1 Amino acid metabolism in intestinal bacteria and its potential implications for mammalian ...

55 Pages·2015·0.45 MB·English

MolecularHumanReproduction,Vol.21,No.5pp.389–409,2015
AdvancedAccesspublicationonJanuary20,2015 doi:10.1093/molehr/gav003
REVIEW
Amino acid metabolism in intestinal
bacteria and its potential implications
for mammalian reproduction
Zhaolai Dai1, Zhenlong Wu1,*, SuqinHang2, Weiyun Zhu2, D
o
w
and Guoyao Wu1,3 n
lo
a
1StateKeyLaboratoryofAnimalNutrition,ChinaAgriculturalUniversity,Beijing100193,China2CollegeofAnimalScienceandTechnology, de
NanjingAgriculturalUniversity,Nanjing210095,China3DepartmentofAnimalScience,TexasA&MUniversity,CollegeStation,TX77843,USA d fro
m
*Correspondenceaddress.E-mail:[email protected] h
SubmittedonSeptember28,2014;resubmittedonDecember27,2014;acceptedonJanuary15,2015 ttps
://a
c
abstract:Reproductionisvitalforproducingoffspringandpreservinggeneticresources.However,incidencesofmanyreproductivedis- ad
e
orders(e.g.miscarriage,intrauterinegrowthrestriction,prematuredeliveryandlowerspermquality)haveeitherincreaseddramaticallyor m
ic
remainedathighratesoverthelastdecades.Mountingevidenceshowsastrongcorrelationbetweenenteralproteinnutritionandreproduction. .o
u
Besidesservingasmajornutrientsinthediet,aminoacids(AA)aresignalingmoleculesintheregulationofdiversephysiologicalprocesses,ranging p.c
fromspermatogenesistooocytefertilizationandtoembryoimplantation.Notably,thenumbersofbacteriaintheintestineexceedthenumbersof om
hostcellsby10times.Microbesinthesmall-intestinallumenactivelymetabolizelargeamountsofdietaryAAand,therefore,affecttheentryofAA /m
o
intotheportalcirculationforwhole-bodyutilization.ChangesinthecompositionandabundanceofAA-metabolizingbacteriainthegutduring le
h
pregnancy,aswellastheirtranslocationtotheuterus,mayalteruterinefunctionandepigeneticmodificationsofmaternalphysiologyandme- r/a
tabolism,whicharecrucialforpregnancyrecognitionandfetaldevelopment.Thus,thepresenceofthematernalgutmicrobiotaandAAmeta- rtic
le
bolitesintheintrauterineenvironments(e.g.endometriumandplacenta)andbreastmilkislikelyauniquesignaturefortheprogrammingofthe -a
b
whole-bodymicrobiomeandmetabolisminboththefetusandinfant.DietaryinterventionwithfunctionalAA,probioticsandprebioticstoalter stra
theabundanceandactivityofintestinalbacteriamayameliorateorpreventthedevelopmentofmetabolicsyndrome,whileimprovingreproduct- c
t/2
iveperformanceinbothmalesandfemalesaswellastheiroffspring. 1
/5
/3
Keywords:aminoacids/bacteria/intestine/metabolism/reproduction 8
9
/1
0
8
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Introduction varieties of proteins, hormones, and secretions (Wu et al., 2012a; 0 b
y
Linetal.,2014).Thus,itisessentialtoelucidatetheroleofnutrients g
u
Reproductionisafundamentalandimportantbiologicalprocessforpro- andotherdietaryfactorsinreproductionofbothsexesinhumansand e
s
ducingoffspringandpreservinggeneticresources.Sexualreproductionin other animals (Wu et al., 2004; Cross and Mickelson, 2006; Gaskins t o
n
mammals(includinghumansandlivestockspecies)iscomplexandhighly etal.,2012;Bazer,2013;Mora-EstevesandShin,2013). 1
0
organized.Thisphysiologicaleventinvolvesthegenerationofmaturere- Asmajormacronutrientsindiets,AAarenotonlythebuildingblocks A
p
productive cells (sperm and oocyte) and associated fluids/secretions ofproteinsandpeptidesbutalsoareessentialforthesynthesisofmany ril 2
(e.g. seminal plasma and uterine secretions) in the reproductive bioactive molecules that participate in the regulation of signaling 01
9
system of both males and females, the transport of sperm to the pathways and metabolism in the body (Sato et al., 2006; Wu, 2013;
femalereproductivetract,thefertilizationoftheoocyte,thedevelop- Wuetal.,2014).CompellingevidenceindicatesthatAAplayacrucial
ment of the zygote, pregnancy recognition, implantation of the role in both female and male reproduction (Bazer, 2013; Wu et al.
embryo,themaintenanceofpregnancy,conceptusdevelopment,par- 2013a).Studieswithhumansandanimalsoverthelastdecadesshowed
turitionandlactation,aswellasgrowthanddevelopmentofneonates thatcertainAAareabundantinseminalplasma(e.g.serine,threonine,
(OwenandKatz,2005;Bazer,2013).Tosuccessfullycompletethese glycine, glutamate, arginine and tyrosine), uterine secretions (e.g.
biologicalprocesses,manyessentialnutrients,includingwater,carbohy- arginine, leucine, proline and glutamine), allantoic fluid (e.g. glutamine,
drates,aminoacids(AA),lipids,minerals,andvitamins,arerequiredfor alanine,serine,glycine,arginine,ornithineandcitrulline),andmilk(e.g.as-
theformationandmaturationofreproductivecellsandthesynthesisof partate,glutamate,glutamine,leucine,prolineandtaurine),indicatingtheir
&TheAuthor2015.PublishedbyOxfordUniversityPressonbehalfoftheEuropeanSocietyofHumanReproductionandEmbryology.Allrightsreserved.
ForPermissions,pleaseemail:[email protected]
390 Daietal.
importantbiologicalfunctionsinfertility,embryonicandfetalsurvival,as AA metabolism and nitrogen
well as offspring growth and development (Brown-Woodman and
recycling in the gut pertinent to
White,1974; Fro¨hlichetal.,1980;WuandKnabe,1994; Davisetal.,
1994a;Wu,2009;Wangetal.,2012).Ofparticularinterest,dietarysup- reproduction
plementationwithspecificAA(e.g.arginine,glutamine,leucine,glycineand
Asthemajorsourceofnitrogeninthegut,dietaryproteinisdigestedand
methionine)hasbeneficialeffectsinimprovingreproductiveperformance
itsproducts(freeAA,dipeptidesandtripeptides)areabsorbedintothe
(e.g. embryonic/fetal survival and growth) in both humans and other
portalcirculationforthesynthesisofproteins,enzymes,hormonesand
animalsthroughtheregulationofkeysignalingandmetabolicpathways
metabolitesinthebody(Winckleretal.,1999;BergenandWu,2009).
(Wangetal.,2012;DelCurtoetal.,2013;Wu,2013).However,more
However, at the same time, relatively large amounts of proteins and
workiswarrantedtouncovertheimportantfunctionsofAAinreproduc-
AAundergoextensivemetabolismintheintestinebyeitherintestinalepi-
tionandtheunderlyingmechanisms,especiallyinhumansandlivestock
thelialcellsorthegutbacteria(Stolletal.,1998;Wu,1998).Theutiliza-
species(Bazer,2013;Wu,2013).
D
Results of extensive studies over the last decades have revealed tionandmetabolismofAAintheintestineincludes:(i)catabolismofAA o
w
thatbacteriainthegutplayanimportantroleinthemetabolismandre- forATPproductioninsmall-intestinalmucosalcells(e.g.aspartate,glu- nlo
cyclingofnitrogenouscompounds,includingAA(FullerandReeds,1998; tamateandglutamine);(ii)synthesisofimportantmoleculesformaintain- ad
e
B20e1rg2e)n. Tanhde Wguut,b2a0c0te9r;iaDaoiregtraolu.,p2s0o1f1;bMacatcefraiarla(nmeicarnodbiMotaac)faerliathneer, icnitgrnuollirnme,aplrnoultinrieti,oNnOan,dpoplhyyasmioinloegsyaonfdthneeuinrotetsrtainnsemanitdtewrsh);o(lieii)bsoydnyth(ees.gis. d from
uthtieliizresythnetheAsAisdoefrpivreodtefirnosmorfofoudrthoerrtmheethaobostlizaes tbhueilsdeinngubtrloiecnktss fvoiar oanfdimfupnocrttiaonnt(per.ogt.eminuscainnsd,ipmemptuidneosgfloorbumlianisn,tdaienfienngsninosrmanadlgguluttsattrhuioctnuer)e; https
conversion or fermentation to produce varieties of metabolites (iv)synthesisofproteinsandpeptidesforthegrowthandcell–cellinter- ://ac
a
(ammonia,hydrogensulfide(H S),nitricoxide(NO),polyamines,phen- actionsofgutbacteria(e.g.peptidoglycan,Slayerproteins,chemotactic d
2 e
olicandindoliccompounds)inboththesmallandlargeintestine(Dai peptides,acylhomoserinelactones);(v)fermentationofproteinsandca- mic
etal.,2011;MacfarlaneandMacfarlane,2012).Furthermore,intestinal tabolismofAAforenergyprovisioninbacteriaespeciallyinthelargein- .o
u
p
bacteria can de novo synthesize some of the nutritionally essential testine[productslikeshortchainfattyacids(SCFA),branched-chainfatty .c
o
amino acids (EAA), which may contribute to the regulation of AA acids(BCFA),phenolicandindoliccompounds,andH2S];and(vi)trans- m/m
homeostasisinthebody(Metges,2000).Thesefindingsindicatetheim- formation of AA to produce AA metabolites [e.g. biogenic amines, o
portanceofAAmetabolisminthegutmicrobiotaonthenutritionand gamma-aminobutyric acid (GABA),dopamine,serotonin(5-HT), and leh
pethayls.i,o2lo0g1y2;oMf athcefarhlaonset a(BnldacMhiaecrfaertlaanle.,,22000172;).Dai et al., 2011; Collins LNeOD]ucin, b1a9c8t8e;riSamfoitrhthaendadMapatcafatirolannteo, 1h9ar9s7h;gHuetrcnoa´nnddietizonest(aNl.,as2t0a0n5d; r/article
Resultsofextensivestudiesindicatethatthecompositionofthegut Konstantinov et al., 2008; Vermeiren et al., 2009, 2012; Wu, 2009, -ab
s
microbiotainmammalschangesdramaticallyduringthecourseofpreg- 2010;Blachieretal.,2010;Daietal.,2011,2012a;CryanandDinan, tra
c
nancyand is in parallel with the alteration of whole-body metabolic 2012;MacfarlaneandMacfarlane,2012;Davilaetal.,2013). t/2
status (Collado et al., 2008; Santacruz et al., 2010; Koren et al., ThemetabolictransformationofAAandtheirnitrogenousmetabo- 1/5
2012).Forexample,theabundanceofpotentialAA-metabolizinggut litesinmucosalepithelialcellsandmicrobesinthesmallandlargeintes- /38
9
bacteria (e.g. the Enterobacteriaceae family of bacteria, Streptococcus tinesconstitutesextensivenitrogenrecyclinginthegut,whichplaysan /1
0
genus bacteria) increases during the late stage of gestation (Koren importantroleinaffectingtheefficiencyofAAutilizationinthebody 8
6
8
etal.,2012).Inaddition,thesebacteriawerefoundtobeabundantin (FullerandReeds,1998;BergenandWu,2009;Fuller,2012).Thesecre- 1
0
overweightcomparedwithnormal-weightpregnantwomen(Collado tionofnitrogenintheformofdigestiveenzymes,mucins,immunoglobu- b
y
etal.,2008;Santacruzetal.,2010).Furthermore,dietarysupplementa- linsandureatothelumenofthesmallintestinecanbefurtherdegraded, gu
e
tionwitharginine,whichinducesashiftintheFirmicutes:Bacteroidetes utilizedandmetabolizedbythegutbacteria.ThedenovosynthesisofAA, s
t o
ratiotofavorBacteroidetesinthejejunumandileum(Renetal.,2014a), especiallylysine,bygutbacteriatakesplaceinboththesmallandlarge n
1
enhancesembryonicsurvivalinmammals,includingmice(Renetal., intestine (Metges, 2000; Metges et al., 2006). The major nitrogen 0
A
2012) and pigs (Mateo et al., 2007; Li et al., 2014). Although many sourceforthebacterialsynthesisoflysineisammonia,whichisderived p
factors affect the gut microbiotacomposition during gestation, such fromthebacterialcatabolismofAAorureaintheintestine(Metges, ril 2
0
as diet and hormones, the above findings suggest an important role 2000). In pigs, the absorption of bacterial lysine occurs mainly in the 19
fortheAA-metabolizingbacteriainfemalereproduction.Theunder- smallintestine(Torrallardonaetal.,2003a,b).Thisisofnutritionaladvan-
lyingmechanismsareunknownbutmayinclude:(i)regulationofthedi- tage,aslysineisoneoftheEAAforallanimalsandtheprovisionofan
gestion and absorption of protein and AA in the small intestine; (ii) extraamount of lysine by the gut microbiotato the host can reduce
availabilityofdietaryAAforusebyreproductiveorgans;(iii)strategic dietaryrequirementoflysine.However,todate,thenutritionalimport-
changesinthecompositionandabundanceofthemicrobiotaduring anceofthebacterialdenovosynthesisofAAtothehostisstilluncertain
pregnancy;(iv)alterationsinuterinecapacityandfunctionaswellas duetothelackofquantitativedata(Metgesetal.,2006;Fuller,2012).
thebodymetabolicstatus;(v)programmingofmetabolicchangesin ThereisgrowinginterestintheutilizationandmetabolismofAAby
thegutmicrobiotaofthemotherandheroffspring;and(vi)changes bacteriainthesmallintestineaswellasthesignificanceofthesebiochem-
intheproductionofreproduction-relatedAAmetabolites(e.g.NO, icalreactionsforhostnutrition(Booijink,2009;Miner-Williamsetal.,
polyaminesandglutathione)directlyorindirectlylinkedtoreproduct- 2009;Daietal.,2010,2012a).Transcriptomicanalysisofgeneexpres-
ivephysiologyofthehost.Detailsoftheseaspectsarediscussedinthe sioninbacteriafromtheilealeffluentsamplesofhumansshowedthat
followingsections. mRNA levels for the genes related to AA utilization and metabolism
Gutbacterialaminoacidmetabolismandreproduction 391
comprise(cid:2)20%ofthetotalmetabolism-relatedgenes(Booijink,2009). identifyrelationshipsbetweenvariationinthebacterialcommunityand
Usingthepigastheanimalmodel,Miner-Williamsetal.(2009)reported AAmetabolisminthisorgan.
thatbacterialproteinwasthemajorcomponentofthedigestaprotein
fromtheileum,evenwhenthepigswerefedahighlydigestablecasein-
Possible links between
baseddiet.Also,bacteriainthepigsmallintestineutilizelargeamounts
ofAA,includingEAA,andsomeoftheAAwereutilizedextensivelyby AA-metabolizing bacteria
catabolicpathways(Daietal.,2010,2012a).Whilesmall-intestinalenter-
and pregnancy
ocyteswereabletometabolizebranched-chainAA(BCAA)(Val,Leu
andIle)butnototherEAA(Chenetal.,2007,2009),smallintestinal
Manybiologicalprocessestakeplaceduringpregnancy,suchasthedevel-
microbes exerted extensive metabolism of EAA, including BCAA
opment of an embryo to a blastocyst, peri-implantation signaling
(Yangetal.,2014).Thesefindingsindicatethatthesmall-intestinalbac-
betweentheblastocystandtheuterineepithelium,developmentand
teriaplayanimportantroleinregulatingtheAApool (totalamount)
morphologicalchangesofthetrophectoderm,aswellasinitiationofim- D
andprofile(compositionofeachAA)duringtheprocessofthedigestion o
plantation andplacentation(Bazeret al.,2009).Histotroph,including w
andabsorptionofAAbythesmallintestine.This‘modification’notonly AA,isessentialformaintainingnormalpregnancyinmammals(Cross nlo
a
affectstheefficiencyofAAsupplementationtoreproductiveorgansfor andMickelson,2006;Bazeretal.,2012a).Thecompositionandactivity de
protein synthesis and cell growth, but also regulates reproduction- ofthegutmicrobiotachangedramaticallywithgestationalstages(Koren d fro
relatedsignalingpathwaysdirectlyorindirectlythroughproductionof etal.,2012).This,inturn,hasamajorimpactontheprogressofpreg- m
theirmetabolites(CrossandMickelson,2006;Bazer,2013;Wuetal., nancy,especiallyduringcriticalwindowsofembryonicsurvival,growth http
2013a). However, further studies are warranted to investigate the s
detailedmodeofaction. anddevelopment(CrossandMickelson,2006;Wuetal.,2013a). ://ac
a
d
Fluctuationsofthegutmicrobiotaduring e
m
Diversity of AA-metabolizing pregnancy ic.o
u
p
bacteria in the gut Recent studies with women indicate that the composition of the gut .c
o
microbiotashiftswithdifferentstagesofpregnancyandisaffectedby m
/m
Recentstudieswiththehumancolonicbacteriahaveshownthatprotein- the maternal body weight (Koren et al., 2012). For example, during o
le
andAA-fermentingbacteriaareabundantanddiverseinthecolon.The latepregnancyinwomen(thirdtrimester,33.7weeks),theabundance h
ahbiguhnadnadncteheoirftnhuemAbAer-fcearnmreenatcinhgubpactote1ri0a1i1nptehreglraarmgedinrytefsetcineesi(sSmveitrhy othfeguEtnbtearcotbearicatebreialocenageinfgatmoilPyraontedoSbtarecptetoricaoaccnudsAgectninuos,biancctreeraias,eessupbesctiaanlly- r/article
andMacfarlane,1998).Usingthetraditionalplatecountingtechnique, tially(Korenetal.,2012).Incontrast,butyrate-producingbacteria(e.g. -ab
s
theauthorshavealsoreportedthatthedominantbacterialspeciesfor FaecalibacteriumandEubacterium)dominateinthefirsttrimester(13.8 tra
c
theutilizationofsingleAAorpairsofAAareverydifferent.Forinstance, weeks) and decrease in the third trimester (Koren et al., 2012). At t/2
Clostridiumbifermentansisthepredominantbacteriafortheutilizationof earlylactation/post-partum,thecontentofStreptococcustendstode- 1/5
lysineorproline,andpairsofAA(e.g.phenylalanine/leucine,isoleucine/ crease,butremainsrelativelyhighwhencomparedwiththefirsttrimes- /38
9
tryptophanandalanine/glycine),whereasPeptostreptococcusspp.bac- ter(Korenetal.,2012;Jostetal.,2014).Metabolicanalysissuggeststhat, /1
0
teria are predominant for the utilization of glutamate or tryptophan. duringthirdtrimester,thegutmicrobiotamayinducegreateradiposity 8
6
8
ManyspeciesofbacteriautilizethesameAAassubstratesforgrowth andinsulininsensitivityinthemothertofacilitatethematernalstorage 1
0
(SmithandMacfarlane,1998).Overall,bacteriabelongingtotheClostrid- ofdietaryenergyastriacylglycerolsandincreasetheavailabilityofnutri- b
y
iumspp.dominateinAAfermentationinthehumanlargeintestine,but entsinthematernalplasmafortransfertoherfetus(Korenetal.,2012). gu
e
other bacterial species, such as Fusobacterium spp., Bacteroides spp., Similarly,comparedwithnormal-weightpregnantwomen,thenumbers s
t o
Veillonellaspp.,MegasphaeraelsdeniiandSelenomonasruminantium,may ofBacteroides,StaphylococcusandEnterobacteriaceaearehigherinover- n
1
alsobeimportantforAAmetabolisminthelargeintestine(Smithand weight pregnant women during the entire gestation (Collado et al., 0
A
Macfarlane,1998;Daietal.,2011). 2008; Santacruz et al., 2010). The increased numbers of Bacteroides p
TherearefewstudiesonAAutilizationandmetabolisminbacteria and Staphylococcus are associated with enhanced accretion of white ril 2
0
from the human small intestine. Metatranscriptomic analysis of the adipose tissuein pregnantwomenand thefetus. Theseobservations 19
human ilealbacteria revealsthatbacteria belonging to theClostridium suggestthattheabundanceofbacteriarelatedtointestinalAAmetabol-
clusters, the Bacillus-Lactobacillus-Streptococcus group, and Proteobac- ism increases at late gestation and in overweight pregnant women.
teria are primarily responsible for the utilization of AA (Booijink, MicrobialmetabolitesofAAthatmayregulatematernalandfetalwhole-
2009).ResultsofstudieswithAA-metabolizingbacteriainthepigsmall bodyenergymetabolisminatissue-specificmannerareunknown.
intestineindicatethatbacteriabelongingtotheEscherichiacoli,Klebsiella ItisnoteworthythattotalfecalSCFAconcentrationsandespecially
sp.,Streptococcussp.,MegasphaeraelsdeniiandAcidaminococcusfermen- BCFAconcentrationsarehigherinperinatalwomen,whencompared
tans,playanimportantroleinutilizingAAinthepigsmallintestine(Dai withnon-pregnantsubjects(Jostetal.,2014).SomeoftheSCFApro-
etal.,2010).Further,studieswithmucin-degradingbacteriasuggestthat ducedbythelarge-intestinalbacteriaarederivedfromthefermentation
Akkermansia muciniphila makes a substantial contribution to nitrogen of AA, whereasBCFAareproducedsolely fromthe fermentation of
cycling in the small intestine (Derrien et al., 2008). Considering that BCAA by AA-fermenting bacteria in the large intestine (Smith and
thesmallintestineisthemajorsitefornutrientabsorptionandalsohas Macfarlane,1997).Therefore,thisphenomenoniscorrelatedwiththe
immunologicalandendocrinefunctions,itisofutmostimportanceto observation of increased abundance of gut AA-metabolizing bacteria
392 Daietal.
atthisstage.Themetabolicshiftofthegutmicrobiotabeneficiallyaidsin throughsystemicbloodcirculationorlocaldiffusion(Nishimuraetal.,
adaptationtodietandATPproductioninthecolon(Jostetal.,2014).Itis 2013). Changes in concentrations of AA metabolites (such as polya-
still unclear whether the driving force for the fluctuations of the gut mines,NO,H S,ammoniaandserotonin)intheuterusmaymodulate
2
microbiotaandtheiractivityduringpregnancyisthemicrobiotaitself, cellularsignalingpathways[e.g.AKT(proteinkinaseB),AMPK(5′adeno-
dietarychanges,oraltereddigestivefunctionofthegut.However,the sine monophosphate-activated protein kinase), MTOR (mechanistic
availableevidencesuggeststhatmanyoftheAAmetabolitesproduced target of rapamycin), and RAS (Renin–angiotensin system) signaling]
by intestinal bacteria may play important roles in perinatal women aswellasnutrienttransportandmetabolisminboththeuterusandcon-
(Jostetal.,2014). ceptus,whichwillaffectthemigration,implantationanddevelopmentof
cellsintheconceptus(Kimetal.,2011;Bazeretal.,2012a,c;Gaoetal.,
2012a,b;Wangetal.,2014a,b,c).Theembryoandfetusareverysensi-
AAnutritionandmetabolismforuterineand
tivetothetoxicityofelevatedlevelsofammoniainmaternalandfetal
placentafunction
plasma,aswellasfetalamnioticandallantoicfluids(Wuetal.,2013b).
D
Abundance of certain AA (e.g. glutamine, ornithine and arginine) o
w
increasessubstantiallyinuterinesecretionsaswellasfetalallantoicand Presenceofthegutmicrobiotainthefemale nlo
a
amnioticfluidsduringearlypregnancyduetoincreasedexpressionof d
reproductivetractandthelinksto e
AA transporters in the conceptus (Bazer et al., 2012b; Wu et al., reproductivehealth d fro
2013b). Such biochemical changes not only provide nutrients for the m
growth and development of the fetus but also activate the signaling Alargenumberofbacterialspeciesthatresideinthedigestivetracthas http
pathwaysthatsupportnormalgestation(Bazeretal.,2012a;Wuetal., beenreportedtobepresentinthefemalereproductivetract,including s
2013a,b).Studiesofthenutritionalstatusinpregnantanimalsshowed thevagina,theendometriumandtheplacenta(Gajeretal.,2012).The ://ac
a
thatundernutritionledtothedevelopmentofintrauterinegrowthre- overall diversity and abundance of these bacteria are reduced during d
e
m
striction(IUGR)andhighmortalityrateofneonates(Wuetal.,2004; pregnancy,withLactobacillusspp.andtheordersofLactobacillales,Clos- ic
Waltheretal.,2011).Underconditionsofnutrientrestriction,intestinal tridiales,Bacteroidales,andActinomycetalesdominatingindifferentvaginal .ou
p
nitrogenrecyclingthatinvolvesgutmicro-organismsisreduced(Allison subsites(Aagaardetal.,2012).Similarly,dynamicchangesofthevaginal .c
o
and Macfarlane 1989; Fuller and Reeds, 1998) in association with microbiotaoccurduringthemenstrualcycle,withLactobacillusspp.and m
/m
decreasedactivitiesofenzymesrequiredforsynthesisofNOandpoly- Streptococcusspp.beingthemajorbacterialspecies(Eschenbachetal., o
le
aminesinplacentaandendometrium(Wu,2010)anddecreasedcon- 2000; Gajer et al., 2012). Disturbance of the vaginal microbiota h
cfleunidtsra(tWionuseotfathl.e, 1a9rg9i8nain,be-;faKmwiolynoeftAaAl.,,B2C00A4A).aOndnepoployassmibinilietsyiinsftehtaatl rluesdsupcpe.d(eth.ge.Laabcutnobdaacniclluesocfritshpeathuysd),raongdenanpeinrcorxeiadsee-dpraobduuncdinangcLeacotfoGbaacrdil-- r/article
gutbacteriaprovideprecursors(e.g.S-adenosylmethionineandagma- nerellavaginalisandPrevotellaspp.isassociatedwithbacterialvaginosis -ab
s
tine)forthesynthesisofpolyaminesintheintestinalmucosaandother and pelvic inflammatory disease (Eschenbach et al., 2000; Andrews tra
c
tissues(e.g.thereproductivetract)(Wangetal.,2014a).Nonetheless, etal.,2006;Martinetal.,2012).Furthermore,bacterialspecies,such t/2
adequateprovisionofdietaryAAisrequiredtomaintaintheintestinal as Streptococcus, Escherichia coli, Shigella, Proteus, Enterobacter, and 1/5
microbiota(Daietal.,2010,2011)whosenitrogenousproducts(e.g. Candida species which is present in the digestive tract, have been /38
9
agmatine,NOandpolyamines)maybebeneficialfortheregulationof detectedinthevaginaandshowntobecorrelatedwithgestationalage /1
0
cellproliferationintheuterus,placentaandembryo/fetus(Kongetal., inpregnantwomen(Dechenetal.,2010;Martinetal.,2012).Consider- 8
6
8
2014; Wang et al., 2014a,b,c). Like underfeeding, overnutrition also ingthatmostoftheabovebacterialspeciescanmetabolizeAA,itisim- 1
0
has negative effects on pregnancy. For example, a high-protein diet portanttofurtheruncovertheirroleinfemalereproductivephysiology b
y
during pregnancy and lactation in mice caused lower birthweight, andhealthaswellasspermviabilityandtransportinthefemalerepro- gu
e
smallerlittersize,andahighermortalityrateintheoffspringduringthe ductivetractandfertility(SuarezandPacey2006;Barbonettietal.,2011). s
t o
lactation period (Walther et al., 2011). Maternal obesity results in Inpatientswithendometritis,bacteriasuchasChlamydiatrachomatis n
1
increasedrisksforobstetricproblems,includingdiabetesmellitus,hyper- andNeisseriagonorrhoeaewerefrequentlyisolated(Eckertetal.,2002; 0
A
tension,pre-eclampsia, thrombosis events, respiratory complications, Haggertyetal.,2004;Swidsinskietal.,2013).However,inperipartum p
IUGR,anddeliverycomplications(e.g.Cesareansectionandneonatal andpost-partumwomenwithendometritis,thebacterialisolateswere ril 2
0
deaths)(McKnightetal.,2011). dominatedbyE.coli,enterococci,Streptococcus,aswellasanaerobicbac- 19
BasalAAandnitrogenrequirementsforthegrowthandsurvivalofin- teriasuchaspeptococcusandBacteroidesfragilisandUreaplasmaurealy-
testinalbacteriaarerelativelystable,butmayvarymarkedlywithchanges ticum(Plattetal.,1979;Cicinellietal.,2009,2012).Similarobservations
inthehost’sphysiologicalconditions(Daietal.,2010,2011,2012a).In werereportedforuniparousfarmanimals.Forexample,indairycows,
caseofundernutrition,especiallyproteinrestriction,thegutmicrobiota thepost-partumendometritiswasassociatedwithincreasedabundance
willcompetewiththehostforAAduringAAdigestionandabsorption oftotalbacteriaandespeciallytheprevalenceofE.coli,Arcanobacterium
processesinthesmallintestine,therebyfurtherreducingtheavailability pyogenes,Bacteroidesspp.,Fusobacteriumspp.,Peptostreptococcusspp.,
ofdietaryAAforreproductiveorgans.Forahigh-proteindiet,excessive Prevotellaspp.,Ureaplasmaspp.,Streptococcusspp.,Pseudomonasspp.,
AAthatexceedthecapacityofabsorptionbythehost’ssmallintestine and Staphylococcus spp. in the uterus (Sheldon et al., 2009; Machado
undergocatabolismbygutbacteriatogenerateexcessiveamountsof etal.,2012;SantosandBicalho,2012;Pengetal.,2013).Thesekinds
ammoniaandtoxicmetabolites,suchasindolicandphenoliccompounds ofvariationswerealsofoundinaccordancewithhealthstatusanddays
intheintestine(SmithandMacfarlane,1996,1997,1998).Asnotedpre- post-partumoftheanimals(Machadoetal.,2012;SantosandBicalho,
viously, the microbial AA metabolites can reach reproductive organs 2012;Pengetal.,2013).
Gutbacterialaminoacidmetabolismandreproduction 393
Theplacentaharborsauniquemicrobiome,whichresemblestheoral Environmentalfactors(e.g.deliverymode,maternalhealthconditions,
microbiota(Aagaardetal.,2014).Basedonhighthroughputsequencing diet,diseaseandmedication)willshapethemicrobialdiversity,aswell
ofthebacterial16SribosomalDNAandwhole-genomeshotgunmeta- as the abundance and metabolism of the developing gut microbiota
genomicstudies,Aagaardetal.(2014)reportedthatthenon-pathogenic (Matamorosetal.,2013).Thiswill,inturn,affectthematurationofthe
E.coliwasthemostabundantbacteriumintheplacentaofmostindivi- innate immunity and metabolism of the infant (Konstantinov et al.,
duals(Aagaardetal.,2014).BacteriasuchasBacteroidesspp.,Neisseria 2013).Theeffectofmaternalfactorsonthedevelopmentofgutmicro-
lactamica,Staphylococcusepidermidis,andPropionibacteriumacneswere biotaandmetabolismoftheneonatewillbediscussedinthefollowing
also predominant in the placental samples (Aagaard et al., 2014). sections(TableI).
Notably,theoralbacteriasuchasPrevotellatanneraeandnon-pathogenic
Neisseriaspp.weredetected(Aagaardetal.,2014).EnrichmentofActino-
Programmingoftheneonatalgut
mycetales,Alphaproteobacteria,Streotpcoccus,Acinetobacter,andFusobac-
microbiotaandmetabolism
terium nucleatum in the placenta was associated with antepartum
D
infectionandincreasedriskforpretermbirth(Aagaardetal.,2014).Ana- Therearemanystagesandwindowsfortheestablishmentofthegut o
w
lysis of the metabolic pathways of the placental microbiota showed microbiotaintheneonate.The‘programming’oftheneonatalgutmicro- nlo
a
strong correlation between gestational age at delivery and increased biotaandmetabolismisnotuniqueandcanbealteredbeforebirthandin d
e
abundanceofbacterialpathwaysinvolvedinglycine/serine/threonine post-natallife(Clementeetal.,2012).Beforebirth,thegutofthefetus d fro
metabolism(Aagaardetal.,2014).Duetolowabundanceoftheplacen- wasthought to be sterile.However,recentfindings haveshownthat m
talmicrobiotaandtothesamplingmethodused,furtherstudiesarewar- thepresenceofbacteria,suchasEscherichiacoli,Enterococcus,Streptococ- http
rantedtovalidatetheseobservations. cus, Staphylococcus, and Propionibacterium species, in the intrauterine s
Collectively,theabovefindingssuggestthatthepresenceofbacteriain environment (e.g. meconium, umbilical cord and amniotic fluid) may ://ac
a
the female reproductive tract that originate from the digestive tract result from the translocation of the bacteria from the gut of the d
e
m
throughtheblood,oralorfecespathwaysmayplayimportantrolesin mother(Matamorosetal.,2013).Atterm,deliverymodeaffectsthebac- ic
female reproductive health. The driving force for the changes of the terialcompositionofthemeconiumoftheneonate.Vaginallydelivered .ou
p
microbiotamaybeeitheranadaptationofthebacteriatothechanging infantshavethegutmicrobiotathatresemble,toagreatextent,their .c
o
environment(e.g.AAorglycogenconcentrations)ofthefemalerepro- mother’svaginalmicrobiotawhichisdominatedbyLactobacillus,Prevo- m
/m
ductivetractorachronicinfectionwithcertainbacteria(Cicinellietal., tellaorSneathiaspp.,whereastheCesareansectioninfantharborsgut o
le
2009;Gajeretal.,2012;Martinetal.,2012).Nitrogenmetabolismin microbiotathatismoresimilartotheirmother’sskinmicrobiotawhich h
tsheecrbeaticotnesriaincmreaaysiencdrueraisnegapsreAgAnancocyncaenndtrpaotisotn-psairntuvmag.inCahlaanngdesutinertinhee sispdpo.(mDinoamteindgubeyzS-tBaeplhloyleotcoacl.c,u2s0,1C0o)r.ynebacterium,andPropionibacterium r/article
abundance of metabolites of bacterial proteolysisand AA catabolism Physiologicalconditionsofthemothercanaffecttheestablishmentof -ab
s
mayserveassignalstomodulatethefunctionofthefemalereproductive theinfantmicrobiota.Asnotedpreviously,overweightpregnantwomen tra
c
tract,suchashormonesecretion,ovulation,andendometrialreceptivity havehighernumbersofBacteroides,StaphylococcusandEnterobacteria- t/2
(Sheldonetal.,2009;Aagaardetal.,2014).Thesephysiologicalchanges ceaeintheirgutmicrobiota(Colladoetal.,2008).Accordingly,infants 1/5
maycontributetomiscarriage,IUGR,andpretermbirth(Aagaardetal., of overweight mothers have a higher abundance of Bacteroides and /38
9
2014).However,furtherstudiesarerequiredtoidentifykeybacterial Staphylococcus in their fecal samples during the first 6 months after /1
0
metabolitesinthefemalereproductivetractthathavestrongcorrelation birth (Collado et al., 2010). Also, infants of normal-weight mothers 8
6
8
withfemalereproductivedisorders.Furthermore,itwillbeimportantto and of mothers with a normal weight gain during pregnancy have a 1
0
investigatethehealthstatusofthedigestivetractandfemalereproductive lowerabundanceofAkkermansiamuciniphila,Staphylococcus,andClostrid- b
y
healthwithspecialemphasisonthefluctuationsofthecompositionand iumdifficileinthegut,whencomparedwithoverweightorobesemothers gu
e
activityoftheAA-metabolizingbacteriainthedigestivetract(Offenba- (Colladoetal.,2010).Studieswithvaginallydeliveredneonatesdemon- s
t o
cheretal.,1996;Hanetal.,2009;Suwabeetal.,2011;Yoshidaetal., strated that babies born large for gestational age (LGA) mainly from n
1
2011).Hereweproposethenotionthatthemicrobiotaresidinginthe obese/overweightmothershadahigherabundanceofProteobacteriaes- 0
A
differentnichesofthefemalereproductivetractplayuniquerolesindif- peciallyE.coli,whencomparedwithbabieswithanormalbirthweightfor p
ferenteventsofreproduction.Furtherstudiesarewarrantedtouncover anappropriategestationalage(Bodnaretal.,2010;Karlssonetal.,2011). ril 2
0
theroleofbacteriaoriginatingfromthedigestivetractinmodulatingthe Thelong-termeffectoftheshort-term‘programming’oftheneonatal 19
metabolismandsignalingofthevaginalepithelium,endometriumandthe andinfantgutmicrobiotaislargelyunknown.Thealteredmicrobiota,
maternal-fetalinterface,aswellastheirpossiblelinkstofemalerepro- especially the increased abundance of protein-degrading and AA-
ductivehealth(Erlebacher,2013). metabolizingbacteriainthemother’sgutand‘inherited’transferinto
thegutoftheinfant,maymodulatethemetabolicstatusoftheinfant.
Thus,anelevatedabundanceofBacteroidesisassociatedwithincreased
Important role of the gut
SCFAproductioninthelargeintestine.Thismaystimulatefattyacidsyn-
microbiota in the mother-to-
thesisandstorage,whileinhibitingfattyacidoxidationthroughtheregu-
infant transfer of materials lationofthefasting-inducedadiposefactor(FIAF)andAMPKsignaling
pathways,respectively(CaniandDelzenne,2009).Theincreasedabun-
Afterbirth,theneonategrowsrapidly.Developmentandmaturationof danceofGram-negativebacteriasuchastheBacteroidesandE.coliinthe
thedigestiveandimmunefunctionsoftheintestineiscriticalforsupport- gut of overweight and obese mothers or LGA babies may lead to
ing the survival, growth and health of the infant (Wu et al., 2012a). increased concentrations of lipopolysaccharide (LPS) in the gut and
3
TableI Possiblelinksbetweengutbacteria,femalereproductionandinfanthealth. 94
Subjects/target Keybacteria Possiblemodeofaction References
organs
..........................................................................................................................................................................................................................................................
Female
D
Digestivetract Firsttrimestera:Faecalibacterium,Eubacterium Metabolicre-programmingduringpregnancy:increasedbacterial Colladoetal.(2008),CryanandDinan(2012),Daietal. ow
Thirdtrimestera:EnterobacteriaceaefamilyandStreptococcus fermentationofcarbohydratesandaminoacidinthelarge (2011),Ferna´ndezetal.(2013),Jostetal.(2014),Konstantinov nlo
genusbacteria intestineofperinatalwomen;increasedconcentrationsof etal.(2013),Korenetal.(2012),NastandLeDuc(1988), ad
Post-partum/earlylactationa:Streptococcus. SCFAinthelargeintestinemayinducegreateradiposityand Santacruzetal.(2010)andLietal.(2009) ed
Overweightpregnantwomena:bacteriabelongtoBacteroides, insulininsensitivity fro
Staphylococcus,Enterobacteriaceae Regulateimmuneandneuroendocrinefunction:productionof m
h
bioactivemoleculescellwallcomponentsandpeptides; ttp
translocationofbacteriabydendriticcellsandmacrophagesto s
otherorgans(breast,vagina,uterus,etc.);mediatethe ://a
c
productionofAA-derivedneurotransmittersandgaseous ad
signalingmolecules em
Breast Dominantbacteriainbreastmilk:Weisella,Leuconostoc, Regulatebreastmilkcomposition:compositionofmicrobiota Cabrera-Rubioetal.(2012),Ferna´ndezetal.(2013),Gabrielli ic.o
Staphylococcus,Streptococcus,Lactococcus,Lactobacillus, shiftwithdifferentphysiologicalconditions;utilizeand etal.(2011),Lo¨nnerdal(2014),Paliyetal.(2014), up
Propionibacterium,Bifidobacterium transformAA,polysaccharidesandothermilkcomponents Plaza-Zamoraetal.(2013)andSmilowitzetal.(2013) .co
Increasedabundanceoforalbacteriainbreastmilkwith intobioactivemoleculessuchaspolyamines m
/m
lactation:Veillonella,Leptotrichia,Prevotella Helpthedevelopmentofinfantgutmicrobiota:providecontinues o
Overweight/obesemother:highnumbersoftotalbacteria, sourceofmicrobial‘inocula’forthebaby le
h
Lactobacillus,Staphylococcus;lownumberofBifidobacterium r/a
Vagina Commensalbacteria:hydrogenperoxide-producing Maintainingnormalcompositionandactivityofthevaginal Aagaardetal.(2012,2014),Andrewsetal.(2006),Dechen rtic
le
Lactobacillus(especiallyLactobacilluscrispatus),Prevotella, microbiota:createlow-pHenvironmentinhibitthegrowthof etal.(2010),Dominguez-Belloetal.(2010),Martinetal. -a
Sneathiaspp.,Lactobacillales,Clostridiales,Bacteroidales, pathogenicbacteriabytheproductionofacidsandhydrogen (2012)andWiesenfeldetal.(2012) bs
Actinomycetales peroxide tra
c
Pathogenicbacteria:Gardnerellavaginalis Helpthedevelopmentofinfantgutmicrobiota:first‘inoculation’of t/2
Changesinabundanceduringpregnancy:Streptococcus, bacteriaforthevaginallydeliveredneonates 1
/5
Escherichiacoli/Shigella,Proteus,Enterobacter,Candida(fungi) Mediatetheoccurrenceofbacterialvaginosis,pelvic /3
8
inflammatorydiseaseandinfertility 9
/1
Uterus Pathogensassociatedwithendometritis:Chlamydia Regulateendometriumhealthandfunction:endocrine,transport Aagaardetal.(2014),Capeetal.(2013),Cicinellietal.(2009, 0
8
trachomatis,Neisseriagonorrhoeae ofnutrients,pregnancyrecognition,implantationofthe 2012),Eckertetal.(2002),Erlebacher(2013),Haggertyetal. 68
Associatewithperi-andpost-partumendometritis:E.coli, embryo,maintenanceofpregnancy,post-partumrecovery, (2004),Swidsinskietal.(2013)andPlattetal.(1979) 10
enterococci,Streptococcus,anaerobicbacteriasuchas etc. by
peptococcusandBacteroidesfragilis,Ureaplasmaurealyticum Mediatetheoccurrenceofpregnancycomplications g
u
(miscarriage,IUGR,pretermbirth,stillbirth)andinfertility es
Conceptus Dominantbacteriaoftheplacenta:E.coli,Bacteroidesspp., Regulatematerialexchangeatthematernal-fetalinterfaceand Aagaardetal.(2014),Erlebacher(2013)andMatamorosetal. t on
Neisserialactamica,Staphylococcusepidermidis, fetusdevelopment:mediateaminoacidmetabolism;regulate (2013) 1
0
Propionibacteriumacnes;presenceoftheoral-typebacteria immunitythroughbacterialcellcomponents;participateinthe A
p
B(Parcetveortieallparteasnennetrainet,hneomn-epcaothnoiugmen,uicmNbeiliiscsaelrciaosrdp,pa.)ndamniotic mMeetdaiabtoelitshmeaoncdcuimrrmenucneitoyfopfrtehgenafentcuyscomplicationssuchas ril 20
fluid:E.coli,Enterococcus,Streptococcus,Staphylococcus, pretermbirth,IUGRandstillbirth 19
Propionibacterium
Associatedwithantepartuminfection:Actinomycetales,
Alphaproteobacteria,Streotpcoccus,Acinetobacter,
D
Fusobacteriumnucleatum a
i
e
t
a
l.
Gutbacterialaminoacidmetabolismandreproduction 395
cause metabolic endotoxemia, which promotes low-grade inflamma-
0), tion and metabolic disorders such as insulin resistance, oxidative
Bodnaretal.(2010),Chungetal.(2012),Colladoetal.(201DelCurtoetal.(2013),Dominguez-Belloetal.(2010),Donnet-Hughesetal.(2010),Favieretal.(2002),Karlssonetal.(2011),Konstantinovetal.(2013),Matamorosetal.(2013)andPerezetal.(2007) spabatfaisfswenraothhnbntryorciooolatdueybltmi‘,lduroonosr.otLi,esludrnxudt‘2G,st-coahineddpt0tnbAguctriibar0oachmeorone6cbennesbntgah;ee,oaagrtroWitg-rralnubrdetfeilmbdutyiisotregnupbutheu’amst,aeatenhnl2tematct’eehdhlo0ttaomtriietee1ooannnoAprbi0dndwbcgicrao;AeerteohrDaho,alstuviomdmhseinbetnenmlaoydeipneleostC(l-(otbuethZtobCauasrosabtfoobociarhpdottidtoeenntiehiyotornyntliheiatetnagtdtehminesngnsteehossusdadeav(mu,otfnaPgetlDse.sadmluti,alutotsbheet2ltciipmteoeyalc0ohzgmacrrl1eeafieogtasln3.yniseotumsb,ven)onbtbi2iav.toretteeay0laTmoy.,tns,sa0oap2hteoiodof1f2cee0f(/dfenr;D0rm0hooiceiT1lta9onaatvbehf4ni)e,omtiemtie.o)dodearraO.esterwtbnbgsaoHa,eoenduyeislNtntl.otiittti,ngcvhaphaiwO2shmilesoer.es0tnei,olscyidiay1evmc2tnnoni(ahe0rc0vmJdnomodereo)e1r,t.trbserb3roHihTsnsoiang)otmaeie2hr.ntehtrtrSyyasineeeayss,,,,l Downloaded from
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Developmentofthemicrobiotainthedigestivetract:healthconditionsofthemother,deliverymode,diet,diseaseandmedicationallmaketheiruniquecontributionsforthedevelopmentoftheinfantgutmicrobiotaMetabolicprogramming:short-termeffectoftheintestinalmicrobiotaonthemetabolismofcarbohydrates,AAandfatininfantwillprogramthemetabolismofthebodyinthelongrunMaturationofimmunesystem:expandnumbersofTcells,dendriticcellsandproductionofantimicrobialpeptidesintheintestine 2008;Santacruzetal.,2010;Korenetal.,2012;Jostetal.,2014). 2toCIcmigedoiWhltsanilotu0oiubfoucoammr1ranunsttmltneiaael4eosni.pautmooar,t)rgrionovco.nnfsm1iiafitmtscndCann9artfialeterfina9aoinolriK(le,ondk4emWucnlaeansneaiotsninsaprri;tvpsnuodboiiAaahotoWadwneirfluAonrailielon,ytmtm’nnuedsiaestof1(dariita,icnlma9nwoelnknotonse9sK,mchsiit,dn)lita4flanrkssuhfibse)thaicdbKp.ncurirotbonomioeacnsenOnrecwlrramar(ogier,eeaLnmsbfeesdgapteeg1etdaanisllrinm9mi,uesoianutesnee9xht1nttmiitga,sll4ea9adkkpmoap,t;l9,im.rntamrnit,a4csooZpohdr2to)eggremlthe0.iieminrhvnna,lsm1eTtaaceekntiaeg2sntreuhogturslaim)enueduemsi.rnvttsriteSea(ederapeatZtjamwsmlouabybmthmatr(diiuiriottaBllwnia.ikehnilfen,nlkaeonkridsghstl,2snoc,dha(wathe0pdDeownadotea1irogtf´taifofdad3htehAonfvhllf-v;ri.irtriAgcn,oeeasheBchhet2nnefeeaoeeaa,c0ealrAtilanrgeAlo1ndme.clc,dAacu3neAgtAeeo2lta)oal.´ncsuta,,A0nttnhctotmtieb1cao1rhaim(soueg4ae9nmiaD.nettnn)tn9piTe.saaatiotg4onarhAtnvhneoabeesiliidne.sssss--,,f;, ttps://academic.oup.com/molehr/article-abstract/21/5/38
Infant DigestivetractVaginallydelivery:Lactobacillus,Prevotella,Sneathiaspp.Cesareansection:Staphylococcus,Corynebacterium,Propionibacteriumspp.Withoverweight/obesemothers:Bacteroides,Staphylococcus,Akkermansiamuciniphila,Clostridiumdifficile,Proteobacteria(especiallyE.coli)Breast-feeding:BifidobacteriaConsumeformulamilk:Ruminococcus,increasedabundanceofEnterobacteriaceae AA,aminoacids;IUGR,intrauterinegrowthrestriction;SCFA,shortchainfattyacids.aDatawerebasedonstudieswithluminalcontentofthecolonandfecalsamples(Colladoetal., 2pswm(hpppmhmsinbtpaSnhltpnteie0ohooireagcoiaiooeeetdlanpy1Bnllhnrkphyyatndrlset1teaecthaahccmsitioLhfaco;nnerommehtyadesmtiiSils,tlrtvnmoneooieusiimfscgoenncifergcdifgnmohpeinoieefgolniiaoiaclrroncdidnspnoivleenamatlbccasaeofakriwhilnnlatuniencuorilsyc,tinyentdselttgniilsrtbkstoeo,a,tteetzmuhbabsocptpianraimSamiccenieaidfrohirs(rtrthl(ettsorLtkipyeltneeembipaehshoasofdoamr¨cpooeo(iliainrsonc.rtltteatntfnk,ebblaotoshonhsl.ithaoe2gtmugrcoeievnninuatac.0ogatooarfdemnrttmicrt1badrnfcictridaocentyl3hr1aamuoamtuilm(-,epoel;ele0nndpnPls,oaaosePrn,3osiurclc2ssncecabtlsao–tegroytaaat0ofdzhleitalaanooi1nnnbnao1ylemesnmlotf0fd-dgdwobt4biretZnasi5iiual)isupnolllttitintskai.tLatt,mirvlf/oir)ohaeiecinaamuTomne,dmllmtsnsincy.mnssnaeaohd,otsotatLt,ionsreisl2o(ocirmiftincos.dgfaar0hofiocleLoecnoaFonine1kfnrferocacacotsd,bere4tcethcrtrsnhasrmhdisune)ogtpoeaccami.eoeeswtittsfcileotevno.ryeAxptbaah,ernbstiiip(rrantenmathtta2Ctrryhmeubhmaecn)rreiep0ni.argaaeii,didrpaialdr1pmele,bltveskiCearisrie3clnnesroenetelmsmoose)eoge(e,nt.,dmoaisssGrnenudincosatOh)ullaifcrcsknnoeie,tan-nolrmoeo,elkcoRonbtmiadwfannfnnht.rotgrpcuvhregtiipoteitSlntnhfiilboeerorehtalarattoaefoaailnsbuetatolrttWtactdliwierhtehdunsioyiloomifo.deeldnoaplteieeneiemnscnnttdeortiwwsssossfiaahspnuettAaamornniihhaboelbttoooslll)dddnhh..eeays---t,f,ff, 9/1086810 by guest on 10 April 2019
2012). This may explain the presence of agmatine in the milk of
396 Daietal.
nonruminants(e.g.6.3mmol/Linsow’smilk)thatmaybebeneficialfor presenceofspecialcommunitiesofbacteriasuchastheEnterobacteria-
polyaminesynthesisinthesmall-intestinalmucosa(Daietal.,2014).Like- ceaeintheneonatalgutmodulatesinfantmetabolismdirectlythrough
wise,theabundanceoftheoralcavityinhabitants,suchasVeillonella,Lep- the generation of AA metabolites and indirectly via the production
totrichia,andPrevotella,increasesinmilksamplesobtainedat6monthsof ofLPSorotherbacterialproducts.Thesequentialchangesinthecom-
lactation,whencomparedwithcolostrumandmilksamplesobtainedat position of milk not only provide essential nutrients to support the
1monthoflactation(Cabrera-Rubioetal.,2012).BacteriasuchasLacto- growthofneonatesbutalsofacilitatetheestablishmentoftheindigenous
bacillus,PropionibacteriumandBifidobacteriumarealsopresentinbreast gut microbiota, as well as body metabolism and the development of
milk(Ferna´ndezetal.,2013).Ofnote,maternalbodyweightinfluences immunesystems(Perezetal.,2007;Donnet-Hughesetal.,2010).
thecompositionofbacteriainbreastmilk.Forexample,comparedwith
normal-weight mothers, obese mothers have a higher total number
Bacteria and reproduction
of bacteria (including Lactobacillus and Staphylococcus) and a lower
numberofBifidobacteriumintheirmilkoverthefirst6-monthsofbreast- in the male
D
feeding(Cabrera-Rubioetal.,2012).Similarly,motherswithexcessive o
w
weightgain during pregnancy havea higher numberof Staphylococcus Malereproductiveperformanceisinevitablyrelatedtotheutilizationand nlo
a
aureus in 1-month milk and a higher number of Lactobacillus but a metabolismofAA.AdequateamountsofAA,especiallyarginine,inthe d
e
lowernumberofBifidobacteriuminthe6-monthmilk(Cabrera-Rubio circulationareessentialforthegeneration,differentiationandmaturation d fro
etal.,2012).Originofthebacteriainthebreastmilkcanbethetransloca- ofspermatozoa,therebyaffectingtheirquantityandquality(Eskiocak m
tionofthemother’sgutbacteriaalongwithdendriticcellsandmacro- etal.,2006;Wuetal.,2009).Earlystudiesshowedthatdietaryarginine http
phages,aswellasbacteriafromtheskinofmotherandoralcavityof deficiencyinmenfor9daysresultedinsharpdecreasesofthenumber s
theinfant(Ferna´ndezetal.,2013).Macrophagescomprise40–60%of and motility of sperms (Holt and Albanese, 1944). On the contrary, ://ac
a
the cells in colostrum and up to 80–95% in mature milk (Wagner dietarysupplementationwitharginine-HCl(0.5g/day)toinfertilemen d
e
m
etal.,2008).ThesecellsareresistanttolowpHandcanpassthrough for up to 2 months markedly increased sperm counts and motility, ic
thelumenofthestomachandreachthelumenofthesmallintestinein leading to successful pregnancies of their partners (Tanimura, 1967). .ou
p
theinfant(Wagneretal.,2008).Therefore,thecompositionofbreast Dietaryargininesupplementationnotonlyimprovesspermqualitybut .c
o
milkplusasufficientloadofbacteriainthemilkthatreachthesmallintes- also enhances concentrations of polyamines, ornithine, arginine and m
/m
tineguaranteethesuccessfulcontinuous‘inoculation’ofthemother’sgut proline in seminal fluid, which is crucial for fertilization (Wu et al., o
le
microbiotatotheinfantgut.However,formula-fedinfantslacksucha 2007, 2009). An increase in the number of microbes (particularly h
mdisepclhaaynaisnmincforeratsheedeabstuanbdliashnmceeontfEonftetrhoebancotermriaacleageutinmthicerogbuito(taMaatnad- tthinoesewtilhlaptreoxmporetesscaahtaigbholleisvmelooffadrigeitnaarsyea)ringinthineeluamnde,ntohfetrheefosrmea,lcloinnttersi-- r/article
morosetal.,2013). butestolowspermviability. -ab
s
Researchhasshownthatbreast-fedinfantsharbordifferentkindsof Furthermore,studiesoverthelastdecadeshaveidentifiedanimport- tra
c
the gut microbiota, when compared with formula-fed infants (Favier antroleforgaseousmetabolitesofAAinmalereproductivefunction t/2
et al., 2002). By tracing the succession of the fecal microbiota from (Lietal.,2009;Gratzkeetal.,2010;d’EmmanuelediVillaBiancaetal., 1/5
newbornbabiesforupto1yearusingmolecularfingerprintingtechni- 2011). As an important metabolite of arginine, physiological levels of /38
9
ques,theseauthorsfoundthatbacteriarelatedtothegenusofRumino- NOstimulatepenileerectionthroughtheactivationofguanylylcyclase /1
0
coccus dominate in fecal samples from babies supplemented with togeneratecyclicGMP(cGMP),whichinducesrelaxationofvascular 8
6
8
formula milk after 17 days of age (Favier et al., 2002). Bifidobacteria andcavernosalsmoothmuscles(Gratzkeetal.,2010;Wu,2010).As 1
0
remained dominant in fecal samples from breast-fed babies until anothergaseousmetaboliteofsulfur-containingAA(e.g.cysteineand b
y
weaning.Moreover,comparedwithbreast-fedbabies,compositionof methionine), H2S acts in concert with NO on thecGMP pathway to gu
e
the fecal microbiota became more diverse in babies consuming inhibittheactivityofphosphodiesterasetype5insmoothmusclecells s
t o
formulamilk(Favieretal.,2002).OtherbacteriasuchasBacteroides,Clos- and stimulate penile erection (d’Emmanuele di Villa Bianca et al., n
1
tridia,Enterobacter,andStreptococcuswerealsopresentinthefecesfrom 2011).NOandH Sinthesmoothmusclecellsarederivedfromthecav- 0
2 A
bothbreast-andformula-fedbabies(Mackieetal.,1999;Favieretal., ernousnerveandendothelialcellsofthepenis.H Scanalsobeproduced p
2002).ItisnoteworthythatbacteriabelongingtoRuminococcusandBifi- withinsmoothmusclecellsandfromerythrocyt2esbythecatabolismof ril 2
0
dobacteriahavetheabilitytodegradedifferentoligosaccharidechainsof cysteine, methionine or organic sulfate respectively (d’Emmanuele di 19
mucins,releasemono-anddisaccharides,andhydrolyzepeptidestoAA VillaBiancaetal.,2011).Intestinalbacteriaareasignificantsourceof
forutilizationbyotherintestinalbacteria(Hoskinsetal.,1985;Hoskins, H Sinanimals(Gibsonetal.,1993),anditsexcessiveproductionmay
2
1993;Favieretal.,2002).Thiscanhelptoexplainthedifferenceinthe be deleterious to intestinal and reproductive tissues. Interestingly, in
microbialcompositionandmetabolismofthegutmicrobiotabetween hypoxicconditions,H Sisproducedfromcysteineinthehumanplacenta
2
breast-fedandformula-fedbabies. andfromthiosulfateinbovineandratarterialbloodvessels(Pateletal.,
Thepresenceofthematernalmicrobiotainbreastmilkmayplayan 2009;Olsonetal.,2013).ThesefindingssuggestanimportantroleofH S
2
importantroleintheprogrammingoftheinfantgutmicrobiotaandme- inthepathophysiologyofreproductioninbothfemalesandmales.Thus,
tabolismthroughthefollowingpathways.First,continuous‘inoculation’ sulfurrecyclingmayparticipateinwhole-bodyH Ssignalingandinrepro-
2
totheinfantgutthroughbreast-feedinghelpsestablishtheindigenous ductivefunction.
microbiotaanditsassociatedmetabolicphenotypes.Second,conver- Serotonin(ametaboliteoftryptophan)isimportantforcontrolling
sionofnutrientsinthemilkintobioactivemolecules(suchaspolyamines ejaculation both centrally and peripherally (Giuliano and Cle´ment,
andglutathione)supportsthematurationoftheinfantgut.Third,the 2005; Berger et al., 2009). It has been reported that serotonin can
Gutbacterialaminoacidmetabolismandreproduction 397
TableII Importantmicrobialmetabolitesofaminoacidsandtheirfunctionsinreproduction.
AA Metabolites Functiononreproduction Keybacteria Niches References
.............................................................................................................................................................................................
Arginine Polyamines Ovulation,ovariansteroidogenesisand Bacteroidesthetaiotaomicron, Large Noacketal.(2000)and
oocytequality;embryoimplantation, Fusobacteriumvarium intestine Wuetal.(2009)
survival,andgrowth;placental
angiogenesis,growth,andfunction;
spermatogenesis,spermquality,and
malefertility
NOa Physiologicalvasodilator;angiogenesis; Lactobaillusspp.,Bifidobacterium Smalland Gratzkeetal.(2010),
spermatogenesis;embryogenesis, spp.,Staphylococcusaureus,Bacillus large Sobkoetal.(2006),
fertility;modulatepenileerection spp. intestine Vermeirenetal.(2012)
D
andWu(2009) o
w
Glutamate GABA Inhibitpenileerection Lactobacillusbrevis,L.paracasei, Smalland Barrettetal.(2012), n
lo
Bifidobacteriumdentium large Gratzkeetal.(2010)and a
d
intestine Komatsuzakietal.(2008) e
d
Serine-and SCFA Tightjunctionandparacellular Clostridiumspp.,Peptostreptococcus Large SmithandMacfarlane fro
m
aspartate-familiesof permeabilityofumbilicalvein; spp. intestine (1997),Miyoshietal.
h
AA,lysine anti-inflammatoryroleinhumanlabor (2008)andVoltolinietal. ttp
(2012) s://a
SulfurAA H2S Physiologicalvasodilator;physiological Escherichiacoli,Salmonellaenterica, Large Blachieretal.(2010), ca
controlofpeniletone Clostridiumspp.,Enterobacter intestine d’EmmanuelediVilla d
e
aerogenes,Peptostreptococcusspp., Biancaetal.(2011)and m
ic
Fusobacterium,Eubacterium, SmithandMacfarlane .o
Desulfovibriospp. (1997) up
.c
Tryptophan Serotonin Inhibitpenileerectionandejaculation Streptococcusspp.,Escherichiacoli, Smalland Gratzkeetal.(2010),Lyte o
m
Enterococcusspp. large (2011)andParketal. /m
intestine (2011) o
le
Tyrosine Dopamine Inhibitpenileerection Bacillusspp.,Serratiaspp. Smalland Gratzkeetal.(2010)and hr/a
lianrtgeestine Lyte(2011) rticle
-a
b
AaNAit,raamteinaolsoaccidosn;tGribAuBtAes,tgoamthae-apmroindoubcutitoynricofaNcidO;Hby2Sb,ahcytderroiagienntshuelfigduet;luNmOe,nn(iVtreicrmoxeiidreen;SeCtaFlA.,,2s0h0o9r)t.chainfattyacids. stra
c
t/2
1
/5
eitherincreaseordecreaseejaculatorylatencythroughtheactivationof etal.,2014). Furthermore, thepresenceofthegutmicrobiotain the /38
9
different 5-HT receptors in the brain or spinal cord (Giuliano and maleurogenitaltractplaysanimportantroleinsemenqualityandmale /1
0
Cle´ment,2005).However,theneteffectofserotoninistoprolongejacu- reproductivehealththroughtheproductionofimportantmetabolites 8
6
8
lationanddelayorgasm(Bergeretal.,2009).Morethan90%ofserotonin (Table III). These observations provide opportunities to uncover 1
0
inthebodyisreleasedfromthesmallintestinewhenanimalsconsume AA-relatedmetabolicor hormonal interactions between gutbacteria b
y
food(Bergeretal.,2009).Therefore,itisimportanttoinvestigatethe andreproductionperformanceinmenandinmalesofotherspecies. gu
e
effectoffoodconsumptionanddifferentnutrientsonintestinalproduc- s
t o
tionandsignalingofserotoninanditslinktomalereproduction. Dietary interventions for sound n
1
Asreportedforfemales,thegutmicrobiotaofmalescanproduceall 0
gut ecology and optimal A
theAAmetabolitesmentionedintheprecedingsection(TableII).The p
utilizationofAAbybacteriainthesmallintestineofmenregulatesnot reproduction ril 2
0
only AA supply to the reproductive organ for the maintenance of 19
normalfunction,butalsothesynthesisofhormonesandsignalingmole- Food is crucial for supporting normal reproduction in both men and
culesinthewholebody.Likewise,theproductionofNO,H S,serotonin, women. The nutritional, metabolic and hormonal effects of diets are
2
dopamineandGABAbygutbacteriainthesmallandlargeintestinecan closelylinkedtothegutmicrobiota.Maintainingoptimalconditionsof
participateinthesignalingandregulationofmalereproduction(Gratzke the gut ecology (i.e. composition and activity of the gut microbiota,
etal.,2010;CryanandDinan,2012).Theproductionandrecyclingofmi- morphologyandfunction)fortheutilizationofdietaryAAiscrucialfor
crobialAAmetabolitesinthebodycanregulatetheconversionofH Sto normalreproductionandthemetabolicprogrammingoftheoffspring.
2
thiosulfateinthecoloniccellsandtheregenerationofH Sfromthiosul- TheeffectsofdietarysupplementationwithAA,prebioticsandprobio-
2
fateinerythrocytesandarteries(Blachieretal.,2010;d’Emmanueledi ticsonreproductionarehighlightedinthefollowingsections(TableIV).
VillaBiancaetal.,2011;Olsonetal.,2013).Recentstudieswithmice
FunctionalAA
showedthatmetabolitessuchasbutyrateproducedbyClostridiumtyro-
butyricumimprovedtestisdevelopmentbymodulatingthepermeability Aminoacidsarenotonlynutritionallyessentialbutarealsofunctionally
oftheblood-testisbarrierandendocrinefunctionoftestis(Al-Asmakh important (Wu, 2009, 2010, 2013). For example, AA (e.g. arginine,
3
9
8
D
o
w
n
lo
a
d
e
d
TableIII Possiblelinksbetweengutbacteriaandmalereproduction. fro
m
h
Target Keybacteria Possiblemodeofaction References ttp
s
..o..r.g..a.n..s................................................................................................................................................................................................................................................ ://a
c
a
Digestivetract Notclear,possiblebacteriaaffectmalereproductionare: Gutmetabolismandhealth:reduceoxidativestress,promote Al-Asmakhetal.(2014),Poutahidisetal.(2014)andLietal. d
e
sulfur-producingbacteria(TableII);NO-producingbacteria butyrateproduction (2009) m
ic
(TableII);tryptophan-metabolizingbacteria(TableII);probiotic Modulationofimmuneandneuroendocrinefunction:production .o
bacteria(ClostridiumTyrobutyricum,Lactobacillusreuteri) ofbioactivemoleculescellwallcomponentsandpeptides; up
translocationofbacteriabydendriticcellsandmacrophagesto .co
reproductiveorgans;mediatetheproductionofAA-derived m
/m
neurotransmittersandgaseoussignalingmoleculesthus o
regulatereproductiveperformance le
h
Urogenitaltract Testis:Chlamydiatrachomatis,E.coli,Brucellaabortus Regulatetestisdevelopmentandpathogenesis:modulate Filipiaketal.(2014),Houetal.(2013),Liuetal.(2013,2014), r/a
Semena:Streptococcus,Staphylococcus,Corynebacteriumspp., permeabilityofblood-testisbarrierandendocrinefunctionof Luetal.(2013),Mackern-Obertietal.(2013),Ma¨ndar rtic
le
Lactobacillus,Prevotella,Veillonella,Peptostreptococcusspp., testisbybacterialmetabolitessuchasbutyrate;causeof (2013),Morettietal.(2009),Nelsonetal.(2012),Priceetal. -a
Gardnerella,Ralstonia,Peptoniphilis,Finegoldia,etc.;pathogens: necrosisandepididymo-orchitis (2010),Ron-Roma´netal.(2012),Rybaretal.(2012),Sellami bs
Chlamydiatrachomatis,E.coli,Corynebacteriumspp.,Ureaplasma Regulatespermatogenesis,spermfunctionandsemenquality: etal.(2014)andTu¨rketal.(2014) tra
c
urealyticum,Enterococcusfaecalis,Neisseriagonorrhoeae,Mycoplasma chromatinintegrityandapoptosisofspermatozoa,sperm t/2
spp.,Candidasp.,Trichomonasvaginalis,Anaerococcus,Morganella motility,morphology;concentrationsofzincandfructose 1
/5
morganii Mediateprostatitis:biofilmproduction /3
8
Urethraandcoronalsulcus:Lactobacillus,Corynebacteriumspp., Induceimmuneresponseandinflammation:expressionof 9
Streptococcus,Sneathiaspp.,Bacteroidesspp.,Staphylococcus pathogenrecognitionreceptors,Toll-likereceptorsand /10
8
epidermidis,Gardnerellavaginalis,etc.;uncircumcised:dominant productionofcytokines/chemokinesoftheurogenitaltract 6
8
bacteriabelongtothefamiliesofClostridialesXIandPrevotellaceae, cells 1
0
Peptoniphilis;pathogens:Chlamydiatrachomatis,E.coli,Prevotella b
y
spp.,Fusobacteriumspp.,Oxobacter,Anaerovorax,Candidasp. g
u
e
aCorynebacteriumspp.werefoundinthesemenofbothfertileandinfertilemen;Mycoplasmaspp.werefoundtobeassociatedwithinfertilityandHIVinfection(Ma¨ndar,2013;Liuetal.,2014). st o
n
1
0
A
p
ril 2
0
1
9
D
a
i
e
t
a
l.