Vaginal Microbiota and the Use of Probiotics

8/17/2019 Vaginal Microbiota and the Use of Probiotics

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(The National Center for Biotechnology Information)

National Center for Biotechnology Information, U.S. National Library of Medicine 8!! "oc#$ille

%i#e , Bethe&da M' , !8* US+

Vaginal Microbiota and the Use of Probiotics

Sarah Cribby,, Michelle Taylor ,, and -regor "eid,

-regor "eid/ 0mail/ ac.o123rogerg

"ecommended by "obert +. Britton

+2thor information 4 +rticle note& 4 Co5yright and Licen&e information 4

"ecei$ed !!8 62l !7 "e$i&ed !!8 ct 97 +cce5ted !!8 No$ 8.

Co5yright : !!8 Sarah Cribby et al.

Thi& i& an o5en acce&& article di&trib2ted 2nder the Creati$e Common& +ttrib2tion Licen&e, 1hich 5ermit& 2nre&tricted 2&e,di&trib2tion, and re5rod2ction in any medi2m, 5ro$ided the original 1or# i& 5ro5erly cited.

Thi& article ha& been cited by other article& in %MC.

Abstract

1. THE MICROBIOTA O THE VA!I"A

The microbial species that inhabit the vaginal tract play an important role in the maintenance of

health, and prevention of infection. Over 50 microbial species have been recovered from the

vaginal tract [1 – 3]. These species do not eist independently, and st!dies in vitro and in h!manshave sho"n that a m!ltispecies microbiota, !s!ally associated "ith bacterial vaginosis #$%&, are

present in dense biofilms [' – (], "hile a lactobacilli dominant microbiota can be sparsely

distrib!ted on the epitheli!m [', 5, )]. *n comparison, the g!t is pop!lated "ith more than )00

species of microbes, the ma+ority of "hich are ecreted in feces, and a n!mber of "hich are "ell

e!ipped to be pathogenic. -espite the close proimity of the vagina to the an!s, the diversity of

microbes present in the vagina is m!ch lo"er than in the g!t. The reason for this lo"er diversity

http://www.ncbi.nlm.nih.gov/http://www.nlm.nih.gov/http://www.nlm.nih.gov/http://www.nlm.nih.gov/http://www.ncbi.nlm.nih.gov/pubmed/?term=Cribby%20S%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Cribby%20S%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Taylor%20M%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Taylor%20M%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Reid%20G%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Reid%20G%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Reid%20G%5Bauth%5Dmailto:dev@nullhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/about/copyright.htmlhttp://www.ncbi.nlm.nih.gov/pmc/about/copyright.htmlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/citedby/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/citedby/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/citedby/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B8http://www.nlm.nih.gov/http://www.ncbi.nlm.nih.gov/pubmed/?term=Cribby%20S%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Taylor%20M%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Reid%20G%5Bauth%5Dmailto:dev@nullhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/about/copyright.htmlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/citedby/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B8http://www.ncbi.nlm.nih.gov/


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is still !nclear, b!t may involve poor receptivity of the vagina, different n!trient availability

compared to the g!t, and competition "ith indigeno!s organisms. ome species fo!nd in the g!t,

s!ch as E. coli and Streptococcus, can also be fo!nd in the vagina, indicating the proper

receptors, n!trients, and oygen tension are present for these organisms to gro".

-ifferent methodologies are being !sed to identify the composition of the vaginal microbiota.

/ach has its strengths and "eanesses. !lt!re2based methods allo" strains to be identified and

!sed for f!rther eperimentation. o"ever, as there remains a ma+or defect in o!r ability to gro"

many bacterial species, "e m!st rely on nonc!lt!re methods to identify the breadth of vaginal

microbiota. This has been achieved by analy4ing their ribosomal -6 se!ences [3, 7], !sing a

combination of 89 and denat!ring gel gradient electrophoresis #-::/& [;, 5, 10 – 1;], and by

!sing degenerate, !niversal polymerase chain reaction primers to amplify an approimately 555

base2pair regions of the !niversal chaperonin2


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mainly Lactobacillus, "ere detected in the vaginal m!cosa of )(@ of the "omen [5]. *n

postmenopa!sal "omen not receiving 9T, almost all s!b+ects had vaginal m!cosa pop!lated

"ith more than 1 organism, many of "hich had pathogenic potential s!ch as Bacteroides,

Prevotella, andGardnerella, associated "ith bacterial vaginosis #$%&, and E.

coli and Enterococcus, associated "ith ?T* [5].

>hile a vaginal tract dominated by lactobacilli appears to protect the host against some vaginal

infections, it does not f!lly prevent coloni4ation by other species. 8athogens are still able to

coeist "ith these commensal organisms, as sho"n by $!rton and 9eid [10], "here G. vaginalis,

a pathogen associated "ith $%, "as detected in a vaginal sample "hich also contained a species

of Lactobacillus. *nterestingly, G. vaginalis "as displaced beyond detectable limits for ;1 days,

follo"ing a single intravaginal instillation of probiotic lactobacilli [11]. 6s more and more

st!dies are !ncovering the diversity microbiota of the vagina, it seems apparent that the balance

bet"een a healthy and diseased state involves some sort of e!ilibri!m or see2sa" effect, "hich

can s"ing in either direction depending on a n!mber of factors, s!ch as hormone levels,do!ching, se!al practices, as "ell bacterial interactions and host defenses [;0, ;1].

>itin et al. [;)] have proposed that innate imm!nity plays an important role in the s"itch to $%

from a healthy state. The mechanism they propose is thro!gh microbial2ind!ced inhibition of

Toll2lie receptor epression andAor activity blocing proinflammatory imm!nity, as "ell as a

lac of (02-a heat2shoc protein prod!ction, and a deficit in vaginal mannose2binding lectin

concentrations decreasing the capacity for microbial illing. Three recent st!dies have provided

f!rther insight into the hostBs role. *n a st!dy of "omen s!sceptible to ?T*, it "as discovered that

imm!nological defects in peripheral blood coeisted "ith a persistently aberrant microbiota

#Cir+avainen et al. [;7]&. *n postmenopa!sal "omen, $% "as associated "ith apparent red!ced

epression of host antimicrobial factors [30]. >hen probiotic L. rhamnosus :921 "as

administered to the vagina of premenopa!sal "omen, it res!lted in 3 53< gene epression

changes and increased epression levels of some antimicrobial defenses [31].

.

#. "O"$E%UA&&' TRA"$MITTE( I"ECTIO"$ O THE VA!I"A& TRACT A"(I"TERERE"CE B' &ACTOBACI&&I

8athogenic organisms are able to infect the vagina, "ith $%, yeast vaginitis, and ?T*s ca!sing an

estimated one billion or more cases per year [3; – 35]. >hile there is some evidence that the

ca!sative organisms can be transmitted by se!al partners, these conditions "ill be disc!ssed

here as nonse!ally transmitted. Other revie"s ade!ately cover se!ally transmitted infections

[3


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problematic [35]. *t is diagnosed by microscopic detection of dense n!mbers of yeast cells on a

vaginal smear, and by physical eamination and the presence of a "hite, m!co!s2lie yeast

discharge. Of note, lactobacilli are often fo!nd in patients "ith yeast vaginitis, therefore, the

ind!ction of infection does not appear to re!ire the yeast displacing or illing off the

lactobacilli.

?rinary tract infections occ!r "hen pathogenic bacteria ascend from the vagina and replicate on,

and sometimes "ithin, the bladder !rotheli!m [3;, 3), 37]. These infections are fre!ent among

"omen, "ith an estimated 50@ s!ffering at some time in their life. ymptoms and signs incl!de

s!prap!bic pain, dys!ria, py!ria, fre!ency and painf!l mict!rition, and occasionally hemat!ria.

6symptomatic bacteri!ria is also a common occ!rrence, partic!larly amongst the elderly. The

most fre!ent pathogen is E. coli, follo"ed by Enterococcus faecalis, and Staphlococcus

saprophticus [37]. -iagnosis can be achieved by presence of symptoms and signs, and !rine

samples containing over 103 organismsAmE of the pathogens. *n a portion of patients, the E.

coli invade the bladder epitheli!m and form dense biofilms that are recalcitrant to antibiotics['0]. *n "omen "ith no history of ?T*, their vagina and perine!m is most commonly coloni4ed

by lactobacilli [;0], "hile in "omen "ith rec!rrent ?T* there is an inverse association bet"een

lactobacilli and E. coli ['1], s!ggesting that lactobacilli play a role in preventing infection.

The most common !rogenital disorder in "omen of reprod!ctive age is $%, a condition

disc!ssed above. The vaginal microbiota of $% patients typically contains a broader range of

species than fo!nd !nder healthy conditions, "ith !topobium

vaginae, Bacteroides spp., Gardnerella vaginalis, "obiluncus, "egasphera, "coplasma

hominis, Peptostreptococcus, and Prevotella being partic!larly prevalent [3, '; – '


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preterm labor and lo" birth "eight [5;, 53]. Other problems associated "ith $% incl!de pelvic

inflammatory disease, ?T*, and increased s!sceptibility to se!ally transmitted diseases,

incl!ding *% [5' – 5(].

The organisms associated "ith $% form dense biofilms on the vaginal epitheli!m, and these are

associated "ith increased resistance to lactobacilli2prod!ced lactic acid and hydrogen peroide

#;O;& "hich are normally antagonistic to plantonic organisms [5)]. The biofilms are also able

to ind!ce host epression of certain inflammatory factors, s!ch as *E21 and *E2) [57]. *t is not

c!rrently no"n "hether the prod!ction of ;O; by lactobacilli has a clinically protective role

against $%. The increased prevalence of ;O;2peroide prod!cing vaginal lactobacilli in healthy

"omen has been given as a reason to believe that it is a protective factor [


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rec!rrences are d!e to antimicrobials failing to eradicate the pathogens, perhaps beca!se of

biofilm resistance, or that the vir!lent organisms come bac from their so!rce #the personBs g!t,

or a se partner& and attac a host "hose defenses are s!boptimal. Do!ng girls "ho s!ffer from

?T* are more liely to have repeated episodes in ad!lthood, and overall many ?T*, $%, and

yeast vaginitis patients "ill have a rec!rrence [;1,


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the oral approach may be the ability of the lactobacilli to red!ce the transfer of yeast and

pathogenic bacteria from the rect!m to the vagina [)0], "hich co!ld potentially lo"er the ris of

infection. *n that randomi4ed, placebo2controlled trial of hen these strains of lactobacilli "ere combined "ith Lactobacillus

brevis -; in a vaginal tablet, adhesion of G. vaginalis "as red!ced by 5(.(@, and


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paste!ri4ed. 8atients "ere not receiving long2term antibiotics or imm!nos!ppressive therapy and

had not cons!med yogh!rt prior to the commencement of the st!dy. They "ere randomly

assigned to one of t"o treatment gro!ps and ingested 150 mE of either paste!ri4ed yogh!rt #n K

;3& or yogh!rt containing L. acidophilus at F 1.0 P 10) colony2forming !nits #n K ;3&. Dogh!rt

"as cons!med daily for t"o months follo"ed by t"o months of no yogh!rt. There "as a


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Candida "as reported in 1'.3@ of s!b+ects in the probiotic gro!p and 13.5@ of patients in the

placebo gro!p. The viable n!mber of bacteria per tampon diminished to 10


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to have a possible lin "ith heavy cons!mption of dairy prod!cts [7(]. Only one case had

a Lactobacillus isolate that "as indisting!ishable from a probiotic strain. There "as no

connection bet"een the species of Lactobacillus isolated and the type of infection or mortality. 6

recent st!dy that directly instilled a si2strain bacterial prod!ct into the intestine of patients "ith

severe, potentially fatal pancreatitis portrayed probiotics as being dangero!s [7(]. o"ever, the prod!ct had never been proven to be probiotic, it "as administered as a dr!g !nlie 77.7@ of

probiotics, the randomi4ation process led to patients "ith m!ltiorgan fail!re being given large

doses of live bacteria, and the a!thors failed to provide a rationale for the st!dy in an appropriate

animal model. 6ll this led to !n"arranted adverse p!blicity for the field of probiotics [7)].

evertheless, safety of probiotic !se m!st contin!ally be monitored and considered "hen doing

clinical st!dies. The potential for transfer of antibiotic resistance is one factor to consider,

altho!gh it remains to be proven that probiotics have contrib!ted in any "ay to dr!g resistance,

or disease. 9ather, the over!se of antibiotics, especially in livestoc feed and long2term

prevention of infection, remains a root ca!se of the increasing concerns over dr!g resistance./fforts to s!bstit!te prophylactic antibiotics "ith probiotics, especially in children "ith rec!rrent

?T* [(0] and perhaps some patients preparing to !ndergo s!rgery [77], are "orthy of p!rs!it.

.

+. CO"C&U$IO"

Holec!lar methodologies are providing a greater !nderstanding of the dynamic microbial

presence, both short and long term, in the vagina. The defenses of the host "hich incl!de some

of these microbes perform a remarable f!nction given the opport!nity of pathogens to ca!se

infection. The !se of probiotic lactobacilli to prevent infection has a good rationale, and an

ecellent safety record, b!t so far only a fe" strains have been clinically proven to be effective,

in partic!lar to prevent $%. *t is critically important that strains be characteri4ed and tested

clinically !sing the delivery system of choice #oral, vaginal, dried po"der, or in s!spension&. 6n

advantage for "omen is that they can self2administer the probiotics. Hany more st!dies are

needed to optimi4e the defensive properties of the vaginal microbiota, b!t the potential remains

that the health of many "omen can be improved by probiotic intervention.

AC,"O-&E(!ME"T

This "or is s!pported by grants from /9 and 6=Hnet.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B96http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B96http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B98http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B69http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B99http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B96http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B96http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B98http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B69http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/#B99http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662373/


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'iseases. 1770I1;#5&G)5omen 8rone to ?rinary Tract *nfections. Clinical/accine &mmunolog. ;007I1hatBs ne" in management of se!ally transmitted infectionsN anadian :!idelines on

e!ally Transmitted *nfections, ;00< /dition.Canadian amil Phsician. ;00(I53#10&G1(37–1('1. [8H free article] [8!bHed]3). ooton TH, choles -, !ghes R8, et al. 6 prospective st!dy of ris factors for symptomatic !rinary tract infection in yo!ng "omen. +he e% England (ournal of

"edicine. 177


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'1. :!pta C, tapleton 6/, ooton TH, 9oberts 8E, =ennell E, tamm >/. *nverse association of ;O;2prod!cing lactobacilli and vaginal Escherichiacoli coloni4ation in "omen "ith rec!rrent !rinary tract infections. +he (ournal of &nfectious 'iseases. 177)I1()#;&G''a"er HR, et al. *%21 infection associated "ith abnormal vaginal flora morphology and bacterial vaginosis. +he

Lancet . 177(I350#70((&G5'altersdorph 6H. ontrol of the microbial flora of the vagina by ;O;2generating lactobacilli. (ournal of &nfectious

'iseases. 1771I1. *mplantation of Lactobacillus casei var rhamnosus into vagina. +he Lancet . 177'I3''#)731&Gp. 1;;7. [8!bHed]

(5. adie! 8, $!rton R, :ardiner :, et al. Lactobacillus strains and vaginal ecology. +he (ournal of the !merican "edical !ssociation. ;00;I;)(#15&G17'0– 17'1. [8!bHed]

(, =raser , einemann , O"en R, enning $. Oral probiotics can resolve !rogenital infections. E"S &mmunolog * "edical "icrobiolog. ;001I30#1&G'7–5;. [8!bHed]((. :ardiner :/, einemann , $aro+a HE, et al. Ora l administration of the probiotic combination Lactobacillus rhamnosus :921 and L. fermentum 921' for h!manintestinal applications. &nternational 'air (ournal . ;00;I1;#;23&G171–17


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);. %elraeds HH, van der Hei , 9eid :, $!sscher R. *nhibition of initial adhesion of !ropathogenic Enterococcus faecalis by bios!rfactantsfrom Lactobacillus isolates. !pplied and Environmental "icrobiolog. 177eintra!b E, Ol!nd 6, ord 2/. $acterial vaginosis is not a simple ecological disorder. Gnecologic and )bstetric

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