Does the change on gastrointestinal tract microbiome affects host?

b r a z j i n f e c t d i s . 2014;18(6):660–663

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Review

article

Does

the

change

on

gastrointestinal

tract

microbiome

affects

host?

Elisa

M.

Beirão

,

Ana

Carolina

B.

Padovan

,

Juvêncio

J.D.

Furtado

,

Arnaldo

L.

Colombo

_,

_Eduardo

_A.S.

_Medeiros

a_{DepartmentofInfectiology,HospitalHeliópolis,SãoPaulo,SP,Brazil}

b_{MicologySpecialLaboratory,DisciplinadeInfectologia,UniversidadeFederaldeSãoPaulo,SãoPaulo,SP,Brazil}

c_{ServiceofHospitalInfectionControl,DisciplinadeInfectologia,UniversidadeFederaldeSãoPaulo,SãoPaulo,SP,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received6February2014

Accepted21April2014

Availableonline15May2014

Keywords:

Gastrintestinalmicrobiome

Human

a

b

s

t

r

a

c

t

Duringthepastdecade,studiesonthecompositionofhumanmicrobiotaanditsrelation

tothehostbecameoneofthemostexploredsubjectsofthemedicalliterature.The

devel-opmentofhigh-throughputmoleculartechnologiesallowedadeepercharacterizationof

humanmicrobiotaandabetterunderstandingofitsrelationshipwithhealthanddisease.

Changesinhumanhabitsincludingwideuseofantimicrobialscanresultindysregulationof

host–microbiomehomeostasis,withmultipleconsequences.Thepurposeofthisreviewis

tohighlightthemostimportantevidenceintheliteratureofhost–microbiomeinteractions

andillustratehowtheseintriguingrelationsmayleadtonewtreatmentandprevention

strategies.

©2014ElsevierEditoraLtda.Allrightsreserved.

Introduction

Thetermmicrobiotareferstoanabundantanddiverse

pop-ulationof microorganismssuch asbacteria and fungithat

resideonbodysites,withthehighestconcentrationofthese

organismsfoundinthegastrointestinaltract.Indeed,humans

harbor acomplex community ofmicroorganismsthat

out-numbershumancellsbytenfold.1

Standard culturetechniquesare limited tofully

charac-terizemicroorganismswithinthemicrobiota,butnowadays,

modern molecular techniques termed metagenomics are

available to allow deep characterization of the microbiota

ofthenasalmucosa,oropharynx,skin,urogenitalsites,and

∗ _{Correspondingauthorat:HospitalHeliópolis,RuaCônegoXavier,276–7}◦_{andar,CEP04231-030SãoPaulo,SP,Brazil.}

E-mailaddress:elisa.m.beirao@gmail.com(E.M.Beirão).

lowerintestine.Thesemethodsrelyonpolymerasechain

reac-tionamplificationof16SribosomalRNA-encodinggenesofthe

microbiota,followedbyDNAsequencing.2

Projects such as the Human Microbiome Project3 _have

already done much to define the variability in the

micro-biotafromdifferentbodysitesandinthemicrobiomesboth

withinthesamehumansubjectandamongdifferentsubjects.

By applyingmetagenomics,itisestimatedthatthehuman

lowerintestinalmicrobiotacontainsatleast1800generaand

15,000–36,000species,mostofwhichhaveneverbeen

success-fullyculturedandthemajorityofthemareclassifiedwithin

FirmicutesandBacteroidetesphyla.4

The humanintestinalmicrobiota matures over the first

year of life and has substantial and continuous effects

http://dx.doi.org/10.1016/j.bjid.2014.04.002

brazj infect dis.2014;18(6):660–663

661

Table1–Reviewsaddressingdiseasesandbiologycalphenomenarelatedtohumanmicrobiome.

Topics Effectofmicrobiota Ref.

Inflammatorybowel diseases

Inindividualswithageneticsusceptibilitytoinflammatoryboweldiseases,abnormalmicrobial colonizationofthegastrointestinaltractmightbetheoriginofsuchdysregulation.

8

Diabetesandobesity Studiesshowtheeffectofgutmicrobiotaonhostmetabolismbyimprovingenergyyieldfrom foodandmodulatingdietaryorthehost-derivedcompoundsthatalterhostmetabolicpathways.

9

Neuropsychiatricillness Recentadvancesinourunderstandingofhowtheintestinalmicrobiotacommunicateswiththe brainviathisaxistoinfluencebraindevelopmentandbehavior.Thisextendedcommunication systemmightinfluenceabroadspectrumofdiseases,includingirritablebowelsyndrome, psychiatricdisorders,anddemyelinatingconditionssuchasmultiplesclerosis.

10

Colorectalcancer Potentialmechanismsofbacterialoncogenesisarepresented,focusisgiventotheoncogenic capabilitiesofenterotoxigenicBacteroidesfragilis

11

Asthma Host’sinnatesensingsystems,combinedwithrecentlydevelopedmethodsthatcharacterize

commensalandpathogenicmicrobialexposure,nowallowaunifiedtheoryforhowmicrobes causemucosalinflammationinasthma.

12

Rheumaticdiseases Microbiotamaybeinvolvedinthepathogenesisofrheumaticdiseasesincludingalteredepithelial andmucosalpermeability,lossofimmunetolerancetocomponentsoftheindigenousmicrobiota, andtraffickingofbothactivatedimmunecellsandantigenicmaterialtothejoints.

13

Antibioticresistance Horizontalgenetransferinguthasthepotentialtoinfluencetheevolutionofmembersofthis microbialcommunityandtomediatethespreadofantibioticresistancegenesfromcommensal organismstopotentialpathogens.

14

onhumanhealthandphysiologicaldevelopment,including

dietaryandnutritionalprocessing,5 _{preventionofpathogen}

invasion,6_{andimmunesystemmaturation(Table1).}7

Changing

in

microbiota

Human behavior influencesthe composition of microbiota

anditscontinuouschangesmayberesponsibleforthe

modi-ficationoftheancientmicrobiota.Someauthorsbelievethat

diseasessucceedandfailinresponsetomankind’sadvances.

Theappearanceanddisappearanceofinfectiousandchronic

diseasesmightberelatedtochangesinhumanecology,

result-inginchangesinthemicrobesthatpopulateourbodies.15

Humancivilizations experiencedmany transformations,

as improvement in sanitization that was implemented to

reducetransmissionofinfections.In orderto providefood

foranincreasingpopulation, food productionincorporated

newstrategies,suchasextensiveuseofpesticides,antibiotics,

andhormonesinanimalsandagriculture.15,16 _The

increas-ingantibioticuseinhumansandfarmingisoneofthemost

importantfactthatleadstoarapidandsometimesirreversible

changeonhumanmicrobiota.17

Helicobacterpyloriisanexampleofanancienthuman

micro-biotamemberthatpresentedadramaticchange.H.pylorihas

beenextensivelyinvestigatedbyDr.Blaseretal.whoobserved

thatthisbacteriumwasprogressivelydisappearingduringthe

twentiethcentury,from individualsindevelopedcountries,

withsecondaryalterationsingastricsecretory,hormonaland

immunephysiology.18

Thisbacteriumisthoughttoberelatedtopepticulcerand

gastriccancerbutthesustainedacidityinH.pylori-negative

hostsincreases the riskofgastroesophageal reflux disease

anditsconsequences,includingesophagealandgastriccardia

adenocarcinomas.19

Thestomachalsoproducesadipokinehormonesknownas

ghrelinandleptin,bothwithmultiplerolesinenergy

homeo-stasis.PatientsunderantibiotictreatmentthateliminatedH.

pylori had increased circulating ghrelin levels.20 _{There is a}

hypothesisthatinrecentgenerationsofchildrengrowingup

indevelopedcountries,therehasbeenlittlegastricH.pylori

-mediatedregulationofthoseadipokinesatthedevelopmental

stage,whenlong-termadiposityisbeingprogrammed. Itis

possible that the disappearance of H. pylori might be

con-tributing tothecurrentepidemicsofearly-lifeobesity,type

2diabetesandrelatedmetabolicsyndromes.

Gordon et al. were also interested instudying the

rela-tionship between obesity and microbiome. They analyzed

fecal samples of lean and obese twins and observed that

obesity was associated with phylum-level changes in the

microbiota,reducedbacterialdiversityandaltered

represen-tationofbacterialgenes,andmetabolicpathwaysrelatedto

glycosidehydrolases.21_{Cardiovascularriskalsohasinfluence}

on intestinal microbial metabolism,as shown byHazen et

al.,whoobservedanincreaseinaproatherosclerotic

metabo-lite,trimethylamine-N-oxide(TMAO),inhealthyparticipants

afterthesuppressionofintestinalmicrobiotawithoral

broad-spectrumantibiotics.22

Stimulation of the immune system is another

impor-tant function of the microbiome where the disruption of

immune homeostasis may be associated with

inflamma-toryandatopicdiseases.23_{Epidemiologicalstudiesshowthat}

H. pylori-positive individuals have lower risk of childhood

asthma,allergicrhinitisandskinallergiesthanthose

with-outH.pylori.24H.pylori-positivestomachhasarichpopulation

ofimmunecells whichregulatesimmunefunctions.

Stom-achsofH.pylori-negativehostshavemuchlowernumberof

thesecells,whichhavesystemic,aswellaslocalactivities.25

Theincreaseinprevalenceofimmunologicaldisorders(both

ofautoimmuneandofatopicorigin)inthedevelopedworld

hasbeenassociatedwithchangesinmicrobiome,whichgave

supporttothehygienehypothesis.26

Microbiome

and

infectious

diseases

Therelationshipbetweenthemicrobiomeandinfectious

662

regardingtheeffectofantibiotictherapy,asantibiotic

treat-ment to prevent or eradicate a pathogenic infection also

impactsthecompositionofthecommensalmicrobiota.

Combined antibiotic therapy with clarithromycin and

metronidazolereducedbacterialdiversityofhealthysubjects

inshortandlong terms.27 _{Adeclinetrendwasobservedin}

Actinobacteria in both throat and feces immediately after

treatment.Themicrobiotaremainedperturbedinsomecases

foruptofouryearsposttreatment.27_{Theeffectoftwocourses}

ofciprofloxacintherapywasanalyzedbyanotherstudy.A

pro-foundand rapid shiftincommunity composition occurred

withinthreeto four daysof druginitiation, withaloss of

bacterialdiversity. Oneweekafter the endof each course,

communitiesreturnedincompletelytotheirinitialstate.28

Theconsequencesofantibiotictherapymightbedifficultto

understandasthemicroorganismsthatareaffectedmaynot

bethosethataredirectlytargetedbytheantibiotic.A

com-plexnetworkofco-dependenceexistsamongmembersofthe

microbiota,drivenbydifferentways.Oneintriguing

interac-tionwasdescribedbyHoganetal.29_{thatdescribedaquorum}

sensingmolecule(3-oxo-C12homoserinelactone),produced

byPseudomonasaeruginosa,thatinhibitsCandidaalbicans

fila-mentationanditsvirulenceinvitro.

The microbiota has also protective functions. A mouse

modelforS.typhimuriumdiarrheawasusedtostudytherole

ofmicrobiotaandsecretoryantibodies(sIgA).Whenexposed

oinfection,micethatharboralowcomplexitygutflora,lack

S.typhimuriumcolonizationresistanceanddevelopanormal

sIgAresponse,butfailtoclearitfromthegutlumen.Inthese

mice,pathogenclearancewasachievedbytransferringa

nor-malcomplexmicrobiota.Thisstudywasabletodeterminate

thecapacityofmicrobiotatoconfercolonizationresistance

and to mediate pathogen clearance in primary infections,

despitesIgA.30

Clostridiumdifficile-associateddiarrhea(CDAD)ispossibly

oneofthemostimportantexamplesinvivoonhow

antibi-oticsaffecttheresidentmicrobialecosystempatienthealth.

Endogenousmicrobialinhabitantsprovidecolonization

resis-tancetoinfectionbyothermicrobes,mostnotablyC.difficile.

UntilnowthetherapeuticoptionforCDADrelieson

antibi-otictreatmentwithvancomycin or metronidazole,but this

approachwasassociatedwithdepletionofhostmicrobiota

andrecurrenceofsymptomsin35%ofpatients.31

Transplan-tationofindigenousmicrobiotawastestedasanalternative

treatmenttorestorethemicrobiotaofapatientwithCDAD.

Not surprising, the intestinal microbiota transplantation

approachresultedinresolutionrateof94%,statistically

supe-riortovancomycin-containingregimens(p<0.01).32

Use of probiotic is an intervention that seeks the

restorationofthebeneficialmicrobiota.Strategiesarebeing

implemented following antibiotic therapy in infants with

necrotizing enterocolitis (NEC),33 _{as well as in individuals}

beingtreatedforantibioticassociateddiarrhea,34_and

bacte-rialvaginosis.35

Understanding the importance of microbiome is also

critical given the huge number ofmicroorganisms in this

ecosystem, and the possibility of gene transfer between

species. Transfer of resistance genes may occur through

horizontal gene transfer (HGT) from commensal bacteria

toopportunisticpathogens, aspreviouslydescribed CTX-M

extended-spectrum beta-lactamase(ESBL)resistancegenes,

whichoriginatefromKluyverasp.36_{Usingfunctional}

metage-nomic methods, Sommer et al.37 _{studied individuals after}

antibiotictreatmentandfoundclonesconferringresistanceto

13differentantibioticsandenabledthediscoveryof95unique

insertscontainingfunctionalantibioticresistancegenes.The

majority of these genes were evolutionarily distant from

knownresistancegenes,including10previouslyunidentified

beta-lactamasegenefamilies.

Because of the harmful effects of antibiotics on the

commensal microbiota, alternative therapies are under

investigation,as antimicrobialpeptidesthat havepotential

antibioticadjunctiveaction.Forinstance,areduced

produc-tion ofthe antimicrobialpeptide REG3␥was related to an

increasedcolonizationbyvancomycin-resistantEnterococcus

(VRE)inmice.Thiswasaconsequenceofdepletedmicrobial

signals38_{inactivatingToll-LikeReceptors(TLR).This}

mecha-nismseemstobeinvolvedinbacterial-mediatedprotection

from diseases,including VRE,suggestingthatTLR agonists

couldbeadministeredduringantibiotictherapytohelprestore

immunehomeostasis,specificallyREG3␥expression,

drasti-callyreducingcolonizationbyVRE.39

Thechallengeofefficientcontrolstrategiesformultidrug

resistant organisms(MDROs) brought the attention for the

hypothesis that restoring and maintaining the commensal

microbiomemaybeakeytopreventMDROcolonizationand

infection.40_{Conversely,acomprehensiveantimicrobial}

stew-ardshipprogramfocusingthepreventionofMDROemergence

isneeded.Inanattempttoidentifyantibioticsthatpromote

KPCcolonization,Perezetal.41_{evaluatedwhetherantibiotics}

promotecolonizationbyKPC-producingKlebsiellapneumonia

(KPC-Kp).Theyfoundthatthoseantibioticsthatfullysuppress

anaerobesandbacteroides (i.e.tigecycline,clindamycinand

piperacillin-tazobactam)promotedsignificantcolonizationby

KPC-Kp,whereasagentsthatdidnotsuppresstotalanaerobes

orbacteroides(i.e.,ertapenem,ciprofloxacinandcefepime)did

not.41

Withanincreasingnumberofstudiesdemonstratingthat

antibioticshavedetrimentaleffectsonthehosthealthandon

hostcolonizationthereisurgentneedtodeveloptreatments

targeting specific pathogens without changing the

indige-nousmicrobiota.Forthis,abetterunderstandingonmicrobial

cross-talkingisessential.Mostofthestudiesarestill

experi-mentalandremaintobevalidated,buttheyholdsubstantial

promise as adjuncttherapies to antibioticsin apromising

future.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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