,bifidobacteriaandclostridia)284areabletodegradePCwiththereleaseofcholine[62].
285286287Followingtheassociationofmethylamineswithmurineinsulin-‐resistancephenotypes[57],Wanget288al.
[63*]proposedalinkbetweendegradationofdietaryPC,theintestinalmicrobiotaandTMAOin289cardiovasculardisease.
Thishypothesiswastestedfurtherinastudyinwhichhumansweregivena290PCchallengeandtheirplasmalevelsofTMAOweremeasuredbeforeandaftersuppressionofthe291intestinalmicrobiotawithantibiotics[64**].
Time-‐dependentincreasesinplasmaTMAOlevelswere292observedatthefirstchallenge,withTMAOproductionsuppressedafterantibioticadministration.
293Removalofantibiotics,and'release'ofthemicrobiota,reinstatedTMAOplasmalevelspost-‐PC294challenge,demonstratingtheroleofthemicrobiotainincreasingcirculatinglevelsofTMAOderived295fromPC.
TheauthorsalsoexaminedtherelationshipbetweenfastingTMAOlevelsin4007patients296undergoingelectivecoronaryangiographyandtheoccurrenceofmajorcardiovascularevents297(death,heartattackorstroke)overathree-‐yearfollow-‐upperiod.
Anincreasedfastingplasmalevel298ofTMAOwasassociatedwithexperiencingamajorcardiovascularevent[64**].
299300TherelationshipbetweenTMAOproducedfromdietarymethylaminesandcardiovasculardisease301hasrecentlybeenextendedtoincludeL-‐carnitine,acompoundabundantinredmeat[65**].
302Antibiotic-‐inducedsuppressionofthemicrobiotaofhumansledtoalmost-‐completeabsenceof303Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
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com/science/article/pii/S1369527413000878TMAOfromplasmaandurineafterL-‐carnitinechallenge.
Inaddition,itwasshownthatomnivorous304humanshavefarhighercirculatinglevelsofTMAOintheirplasmathantheirveganandvegetarian305counterpartsafterL-‐carnitinesupplementation,withnegligibleTMAOformationinveganspost-‐306carnitinechallenge.
Vegetariansandveganshavehigherplasmalevelsofcarnitinecomparedwith307theiromnivorouscounterparts,thoughitisnotknownifthisisduetoreducedmicrobialmetabolism308ofcarnitinetoTMAbytheintestinalmicrobiotaofthenon-‐omnivores.
Thissuggeststhatthehuman309intestinalmicrobiotacanbemodulatedbydietarymeanswithrespecttohowitprocessesdietary310methylamines.
311312Highlevelsofplasmacarnitinewereassociatedwithcardiovasculardiseasebutonlyinthose313patientswithaccompanyinghighlevelsofplasmaTMAOinacohortof2595patientsundergoing314cardiacevaluation[64*UsinganApoe-‐/-‐mousemodel,Koethetal.
[65**]demonstratedthat315atherosclerosisplaqueformationduringcarnitinesupplementationwasmicrobiota-‐dependent,316beingdirectlyrelatedtothepresenceofbacterially-‐derivedTMAO/TMAinplasma.
TMAOis317currentlythoughttoinduceatherosclerosisbypromotingmacrophagecholesterolaccumulationby318increasingcellsurfaceexpressionofCD36andscavengerreceptorA,pro-‐atherogenicscavenger319receptors[63*,65*andbyrepressingreversecholesteroltransportandseveralbileacid320transportersintheliver[65**].
321322Conclusion323Microbial–mammalianco-‐metabolismisshapinghumanhealthinmanyways.
Inthisreview,we324havecoveredrecentfindingsonSCFA,AAAandmethylaminemetabolismandtheirconsequences325onhumanhealthanddisease,whichareillustratingparticularlywellthismetabolicsymbiosis.
With326theconstantrefinementofmetagenomicsandmetabolomics,furtherinsightswillbecomeavailable327fromcohortstudies,bearingpromisesforpersonalisednutritionandhealthcareinthefuture.
328329330Acknowledgements331LHisfundedbyEU-‐FP7METACARDIS((HEALTH-‐F4-‐2012-‐305312),M.
-‐E.
D.
isfundedbyNestlé,332InstitutMérieuxandEU-‐FP7(METACARDIS).
HFandWRacknowledgesupportfromtheScottish333Government(RESAS).
334Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
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531Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878[64]TangWH,WangZ,LevisonBS,KoethRA,BrittEB,FuX,WuY,HazenSL:Intestinalmicrobial532metabolismofphosphatidylcholineandcardiovascularrisk.
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537[65]KoethRA,WangZ,LevisonBS,BuffaJA,OrgE,SheehyBT,BrittEB,FuX,WuY,LiL,etal.
:538IntestinalmicrobiotametabolismofL-‐carnitine,anutrientinredmeat,promotesatherosclerosis.
539NatMed2013,19:576–585.
540**ExtendstheworkofTangetal.
[64**]toincludeformationofTMAOfromdietarycarnitine,and541demonstratesthatTMAOproductionisdependentondiet.
Confirmstheassociationofhighlevelsof542plasmaTMAOwithmajorcardiovascularevents.
Inaddition,theworkdemonstratesamechanism543forthedevelopmentofmethylamine-‐dependentatherosclerosis.
544545546[547Figurelegends548549Figure1.
ImpactofreducedCHOweightloss(WL)dietsinmaleobesevolunteersonfecalSCFA550concentrations.
Dataarefromtwoseparatedietarycross-‐overstudiesthatarereportedin[19]551(study1)and[20*study2):Mweightmaintenancediet(360-‐400gday-‐1CHO,22-‐28NSP),552HPMChighprotein,moderateCHOWLdiet(164-‐182gday-‐1CHO,12-‐13NSPHPLChigh553protein,lowCHOWLdiet(23-‐24gday-‐1CHO,6-‐9NSP).
Inadditiontotheevidentdecreaseintotal554SCFA,bothstudiesdetectedasignificantdecreaseinpercentbutyrateamongSCFA,whileinstudy2555thepercentofminorSCFA(valerate,isobutyrate,isovalerate)thatwerederivedfromaminoacid556fermentationincreased,reflectingthehigherproteinintakeontheWLdiets.
557558Figure2.
Concentrationoffibre-‐derivedferulicacidanditsmajormetabolitesmeasuredinfaecal559samplesfollowinghighproteindietaryinterventions.
Metabolite14-‐hydroxy-‐3-‐560methoxyphenylpropionicacid,Metabolite23,4-‐dihydroxyphenylpropionicacid,Metabolite33-‐561hydroxyphenylpropionicacid.
Mmaintenancediet(fibrecontent22gday-‐1),HPMChighprotein562moderateCHOdiet(fibrecontent14gday-‐1)andHPLChighproteinlowCHOdiet(fibrecontent8.
8563gday-‐1).
Ferulicacid4-‐hydroxy-‐3-‐methoxycinnamicacid.
Dataaregivenasmeanstandard564deviation(n8volunteers).
Statisticaldatawerecalculatedasaone-‐wayANOVAtocomparediet565Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878withblockingforvolunteerand,wheresignificant,aregivenforcomparisonbetweenMandHPLC566diets.
Adaptedfrom[20**].
567568Figure3.
Themethylamines'pathwayandthemicrobial–mammalianmetabolicaxis.
TMAisderived569frommicrobialdegradationofcholine,adietarycomponentthatcanalsobeobtainedbycleavageof570dietaryPC,andofL-‐carnitine.
TMAisabsorbedbythehosttobeN-‐oxidisedintoTMAObyFMO3and571demethylatedintoDMAandMMAbycytochromeP450s(CYP)intheliverduringfirst-‐pass572metabolism.
CirculatingTMAOcanreachothercelltypes,suchasarterialepithelialcellsand573macrophages,leadingtoatherosclerosis-‐associatedinflammation.
PC,synthesizedfromcholine574throughtheKennedy(CDP-‐choline)pathway,isessentialforexportingfattyacidsfromtheliverto575otherstoragetissues;reducedcholinebioavailabilityleadstolowerlevelsofPCbeingformedandto576NAFLD.
PEMTconvertsphosphatidylethanolamine(PE)intoPC,usingS-‐adenosylmethionineasa577methyldonor,andapolymorphisminPEMThasbeenassociatedwithahigherriskofdeveloping578NAFLD.
Whenthereissufficientcholineinthediet,theKennedypathwayisresponsiblefor579maintainingPCsynthesis,withthePEMTpathwaycontributing~30ofthehepaticPC.
When580cholineisatlowlevelsinthediet,thePEMTpathwayisessentialformaintainingthesupplyofPCin581theliver.
Adaptedfrom[41,57,63**,64**,65**].
582583
sciencedirect.
com/science/article/pii/S1369527413000878Colonicbacterialmetabolitesandhumanhealth1WendyR.
Russell1#,LesleyHoyles2#,HarryJ.
Flint1*andMarc-‐EmmanuelDumas2*21.
RowettInstituteofNutritionandHealth,UniversityofAberdeen,GreenburnRoad,Bucksburn,3AberdeenAB219SB,UK42.
ComputationalandSystemsMedicine,DepartmentofSurgeryandCancer,FacultyofMedicine,5ImperialCollegeLondon,ExhibitionRoad,LondonSW72AZ,UK67#WRRandLHmadeequalcontributionstothisreview.
8*jointcorrespondingauthors(emailaddresses):9Marc-‐EmmanuelDumas(m.
dumas@imperial.
ac.
uk)10HarryJFlint(h.
flint@abdn.
ac.
uk)1112Abstract(100-‐120words)13Theinfluenceofthemicrobial–mammalianmetabolicaxisisbecomingincreasinglyimportantfor14humanhealth.
Bacterialfermentationofcarbohydratesandproteinsproducesshort-‐chainfatty15acids(SCFA)andarangeofothermetabolitesincludingthosefromaromaticaminoacid(AAA)16fermentation.
SCFAinfluencehosthealthasenergysourcesandviamultiplesignallingmechanisms.
17Bacterialtransformationoffibre-‐relatedphytochemicalsisassociatedwithareducedincidenceof18severalchronicdiseases.
The'gut–liveraxis'isanemergingareaofstudy.
Microbialdeconjugationof19xenobioticsandreleaseofaromaticmoietiesintothecoloncanhaveawiderangeofphysiological20consequences.
Inaddition,theroleofthegutmicrobiotaincholinedeficiencyinnon-‐alcoholicfatty21liverdiseaseandinsulinresistanceisreceivingincreasedattention.
222324Highlights:25-‐Diet-‐drivenchangesinmicrobially-‐producedSCFAcaninfluencehealthviasignalling26-‐Gutmicrobiotamediatesthereleaseandtransformationofmanybioactivephenolics27-‐Gutmicrobiotadegradesdietarycholinetomethylamines28-‐Interactionsbetweenthemicrobiota,inflammasomesandhostinfluenceliverdisease293031Abbreviations:SCFA,short-‐chainfattyacids;CHO,carbohydrate;FFAR,freefattyacidreceptor;WL,32weightloss;NSP,non-‐starchpolysaccharide'fibre';AAA,aromaticaminoacids;NAFLD,non-‐alcoholic33fattyliverdisease;NASH,non-‐alcoholicsteatohepatitis;HMS,hepaticmacrovesicularsteatosis;PC,34Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878phosphatidylcholine;PEMT,phosphatidylethanolamine-‐N-‐methyltransferase;SNP,singlenucleotide35polymorphism;TMA,trimethylamine;TMAO,trimethylamine-‐N-‐oxide.
36Introduction37Thehumanlargeintestineiscolonisedbydensemicrobialcommunitiesthatutilisebothdiet-‐and38host-‐derivedenergysourcesforgrowth,predominantlythroughfermentativemetabolism.
This39highlydiversecommunityhasthecapacitytoperformanextraordinaryrangeofbiochemical40transformationsthatgowellbeyondthoseencodedbythehostgenome,andtheseactivitiesexert41animportantinfluenceuponmanyaspectsofhumanhealth.
Metabolitesformedbythegut42microbiotaarelargelydeterminedbythecompositionofthedietandthepatternoffoodintake,and43itisnowclearthatthespeciescompositionofthecolonicmicrobiotaisitselfalteredbythediet44[1*,2,3**].
Thisreviewwillconsiderselectedexampleswhererecentprogresshasbeenmadein45understandingthelinksbetweendiet,gutmicrobialactivityandmetabolitesrelevanttohealth.
4647Bacterialmetabolitesderivedfromthefermentationofplant-‐derived48carbohydratesandtheirimpactonthehost4950Manycarbohydrates(CHOs)presentinplant-‐derivedfoodsaredigestedslowly,ifatall,inthesmall51intestine,makingthemavailableformicrobialfermentationinthelargeintestine.
Intakeofstarch52thatisresistanttodigestioninthesmallintestine(resistantstarch)canhavebenefitsformetabolic53health[4]andresultsinchangesinthegutmicrobiota[1*].
Recentworkalsoshowsabeneficial54influenceofwholegrainintakeuponinflammation,againwithconcomitantchangesinthegut55microbiota[5*].
Diet-‐inducedchangesinthemetabolicactivityofthegutmicrobiotaarethought56likelytomediatetheseeffects.
5758Hexoseandpentosesugarsarefermentedbyisolatedhumancolonicbacteriaviapathwaysleading59totheformationofacetate,succinate,propionate,butyrate,formate,lactate,ethanol,hydrogen60andCO2,dependingonthestrainandspecies.
ButyrateformationoccursincertainFirmicutes61bacteria,eitherviabutyratekinase(inmanyClostridiumandCoprococcusspecies)orviabutyryl62CoA:acetateCoAtransferase[6].
Thelatterpathwayisfoundinthenumericallypredominant63butyrate-‐producingspeciesofRoseburia,Eubacteriumrectale,E.
halliiandFaecalibacterium64prausnitzii,andinvolvesthenetuptakeofexternalacetate[7].
Acetateisproducedbymost65anaerobes,includingacetogensthatareabletoperformreductiveacetogenesisfromformateor66hydrogenplusCO2.
Producersofsuccinateandpropionatelargelybelongtothephylum67Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878Bacteroidetes,butalsoincludesomeFirmicutes.
Lactatecanbeformedbymanygroups,butis68generallyconvertedintoacetate,propionateorbutyratebyasubsetoflactate-‐utilizingspecies[8].
69FormationofthegaseshydrogenandCO2varieswidelybetweenspeciesinpureculture;inthe70mixedcommunitytheseproductsarepartiallyconvertedtoacetate,methaneorhydrogensulfide71[9].
Thenetoutcomeofallofthesecomplexcross-‐feedinginteractionsforatypicalhealthy72microbiotaisthat,infaecalsamples,acetateisthedominantshort-‐chainfattyacid(SCFA)detected73(typically4070mM)followedbypropionateandbutyrate(each1030mM)[10].
While74alternativeproductssuchasethanol,succinateandlactatearenormallyfoundatlower75concentrations,theycanaccumulateinsomecircumstancesandalinkhasbeenproposedbetween76endogenousalcoholformationandnon-‐alcoholicsteatohepatitis[11].
7778Attheseconcentrations,SCFAhaveamajorimpactonthelargeintestinalenvironmentandon79absorptionfromthelumen.
Whilebutyrateislargelyutilisedbythegutepithelium,andpropionate80islargelymetabolisedintheliver,acetateistheSCFAthatreachesthehighestconcentrationsin81plasma[10].
Thereisincreasingevidencethatacetateplaysanimportantroleincontrolling82inflammationandincombatingpathogeninvasion[12,13].
Acetateandlactatewerealsofound83recentlytoinfluencecyclingeneexpressionandepithelialcellproliferationinapH-‐dependent84mannerinvitro[14].
Theimportanceofbutyrateasanenergysourceforepithelialcellshaslong85beenrecognised,butitsroleinregulatinginflammation,cellulardifferentiationandapoptosis,and86inhelpingtopreventcolorectalcancer,isstillemerging[15].
Interestingly,butyratewasrecently87foundtobethemostpotentSCFAinactivatingtheAP-‐1signallingpathwayinepithelialcelllines88[16].
InteractionshavebeenrecognisedbetweenSCFAandthehostcellreceptorsFFAR2andFFAR389thatmightinfluencesatiety,protectagainstdiet-‐inducedobesityandimproveinsulinsensitivity,90withpropionateconsideredtohaveapotentiallyimportantrole17,18].
Inviewofthisitis91importanttounderstandhowdietandmicrobiotacompositioncaninfluencerelative,aswellas92total,SCFAproduction.
Studiesinobesesubjectsonweightlossdietsdemonstratethatdietary93intakeofCHOhasamajorimpactonfaecalSCFAconcentrations[19,20**]presumablyreflecting94decreasedfermentationinthecolon(Fig.
1).
Moresurprising,however,isthatbutyratepercent95respondeddisproportionately,aneffectthatcorrelateswithamarkeddecreaseintheRoseburia-‐E.
96rectalegroupofbutyrate-‐producingbacteria[19].
Thismaybeexplainedbythegreaterdependence97ofthisgroup,comparedwithothermembersofthemicrobiota,onintakeofresistantdietaryCHOs,98andprovidesevidencethatSCFArelativeproductionratesareresponsivetodietcomposition.
An99inverserelationshiphasbeennotedbetweenfaecalpHandbutyrateconcentrationinvivo[21];this100Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878islikelytoreflectthegreatcompetitiveabilityofsomebutyrate-‐producersatthereducedpHarising101fromactivefermentationintheproximalcolon[22].
102Decreasednumbersofbutyrate-‐producingbacteria,especiallyFaecalibacteriumprausnitzii,have103beennotedinpatientssufferingfromCrohn'sdisease.
Thisspeciesexertsanti-‐inflammatoryeffects104thatappeartoinvolvesolublefactorsinadditiontobutyrate[23].
Interestingly,F.
prausnitziiwas105recentlyshowntodiminishtheimpactoftheacetate-‐producingspeciesBthetaiotaomicronon106mucusproductionandgobletcelldevelopmentinagnotobioticrodentmodel[24].
107108Formationandmetabolismofaromaticcompounds109110Fibre-‐relatedphytochemicals111Itissuggestedthattheinverserelationshipbetweentheintakeoffibre-‐richdietsandtheincidence112ofseveralchronicdiseasesismediatedinpartbythegutmicrobiota.
Microbialreleaseof113phytochemicalmetabolitesmaybeacontributingfactorandmostwidelystudiedfordisease114preventionarethearomaticmetabolitesproducedbythephenylpropanoidpathway[25,26].
115Increasingthefibrecontentofthedietfrom8.
8to14gday-‐1inahumanvolunteerstudyresultedin116significantlyincreasingcertainphenolicacidsandtheirderivativesinthegut,specificallyferulicacid,1174-‐hydroxy-‐3-‐methoxyphenylpropionicacidand3-‐hydroxyphenylpropionicacid[20].
Ferulicacid,118whichisfoundextensivelyboundtoplantpolysaccharides,canbereleasedandmetabolisedbythe119gutmicrobiota[20,27](Fig.
2).
Indeed,themajorestersofotherphenolicacidssuchascaffeicacid120(chlorogenicandcaftaricacid)arealsorapidlyde-‐esterifiedbyhumanfaecalmicrobiota[28].
It121appearsthatthegutmicrobiotacaneffectivelyde-‐esterifycompounds,whethertheconjugateis122quinicacid,tartaricacidorasugarmoietytoreleasetheaglyconeforfurthermetabolism.
Gut123bacteriacanalsoeffectivelyhydrogenatetheα,β-‐unsaturatedbondpresentonthesidechainof124phenolicacids[27]andtheextenttowhichthisoccursappearstobedependentonadditional125dietaryfactors,withhigh-‐proteindietsdecreasingtheefficiencyofthistransformation[20].
Site-‐126specificdehydroxylationanddemethylationofthephenolichydroxylpresentinphenolicacidshas127alsobeenobserved[20,27].
Theresultantmicrobialproductsofferulicacidmetabolismhad128differingeffectsonprostanoidproductioninvitrosuggestingthatthemicrobialtransformationof129dietarycompoundswillhaveimportantconsequencesforinflammation[27,29].
130131Aromaticaminoacidmetabolites132Proteinmetabolismisamajoralternativemechanismforproductionofaromaticmetabolites[30]as133observedinrecenthumandietaryinterventionsinvolvingcarefullycontrolledintakesofCHOand134Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878protein[20].
Untilrecently,themajormetabolitesofaromaticaminoacid(AAA)fermentationwere135consideredtobephenol,p-‐cresolandindole,withp-‐cresolsuggestedtobeaproductofphenol136catabolism.
Ithasnowbeendemonstratedthatamuchwidermetabolicpathwayofmetabolism137existsforallthreeAAAs[31].
Inparticular,phenylaceticacid,4-‐hydroxyphenylaceticacidandindole-‐1383-‐aceticacidwerefoundtobemajor(de-‐aminatedandchain-‐shortened)productsofphenylalanine,139tyrosineandtryptophan,respectively[31].
Bacteriacapableofproducingtheseproductscould140effectivelymetaboliseallthreeAAAsubstrates.
TheseincludedBacteroidesthetaiotaomicron,B.
141eggerthii,B.
ovatus,B.
fragilis,ParabacteroidesdistasonisandtheGram-‐positivebacteria142ClostridiumbartlettiiandEubacteriumhallii.
Bacterialspeciesthatdidnotsubstantiallyproduce143thesede-‐aminatedandchain-‐shortenedproductswereidentified.
TheseincludedMegamonas144hypermegale,Roseburiaintestinalis,Ruminococcusobeum,Eubacteriumrectaleand145Faecalibacteriumprausnitzii,butstrainsofthesespeciesoftenproducedhigheramountsofbenzoic146acid,4-‐hydroxybenzoicacidandindole-‐3-‐carboxylicacidandoxidationproductsincluding147phenylpyruvicacid,phenyllacticacid,4-‐hydroxyphenyllacticacid,indole-‐3-‐pyruvicacidandindole-‐3-‐148lacticacid.
GiventhatcertainspeciesofgutbacteriacanmetaboliseallthreeAAAsbyspecific149mechanisms,itislikelythatotherstructuralformsofaminoacidscanundergothesemolecular150transformations.
Thiswillgiverisetoarangeofnovelmetabolites,whichrequiretobeinvestigated151toassesstheirpotentialtoaffecthumanhealth.
152153Itisclearthatmacronutrientbalanceinfluencesnotonlythecompositionofthegutmicrobiotabut154alsotheavailabilityofaromaticmetabolites.
CertainmetabolitessuchasSCFAandphenyl155metabolitescanbeproducedbybacterialmetabolismofbothCHOandproteininthelargeintestine,156whereascertainbranched-‐chainfattyacidsandnitrogen-‐containingmetabolitesareconsideredto157bederivedfromproteinmetabolismalone.
Thereisapositiveassociationbetweenanimalprotein158consumption(specificallyredandprocessedmeat)andcolorectalcancer[32].
Evidenceisalso159beginningtoemergethattheconcentrationsofaromaticgutmetabolitesinthesystemiccirculation160playsaroleinvascularhealthand[33].
161162Enterohepaticcirculationandβ-‐glucuronidase163Manydiet-‐derivedaromaticcompounds,includingdrugs,aretreatedasxenobioticsandare164conjugatedintheliverfollowedbyreleaseintotheintestineviathebile.
Oneofthemain165mechanismsforconjugationisglucuronidation,butithasbeenknownforsometimethatbacterial166β-‐glucuronidasesinthelargeintestinetendtocleavetheseconjugates,thusreleasingthearomatic167moietyandmakingitavailableagainforre-‐absorption.
ThegusgenefromEscherichiacoliwas168originallyidentifiedasencodingthisactivity.
Arecentsurveyuseddegenerategusprimerstodetect169Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878relatedgenesamongthefaecalmicrobiotafrom10healthyvolunteers;thisshowedahighlyuneven170distributionwith60ofsequencesaccountedforbyonly4operationaltaxonomicunits,whilein171total96ofsequencescamefromFirmicutesand3fromE.
coli[34].
Itseemslikelythatthis172activityisassociatedwithenzymesinvolvedindegradingplantpolysaccharides.
Thecontributionof173asecondputativeβ-‐glucuronidasegeneidentifiedfrommetagenomiclibraries[35]hasstilltobe174fullyestablished[34].
175176The'gut–liver'axis,dietaryamines,theintestinalmicrobiotaandthe177methylamines'pathway178The'gut–liver'axis179Giventheexposureofthelivertointestinal-‐derivedcatabolitesandthemicrobiotatobiliary/waste180products,the'gut–liveraxis'isreceivinggreatattentionwithrespecttohosthealthanditspotential181toaffectsystemichostprocesses[36].
Arecentstudyhasnicelydemonstratedthedirect182involvementofthegutmicrobiotainthedevelopmentofobesity-‐independentnon-‐alcoholicfatty183liverdisease(NAFLD),andthemicrobiota'sinfluenceonwholebodyglucosehomeostasisandliver184lipidmetabolism[37**].
Germ-‐freemiceinoculatedwithintestinalmicrobiotafromamousethat185developedhyperglycaemiaandhadahighplasmaconcentrationofpro-‐inflammatorycytokinesafter186beingfedahigh-‐fatdietdevelopedhepaticmacrovesicularsteatosis(HMS)afterhigh-‐fatfeeding,187withincreasedexpressionofhepaticgenesinvolvedinde-‐novolipogenesisandlipiduptake(SREBP,188ChREBP,acetyl-‐CoAcarboxylase1andCD36)observed.
Incomparison,germ-‐freemiceinoculated189withfaecesfromamousethatwasnormoglycaemicandhadalowerlevelofsystemicinflammation190afterbeingfedahigh-‐fatdietdevelopedlow-‐levelsteatosisonthesamediet[37**].
Differences191wereobservedinthefaecalmicrobiotaofthetwogroupsofmice:LachnospiraceaeandBarnesiella192(Porphyromonadaceae)sequencesweresignificantlyoverrepresentedintheHMSmice,whilethe193low-‐levelsteatosismicehadanincreasednumberofsequencesrelatedtoBacteroidesvulgatus.
194Concentrationsofisobutyrateandisovalerate,branched-‐chainaminoacidsresultingfromthe195bacterialfermentationofvalineandleucine,respectively,weresignificantlyhigherinthecaecumof196theHMSmice.
Inaddition,theseanimalshadsignificantlyhigherfastingglycaemia,fasting197insulinaemia,homeostasismodelassessment—insulinresistanceindexandleptinaemia,andhigher198plasmaconcentrationsofaspartateaminotransferasethantheanimalsthatdevelopedlow-‐level199steatosis.
Takentogether,theseresultsdemonstratethatthegutmicrobiotaconstitutesan200environmentalfactordrivingtheprogressionofNAFLD[37**].
201202Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878AlthoughbothgroupsofanimalswerefedthesamedietintheLeRoystudy[37**],itiswellknown203thattheintestinalmicrobiotacaninfluencethe'gut–liveraxis'andthedevelopmentofNAFLD(and204otherdiseases)bymicrobialutilizationofdietarymethylamines.
205206CholinedeficiencyandNAFLD207CholineisanessentialnutrientofthevitaminBcomplexwithnumerousrolesinthebody:actingas208amethyldonorinbiochemicalreactions,asaprecursorforthebiosynthesisofphospholipids209[phosphatidylcholine(PC),lysophosphatidylcholine,cholineplasmalogenandsphingomyelin],of210acetylcholineandoflipoproteins,andinhomocysteinereduction[38,39,40].
Themainfateof211cholineinthebodyisitsincorporationintoPCviatheKennedypathway[41].
212213Exogenouscholineisderivedfromeitherdietarycholineor,morecommonly,PCfromplantand214animalmaterial[38,39,42].
Foodshighincholineincludemeatanddairyproducts,fish,soybeans,215nutsandwholegrains,withPCaddedtoanumberoffoodsasanemulsifier[43].
Endogenous216sourcesofcholine,intheformofPC,includebiliarylipids,exfoliatedepithelialcellsandintestinal217bacteria[44,45].
Denovosynthesisofcholineoccursviaareactioncatalysedby218phosphatidylethanolamine-‐N-‐methyltransferase(PEMT)[41].
219220Theintestinalmicrobiotaplaysaroleinthecatabolismofcholineinhumansandrodents221[46,47,48,49,],withtrimethylamine(TMA),acetateandethanoltheproductsoffermentation[50].
222Cholinedegradationbythehumanintestinalmicrobiotaistemporallystable[47].
TMAproducedby223intestinalbacteriafromcholineisabsorbedbycoloniccellsandconvertedtotrimethylamine-‐N-‐224oxide(TMAO)byflavinmono-‐oxygenaseenzymes[51],demethylatedintodimethylamineand225(mono)methylamineintheliver,orexcretedintheurine.
Themethylaminepathwayisatypical226exampleofmicrobial–mammalianco-‐metabolism[52,53](Figure3).
227228KnowledgepertainingtothosemembersoftheintestinalmicrobiotaresponsibleforproducingTMA229fromcholineissparse.
Insilicopredictionshavesuggestedthatseveralmembersofthehuman230intestinalmicrobiota(includingClostridium,Anaerococcus,Collinsella,Desulfitobacterium,Klebsiella,231Escherichia,Providencia,YokenellaandProteusspp.
)havetheabilitytodegradecholinetoTMAvia232cholineTMA-‐lyase[54**].
Inadditiontotheaforementionedspecies,manymoremembersofthe233humanintestinalmicrobiotamaybeabletodegradecholinetoTMAusingthesamemechanism234and/orviaanalternativepathway(s).
235236Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878237Choline-‐deficientdietsinhumans(≤50mgday-‐1)androdentsareknowntoleadtoNAFLD,non-‐238alcoholicsteatohepatitis(NASH)andhepaticdamage[39,55].
Tocombattheseandother239complications(e.
g.
infertility,renalhaemorrhageandhypertension),theFoodandNutritionBoardof240theInstituteofMedicineofAmericarecommendsanadequateintakeofcholineformenis550mg241perdayandforwomen425mgperday[38,43].
Reducedordelayedurinaryexcretionof242TMAO/TMAisspecifictohepaticdisease,andithasbeensuggesteddysbiosisoftheintestinal243microbiotainpatientswithhepatobiliarydiseasesmaydelay/decreaseconversionofcholinetoTMA244andsubsequenturinaryexcretionofTMAO/TMA[47,48].
Analysesofurinarymetabolitesproduced245bymicefedhigh-‐fatdietsledtotheproposalsthatmicrobialutilization,andsubsequentreduced246availability,ofdietarycholinecontributestothedevelopmentofNAFLD[56]andinsulinresistance247[57].
TheonlystudytodatecomparingthefaecalmicrobiotasofhealthyandNAFLDindividuals248foundnodifferenceintheircompositions[58].
However,studiesinrodentshaveshownthat249probiotic[59]andantibioticadministration[60**]canofferprotectionagainsttheonsetofNAFLD.
250TherolefordietarycholineinNAFLDcanbeexplainedbythebioavailabilityoffreecholinetoform251lipoproteinsintheliver(inparticular,VLDL),whichallowstheexportoffreefattyacidsfromthis252organ.
IfthegutmicrobiomeconvertsexcessiveamountsofdietarycholineintoTMA,thisleadsto253reducedcholinebioavailabilityand,therefore,NAFLD[57].
254255Recentworkhasdemonstratedthatchangesincholinelevelsinastandardizeddietmodulatethe256faecalmicrobiotaandcanleadtothedevelopmentoffattyliverinhumansubjects[61**].
Fifteen257females(BMI15–34)ona2-‐weekin-‐patientstudywerefedastandardizeddietinwhichcholine258levelsweremanipulated.
Gammaproteobacteriawereseeminglyinhibitedbyhighlevelsofdietary259choline,andnegativelycorrelatedwiththepercentchangeinliverfat/spleenfatratios.
260Erysipelotrichisequencenumberswerepositivelycorrelatedwiththepercentchangeinliver261fat/spleenfatratios.
Thisledtothesuggestionthatbaselinelevelsofthesetaxamaypredictthe262susceptibilityofanindividualtofattyliverdiseasefromacholine-‐deficientdiet[61**].
Combining263PEMTpromoterSNPrs12325817phenotype,GammaproteobacteriaandErysipelotrichidataproved264apowerfulmethodforpredictingthephysiologicaleffectsofcholinedeficiency,andledthe265researcherstohypothesizethatthosewiththewild-‐typeversionSNPinthePEMTgenewerebetter266abletoproducePCendogenouslyandwerelessaffectedbythecompositionoftheirintestinal267microbiotainrelationtotheeffectsofcholinedeficiency.
268269Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878Interactionsbetweentheintestinalmicrobiota,inflammasomesandNAFLDareknowntooccur.
270DeficienciesoftheNLRP3andNLRP6inflammasomespositivelyregulatedNAFLDprogressioninmice271harbouringacolitogenicintestinalmicrobiota[60**].
Switchingtheanimalstoacholine-‐deficient272dietmodulatedthefaecalmicrobiota,particularlyrepresentationofmembersofthefamilies273Porphyromondaceae,ErysipelotrichaceaeandPrevotellaceae.
Modulationoftheintestinal274microbiotabythecholine-‐deficientdietwasthoughttopromoteaTLR4/TLR9signallingcascadein275theliverthatledtoenhancedhepatictumournecrosisfactorexpressionthatdroveprogressionto276NASHinsusceptibleanimals.
277278MicrobialmetabolismofphosphatidylcholineandL-‐carnitineisassociatedwithcardiovascular279disease280CholinepresentindietaryPCisdegradedbyintestinalbacteria,butismoreresistanttodegradation281thanfreecholine[49,62].
Theintestinalmicrobiotaofmiceisabletocatabolisecholinefromdietary282PCviaanunknownmechanism,whichledtotheproposalofalinearpathwayPCcholineTMA283→TMAO[63*].
Itisknownthathumanintestinalbacteria(bacteroides,bifidobacteriaandclostridia)284areabletodegradePCwiththereleaseofcholine[62].
285286287Followingtheassociationofmethylamineswithmurineinsulin-‐resistancephenotypes[57],Wanget288al.
[63*]proposedalinkbetweendegradationofdietaryPC,theintestinalmicrobiotaandTMAOin289cardiovasculardisease.
Thishypothesiswastestedfurtherinastudyinwhichhumansweregivena290PCchallengeandtheirplasmalevelsofTMAOweremeasuredbeforeandaftersuppressionofthe291intestinalmicrobiotawithantibiotics[64**].
Time-‐dependentincreasesinplasmaTMAOlevelswere292observedatthefirstchallenge,withTMAOproductionsuppressedafterantibioticadministration.
293Removalofantibiotics,and'release'ofthemicrobiota,reinstatedTMAOplasmalevelspost-‐PC294challenge,demonstratingtheroleofthemicrobiotainincreasingcirculatinglevelsofTMAOderived295fromPC.
TheauthorsalsoexaminedtherelationshipbetweenfastingTMAOlevelsin4007patients296undergoingelectivecoronaryangiographyandtheoccurrenceofmajorcardiovascularevents297(death,heartattackorstroke)overathree-‐yearfollow-‐upperiod.
Anincreasedfastingplasmalevel298ofTMAOwasassociatedwithexperiencingamajorcardiovascularevent[64**].
299300TherelationshipbetweenTMAOproducedfromdietarymethylaminesandcardiovasculardisease301hasrecentlybeenextendedtoincludeL-‐carnitine,acompoundabundantinredmeat[65**].
302Antibiotic-‐inducedsuppressionofthemicrobiotaofhumansledtoalmost-‐completeabsenceof303Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878TMAOfromplasmaandurineafterL-‐carnitinechallenge.
Inaddition,itwasshownthatomnivorous304humanshavefarhighercirculatinglevelsofTMAOintheirplasmathantheirveganandvegetarian305counterpartsafterL-‐carnitinesupplementation,withnegligibleTMAOformationinveganspost-‐306carnitinechallenge.
Vegetariansandveganshavehigherplasmalevelsofcarnitinecomparedwith307theiromnivorouscounterparts,thoughitisnotknownifthisisduetoreducedmicrobialmetabolism308ofcarnitinetoTMAbytheintestinalmicrobiotaofthenon-‐omnivores.
Thissuggeststhatthehuman309intestinalmicrobiotacanbemodulatedbydietarymeanswithrespecttohowitprocessesdietary310methylamines.
311312Highlevelsofplasmacarnitinewereassociatedwithcardiovasculardiseasebutonlyinthose313patientswithaccompanyinghighlevelsofplasmaTMAOinacohortof2595patientsundergoing314cardiacevaluation[64*UsinganApoe-‐/-‐mousemodel,Koethetal.
[65**]demonstratedthat315atherosclerosisplaqueformationduringcarnitinesupplementationwasmicrobiota-‐dependent,316beingdirectlyrelatedtothepresenceofbacterially-‐derivedTMAO/TMAinplasma.
TMAOis317currentlythoughttoinduceatherosclerosisbypromotingmacrophagecholesterolaccumulationby318increasingcellsurfaceexpressionofCD36andscavengerreceptorA,pro-‐atherogenicscavenger319receptors[63*,65*andbyrepressingreversecholesteroltransportandseveralbileacid320transportersintheliver[65**].
321322Conclusion323Microbial–mammalianco-‐metabolismisshapinghumanhealthinmanyways.
Inthisreview,we324havecoveredrecentfindingsonSCFA,AAAandmethylaminemetabolismandtheirconsequences325onhumanhealthanddisease,whichareillustratingparticularlywellthismetabolicsymbiosis.
With326theconstantrefinementofmetagenomicsandmetabolomics,furtherinsightswillbecomeavailable327fromcohortstudies,bearingpromisesforpersonalisednutritionandhealthcareinthefuture.
328329330Acknowledgements331LHisfundedbyEU-‐FP7METACARDIS((HEALTH-‐F4-‐2012-‐305312),M.
-‐E.
D.
isfundedbyNestlé,332InstitutMérieuxandEU-‐FP7(METACARDIS).
HFandWRacknowledgesupportfromtheScottish333Government(RESAS).
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401**Thisstudyshowsthatconsumptionofhighprotein,reducedCHOdietsbyhumanvolunteers402resultsinfecalmetaboliteprofileswithalteredSCFAproportions,decreasedconcentrationsof403butyrateandphenoliccompoundsderivedfromplantfibre,andincreasedN-‐nitrosocompounds.
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431Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
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451**Thisstudyprovidesaverygoodexampleofthepotentialofthe'gut–liveraxis'toaffecthost452health.
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463Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
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486[54]CraciunS,BalskusEP:Microbialconversionofcholinetotrimethylaminerequiresaglycyl487radicalenzyme.
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488**Thisstudyhighlightsthepotentialofcomputationalchemistrytoidentifygeneswithspecific489biologicalfunctions,withtheauthorsidentifyingageneclusterresponsibleforanaerobiccholine490degradationinthegenomeofDesulfovibriodesulfuricans.
Thecholineutilizationclusterwasfound491tobepresentinthegenomesofanumberofhumangutbacteria,thoughtheexpressionofthis492clusterinthesebacteriahasyettobedemonstratedinvitroorinvivo.
493[55]Koch-‐WeserD,delaHuergaJ,PopperH:Effectofcholinesupplementsonfatty494metamorphosisandlivercelldamageincholineandproteindeficiency.
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495[56]ZhangAQ,MitchellSC,SmithRL:Dietaryprecursorsoftrimethylamineinman:apilotstudy.
496FoodChemToxicol1999,37:515–520.
497Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
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com/science/article/pii/S1369527413000878[57]DumasME,BartonRH,ToyeA,CloarecO,BlancherC,RothwellA,FearnsideJ,TatoudR,BlancV,498LindonJC,etal.
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509**ThisarticledemonstratednegativeregulationofNAFLDprogressionbytheNLRP3andNLRP6510inflammasomesandIL-‐18.
Inflammasome-‐deficientmicedevelopacolitogenicgutmicrobiotaand511haveexacerbatedhepaticsteatosis,glucosetoleranceandobesity.
Itissuggestedthatdefective512inflammasomesensingresultsinalteredgutmicrobiota–hostinteractionsthatmaygoverntherate513ofdiseaseprogression.
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517**Combininghostgenomeandmicrobiotadata,thestudydemonstratedthephysiologicaleffectsof518cholinedeficiencyonthehostcouldbepredicted,withthesuggestionthatthoseindividualscarrying519thewild-‐typeversionSNPinthePEMTgenewerebetterabletoproducePCendogenouslyandwere520lessaffectedbythecompositionoftheirintestinalmicrobiotainrelationtotheeffectsofcholine521deficiency.
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:Gutflorametabolismofphosphatidylcholinepromotescardiovasculardisease.
Nature5262011,472:57–63.
527*ThisarticlefurtherexploredthehypothesisofDumasetal.
[23]ontheassociationbetween528methylaminesandinsulinresistance/NAFLD.
Wangetal.
[18]expandedtheirscopeto529atherosclerosisandnicelydemonstratedthatTMAOexposurewasassociatedwithmarkersof530inflammation.
531Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878[64]TangWH,WangZ,LevisonBS,KoethRA,BrittEB,FuX,WuY,HazenSL:Intestinalmicrobial532metabolismofphosphatidylcholineandcardiovascularrisk.
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533**ThestudydescribedinthisarticletakesthehypothesisfromWangetal.
[63*],thatmicrobial-‐534dependentconversionofdietaryPCtoTMAOisassociatedwithcardiovasculardisease,andapplies535ittoahumancohort.
Itpresentsthefirstevidenceofanassociationbetweenamicrobiota-‐536dependentproductandcardiovasculardiseaseinhumans.
537[65]KoethRA,WangZ,LevisonBS,BuffaJA,OrgE,SheehyBT,BrittEB,FuX,WuY,LiL,etal.
:538IntestinalmicrobiotametabolismofL-‐carnitine,anutrientinredmeat,promotesatherosclerosis.
539NatMed2013,19:576–585.
540**ExtendstheworkofTangetal.
[64**]toincludeformationofTMAOfromdietarycarnitine,and541demonstratesthatTMAOproductionisdependentondiet.
Confirmstheassociationofhighlevelsof542plasmaTMAOwithmajorcardiovascularevents.
Inaddition,theworkdemonstratesamechanism543forthedevelopmentofmethylamine-‐dependentatherosclerosis.
544545546[547Figurelegends548549Figure1.
ImpactofreducedCHOweightloss(WL)dietsinmaleobesevolunteersonfecalSCFA550concentrations.
Dataarefromtwoseparatedietarycross-‐overstudiesthatarereportedin[19]551(study1)and[20*study2):Mweightmaintenancediet(360-‐400gday-‐1CHO,22-‐28NSP),552HPMChighprotein,moderateCHOWLdiet(164-‐182gday-‐1CHO,12-‐13NSPHPLChigh553protein,lowCHOWLdiet(23-‐24gday-‐1CHO,6-‐9NSP).
Inadditiontotheevidentdecreaseintotal554SCFA,bothstudiesdetectedasignificantdecreaseinpercentbutyrateamongSCFA,whileinstudy2555thepercentofminorSCFA(valerate,isobutyrate,isovalerate)thatwerederivedfromaminoacid556fermentationincreased,reflectingthehigherproteinintakeontheWLdiets.
557558Figure2.
Concentrationoffibre-‐derivedferulicacidanditsmajormetabolitesmeasuredinfaecal559samplesfollowinghighproteindietaryinterventions.
Metabolite14-‐hydroxy-‐3-‐560methoxyphenylpropionicacid,Metabolite23,4-‐dihydroxyphenylpropionicacid,Metabolite33-‐561hydroxyphenylpropionicacid.
Mmaintenancediet(fibrecontent22gday-‐1),HPMChighprotein562moderateCHOdiet(fibrecontent14gday-‐1)andHPLChighproteinlowCHOdiet(fibrecontent8.
8563gday-‐1).
Ferulicacid4-‐hydroxy-‐3-‐methoxycinnamicacid.
Dataaregivenasmeanstandard564deviation(n8volunteers).
Statisticaldatawerecalculatedasaone-‐wayANOVAtocomparediet565Thefull,proofreadversionofthisreviewwaspublishedbyElsevierandcanbefoundathttp://www.
sciencedirect.
com/science/article/pii/S1369527413000878withblockingforvolunteerand,wheresignificant,aregivenforcomparisonbetweenMandHPLC566diets.
Adaptedfrom[20**].
567568Figure3.
Themethylamines'pathwayandthemicrobial–mammalianmetabolicaxis.
TMAisderived569frommicrobialdegradationofcholine,adietarycomponentthatcanalsobeobtainedbycleavageof570dietaryPC,andofL-‐carnitine.
TMAisabsorbedbythehosttobeN-‐oxidisedintoTMAObyFMO3and571demethylatedintoDMAandMMAbycytochromeP450s(CYP)intheliverduringfirst-‐pass572metabolism.
CirculatingTMAOcanreachothercelltypes,suchasarterialepithelialcellsand573macrophages,leadingtoatherosclerosis-‐associatedinflammation.
PC,synthesizedfromcholine574throughtheKennedy(CDP-‐choline)pathway,isessentialforexportingfattyacidsfromtheliverto575otherstoragetissues;reducedcholinebioavailabilityleadstolowerlevelsofPCbeingformedandto576NAFLD.
PEMTconvertsphosphatidylethanolamine(PE)intoPC,usingS-‐adenosylmethionineasa577methyldonor,andapolymorphisminPEMThasbeenassociatedwithahigherriskofdeveloping578NAFLD.
Whenthereissufficientcholineinthediet,theKennedypathwayisresponsiblefor579maintainingPCsynthesis,withthePEMTpathwaycontributing~30ofthehepaticPC.
When580cholineisatlowlevelsinthediet,thePEMTpathwayisessentialformaintainingthesupplyofPCin581theliver.
Adaptedfrom[41,57,63**,64**,65**].
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