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PathogenicGutFloraTiedtoHeartFailureSeverity
DeborahBrauser

|December17,2015

BRESCIA,ITALYPatientswithchronicheartfailure(CHF)arelikelytohave"intestinalovergrowth"ofpathogenic
gutfloraandpermeabilitythatisassociatedwithdiseaseseverity,newresearchsuggests[1].
Astudyof80totalparticipantsshowedthattheCHFpatientshad"massivequantities"ofpathogenicbacteriaand
candidavsagroupofhealthycontrols.Specifictypesoftheincreasedpathogensfoundinstoolsamplesincluded
Campylobacter,Shigella,Salmonella,Yersiniaenterocolitica,andCandidaspecies.ThosewithCHFalsohad
significantlyincreasedinflammation,intestinalpermeability,andrightatrialpressure(RAP),whichisasignalofvenous
bloodcongestion.
Inaddition,mostassociationswerestrongerinthosewithmoderatesevereHF(NYHA34)vsthosewithmildHF
(NYHA12).
"OurstudysuggestsgutmicrobiotaneedtobecontinuallyinvestigatedassoonasCHFisdiagnosed,"notethe
investigators,ledbyDrEvasioPasini(SalvatoreMaugeriFoundation,IRCCS,MedicalCenterofLumezzane,Brescia,
Italy).Theyaddthatusingsimple,noninvasive,reproduciblemethodstomeasuregutfloradevelopmentcouldprovide
"importantclinicalinformationtotreatcomplicatedmultiorgansyndromes."
Thestudyreaffirmsearlierresearch"inaverynice,singlepacket,"commentedDrStanleyLHazen(ClevelandClinic,
OH)toheartwirefromMedscape."It'swellknownthatwithheartfailure,youhaveenhancedintraabdominalpressure
andvasculaturethathaspooredemaandintraabdominallymphflow.Asaconsequence,yougetbowelwalledema,
andthere'sabreakdowninthebarrierofthegut,"hesaid.
"Thisconceptofa'leakygut'inheartfailurehasbeenoutthereforquitesometime."Butthisstudynicelyshows,
throughseveraldifferentmeasures,thatimpairmentinintestinalbowelwallfunctionisassociatedwithseverityofHF,
saidHazen,whowasnotinvolvedwiththisresearch.
ThefindingswerepublishedonlineDecember9,2015inJACC:HeartFailure.
ImportanttoReestablishGutMicrobiota
Inthestudy,60"wellnourishedandstable"patientswitheithermild(n=30)ormoderatesevereCHF(n=30)were
evaluatedandthencomparedwithagroupof20healthycontrols.Allhadabodymassindexoflessthan30kg/m2
andparticipatedina12hourovernightfast,afterwhichbloodvariableswereassessed.
"Inallsubjects,wemeasuredthepresenceanddevelopmentinthefecesofbacteriaandfungi(candida),"addedthe
investigators.Acellobiosesugartestofurinewasusedtodocumentintestinalpermeability,andRAPwasmeasured
byECG.
Exclusioncriteriaincludingrenalfailureormetabolicdisordersandtreatmentduringtheprevious3monthswithany
antibioticsorprobiotics.
Interestingly,100%oftheCHFgrouphadincreasedpermeabilityand78.3%ofthemhadalteredgutflora.
ThefullCHFgrouphadsubstantiallygreateramountsofcampylobactervsthehealthycontrolsgroup(85.3vs1.0
colonyformingunits/mL,respectivelyP<0.001).Theyalsohadlargerquantitiesofshigella(38.9vs1.6)andcandida
(21.3vs0.8bothcomparisons,P<0.001),aswellasofsalmonella(31.3vs0)andYersiniaE(22.9vs0both
comparisons,P<0.0001).

Inaddition,theCHFgrouphadincreasedRAP(12.6mmHg)andsystemicinflammation,asmeasuredwithCreactive
protein(12.5mg/dL),andgreaterintestinalpermeabilityvsthehealthycontrols(10.2vs1.5mg,P<0.001).
ThesubgroupofmoderatesevereCHFpatientshadsignificantlygreaterdevelopmentratesofcandida,campylobacter,
andshigellacomparedwiththesubgroupwithmildCHF.Theyalsohadgreaterintestinalpermeability.
"FurtherstudiesareneededtoconfirmthelinkbetweengutpathogenicbacteriaandCHFseverity,"writethe
investigators,"Ifconfirmed,thislinkcouldsuggestadditionalpersonalizedtherapeuticstrategies...insupportof
traditionaldrugs,"theywrite.
However,theynotethattherearecurrently"noclinicalgutfloramodifiersavailable,"andusingprobioticscouldbe
potentiallydangerous."Atpresent,reestablishingthegutmicrobiotamaybetheonlyoptionforpatientstoreverse
intestinaldysbiosis,"theywrite.
Consequence,NotCauseofHF?
Thestudy'smaintakehomemessage,accordingtoHazen,isareemphasisoftheconnectionbetweencardiacfunction
andbowelwalledema,"andthebreakdownofthebarrierfunctionoftheintestines"inHF.Inaddition,"Ithinkalotof
whatwasshowninthepaperwasaconsequenceoftheheartfailureandnotacauseoftheheartfailure."
HazenandothercolleaguesfromClevelandClinichavewrittenbeforeabouttheseissuesandcontinuetostudythe
associations.AnewpreclinicalstudypublishedinCellearliertoday,forwhichHazenwastheprincipalinvestigator,
showedthattargetingandinhibitinggutmicrobesmaypreventthedevelopmentofatherosclerosis[2]
Forthecurrentstudy,Hazensaidthefindingsgive"anotherfingerprintshowingthatthere'sanabnormalenvironment
goingoninthegutofsubjectswithheartfailureandisdosedependent,dependingontheseverityoftheheartfailure."

PreclinicalFindings:NaturalGutMicrobeInhibitorMayPreventAtherosclerosisDevelopment
Findingsfromanewpreclinicalstudysuggestthatthegutmicrobedependentmetabolite
trimethylamine(TMA),thefirststepintheproductionoftrimethylamineNoxide(TMAO),whichhas
beenlinkedtoatherosclerosisinanimalstudiesandwithCVrisksinclinicalstudies,canbetargeted
andeveninhibited[2].
Thecholineanalog3.3dimethyl1butanol(DMB),whichisfoundnaturallyingrapeseedandsome
extravirginoliveoils,nonlethallyinhibitedTMAformationandreducedthedevelopmentof
atheroscleroticlesionsinmicewhowerefedahighcholinediet.
Thefindings"mayserveasapotentiallytherapeuticapproachforthetreatmentofcardiometabolic
diseases,"writetheinvestigators,ledbyDrZenengWang(ClevelandClinic).
Hazenaddedtoheartwirethatifthesepreliminaryfindingscanbereplicatedinfurtherstudies,itcould
potentiallyleadtoatreatmentthattargetsthisveryspecificmicrobialpathway,whilelettingpatients
avoidtheoveruseofantibiotics.
"Ourstudyshowedthatdietinducedacceleratedatherosclerosiscanbeblockedbygivingthisdrugin
animalmodels.Andwewentwiththisdrugbecauseit'sanaturalproductthatmightbelinkedtothe
Mediterraneandiet,"saidHazen.
"It'slike'drugging'themicrobewithoutkillingitasameansofhavingabeneficialeffectinthehost."
DB

Pasiniandthestudyauthorsreportnorelevantfinancialrelationships.WangandHazenreportbeingnamedasa
coinventorsonpatentsheldbytheClevelandClinic.HazenreportsbeingpaidasaconsultantforEsperionandProcter
&GamblereceivingresearchfundsorsupportfromAstraZeneca,Pfizer,Procter&Gamble,Roche,andTakedaand
"havingtherighttoreceiveroyaltypaymentsforinventionsordiscoveriesrelatedtocardiovasculardiagnosticsand/or
therapeutics"fromtheClevelandHeartLaboratory,Siemens,Esperion,andFrantzBiomarkers.Disclosuresforthe
coauthorsarelistedinthearticle.
References

1. PasiniE,AquilaniR,TestaC,etal.Pathogenicgutflorainpatientswithchronicheartfailure.JACC:Heart
Fail.2015DOI:10.1016/j.jchf.2015.10.009.Article
2. WangZ,RobertsAB,BuffaJA,etal.Nonlethalinhibitionofgutmicrobialtrimethylamineproductionforthe
treatmentofatherosclerosis.Cell2015DOI:10.1016/j.cell.2015.11.055.Article
HeartwirefromMedscape2015Medscape,LLC
Citethisarticle:PathogenicGutFloraTiedtoHeartFailureSeverity.Medscape.Dec17,2015.

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