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Vaginal microbiota form a mutually beneficial relationship with their host and have a major impact on health and disease. In recent years our understanding of vaginal bacterial community composition and structure has significantly broadened as a result of investigators using cultivation-independent methods based on the analysis of 16S ribosomal RNA (rRNA) gene sequences. In asymptomatic, otherwise healthy women, several kinds of vaginal microbiota exist, the majority often dominated by species of Lactobacillus, while others are composed of a diverse array of anaerobic microorganisms. Bacterial vaginosis is the most common vaginal condition and is vaguely characterized as the disruption of the equilibrium of the normal vaginal microbiota. A better understanding of normal and healthy vaginal ecosystems that is based on their true function and not simply on their composition would help better define health and further improve disease diagnostics as well as the development of more personalized regimens to promote health and treat diseases.
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MI66CH18-Ravel ARI 8 August 2012 16:26
Vaginal Microbiome:
Rethinking Health and Disease
Bing Ma,1Larry J. Forney,2and Jacques Ravel1
1Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore,
Maryland 21201; email: bma@som.umaryland.edu, jravel@som.umaryland.edu
2Department of Biological Sciences and the Initiative for Bioinformatics and Evolutionary
Studies, University of Idaho, Moscow, Idaho 83844; email: lforney@uidaho.edu
Annu. Rev. Microbiol. 2012. 66:371–89
First published online as a Review in Advance on
June 28, 2012
The Annual Review of Microbiology is online at
micro.annualreviews.org
This article’s doi:
10.1146/annurev-micro-092611-150157
Copyright c
2012 by Annual Reviews.
All rights reserved
0066-4227/12/1013-0371$20.00
Keywords
vaginal microbiota, vaginal ecosystem, bacterial vaginosis
Abstract
Vaginal microbiota form a mutually beneficial relationship with their host
and have a major impact on health and disease. In recent years our un-
derstanding of vaginal bacterial community composition and structure
has significantly broadened as a result of investigators using cultivation-
independent methods based on the analysis of 16S ribosomal RNA (rRNA)
gene sequences. In asymptomatic, otherwise healthy women, several kinds
of vaginal microbiota exist, the majority often dominated by species of Lac-
tobacillus, while others are composed of a diverse array of anaerobic microor-
ganisms. Bacterial vaginosis is the most common vaginal condition and is
vaguely characterized as the disruption of the equilibrium of the normal
vaginal microbiota. A better understanding of normal and healthy vaginal
ecosystems that is based on their true function and not simply on their
composition would help better define health and further improve disease
diagnostics as well as the development of more personalized regimens to
promote health and treat diseases.
371
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Further
ANNUAL
REVIEWS
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Microbiota:
microbial community
composition and
structure
Contents
INTRODUCTION............................................................... 372
COMPOSITION AND STRUCTURE OF THE VAGINAL MICROBIOTA . . . . . . 373
Culture-Dependent and Culture-Independent Approaches to Survey
Microbial Community Composition and Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Lactobacillus-DominatedVaginal Microbiota..................................... 374
Lactobacillus Species’ Antimicrobial Substances Production . . . . . . . . . . . . . . . . . . . . . . . . 376
Other Types of Vaginal Microbiota. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
BACTERIALVAGINOSIS........................................................ 377
TheBacterial VaginosisEnigma................................................. 377
Complex Etiology of Bacterial Vaginosis ......................................... 379
RETHINKINGNORMAL ANDHEALTHY..................................... 379
TemporalDynamics ofVaginal Communities.................................... 380
Toward a System-Level Understanding of the Vaginal Ecosystem . . . . . . . . . . . . . . . . . 381
CONCLUDINGREMARKS ..................................................... 383
INTRODUCTION
The microbiota normally associated with the human body have an important influence on human
development, physiology, immunity, and nutrition (18, 23, 65, 66, 70, 111). The vast majority of
these indigenous microbiota exist in a mutualistic relationship with their human host, although few
are opportunistic pathogens that can cause both chronic infections and life-threatening diseases.
These microbial communities are believed to constitute the first line of defense against infection
by competitively excluding invasive nonindigenous organisms that cause diseases. Despite their
importance, surprisingly little is known about how these communities differ between individuals
in composition and function and, more importantly, how their constituent members interact with
each other and the host to form a dynamic ecosystem that responds to environmental disturbances.
Major efforts are now under way to better understand the true role of these communities in health
and diseases (84).
The human vagina and the bacterial communities that reside therein are an example of this
finely balanced mutualistic association. In this relationship, the host provides benefit to the mi-
crobial communities in the form of the nutrients needed to support bacterial growth. This is of
obvious importance because bacteria are continually shed from the body in vaginal secretions,
and bacterial growth must occur to replenish their numbers. Some of the required nutrients are
derived from sloughed cells, while others are from glandular secretions. The indigenous bacterial
communities, on the other hand, play a protective role in preventing colonization of the host by
potentially pathogenic organisms, including those responsible for symptomatic bacterial vaginosis,
yeast infections, sexually transmitted infections (STIs), and urinary tract infections (42, 47, 96, 98,
113, 118). Lactobacilli have long been thought to be the keystone species of vaginal communities
in reproductive-age women. These microorganisms benefit the host by producing lactic acid as a
fermentation product that lowers the vaginal pH to 3.5–4.5 (12). Although a wide range of other
species are members of vaginal bacterial communities, their ecological roles and influences on
the overall community dynamics and function are largely undetermined. The vaginal ecosystem
is thought to have been shaped by coevolutionary processes between the human host and specific
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BV: bacterial
vaginosis
Phylotype:
community members
represented by a set of
phylogenetically
related 16S rRNA
gene sequences
microbial partners, although the selective forces (traits) behind this mutualistic association are still
not clear.
The development of culture-independent approaches has greatly facilitated comprehensive
surveys of the composition of vaginal microbial communities. These studies have shown that
several distinct kinds of vaginal communities with markedly different species composition occur
and that the frequency of these types of microbiota varies in different ethnic groups (86, 122–
124). It is hypothesized that differences in species composition may correlate with how vaginal
communities respond to disturbances (52, 104, 115, 123). Conceptually this is important because
vaginal communities continually experience various kinds of chronic and acute disturbances caused
by human behaviors, such as the use of antibiotics, hormonal contraceptives and other methods of
birth control, sexual activity, vaginal lubricants, douching, and so forth, in addition to many other
intrinsic factors such as the innate and adaptive immune systems of hosts (64, 88, 110). Further,
a disturbed state itself may constitute the clinical syndrome known as bacterial vaginosis (BV),
which as a disruption of ecological equilibria is believed to increase the risk of invasion by infectious
agents. Although knowledge accumulated over the past few decades has provided some insights
into the vaginal ecosystem, there remains a need to define and better understand factors that affect
the composition and dynamics of vaginal microbiota, including the role of human genetics and
physiology in both health and diseases. This knowledge will facilitate the development of new
strategies for disease diagnosis and personalized treatments to promote health and improve the
quality of women’s lives. This cannot be accomplished without addressing the fundamental issue
of what constitutes a normal and healthy vaginal microbiota and understanding its function in
health and diseases.
COMPOSITION AND STRUCTURE OF THE VAGINAL MICROBIOTA
Comprehensive surveys of vaginal microbial communities using culture-independent approaches
have revealed that Lactobacillus species are the dominant vaginal bacterial species in a majority of
women. However, an appreciable proportion of asymptomatic, otherwise healthy individuals have
vaginal microbiota lacking significant numbers of Lactobacillus spp. and harboring a diverse array
of facultative and strictly anaerobic microorganisms.
Culture-Dependent and Culture-Independent Approaches to Survey
Microbial Community Composition and Structure
Most of our knowledge of the composition, metabolic function, and ecology of indigenous micro-
bial communities associated with humans has come from studies that depended on cultivating mi-
crobial populations. Hence, our current understanding of microbe-host interactions is limited and
skewed because the overwhelming majority of microbial species (>99%) resist cultivation in the
laboratory (8). Our limited ability to culture may result from strict, yet unknown, growth require-
ments, such as the optimal combination of nutrients, growth temperatures, and dissolved-oxygen
levels, or potentially the need to cocultivate with key microbial partners (3, 27). Our knowledge of
microbial diversity has expanded enormously through the use of culture-independent approaches
based on the analysis of 16S rRNA gene sequences (50, 107). These strategies circumvent the need
to cultivate organisms by directly extracting genetic materials from environmental or biological
samples. This is followed by amplification of the 16S rRNA genes using primers that anneal to
highly conserved regions of the gene, followed by sequencing and classification of the phylotypes
present. This constitutes an efficient way to comprehensively characterize microbial diversity. The
development of next-generation sequencing technologies, including the use of massively parallel
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Community class:
clusters of community
state types’ profiles
that have similar
temporal patterns of
bacterial community
dynamics (applies to
time series)
Community state
types: clusters of
community states that
have similar phylotype
composition and
relative abundance
Community states:
phylotype composition
and relative abundance
of a single sample or a
sample in a time series
DNA sequencing of short, hypervariable regions of the 16S rRNA gene, now affords us the op-
portunity to obtain detailed surveys of microbial communities, including the identification of taxa
present in low abundance that compose the rare biospheres (27, 102). Other conserved genes such
as cpn60,rpoC,uvrB,andrecA have also been used for these purposes (92, 114).
Culture-independent methods have demonstrated that, when surveyed cross-sectionally, sev-
eral kinds of vaginal communities (community state types) exist in normal and otherwise healthy
women, each with a markedly different bacterial species composition. These communities either
are dominated by one of four common Lactobacillus species (L. crispatus,L. iners,L. gasseri,andL.
jensenii ) or do not contain significant numbers of lactobacilli, but instead have a diverse array of
strict and facultative anaerobes (86).
Lactobacillus-Dominated Vaginal Microbiota
Members of the genus Lactobacillus are commonly identified as the hallmark of a normal or healthy
vagina (25, 42, 69, 98). Since they were first identified by cultivation in vaginal secretion in the
late nineteenth century by Donderlein (24, 90, 106), Lactobacillus spp. have been thought to play
a major role in protecting the vaginal environment from nonindigenous and potentially harmful
microorganisms. This is accomplished through the production of lactic acid, resulting in a low
and protective pH (3.5–4.5) (1, 11, 12, 54, 87, 91). Interestingly, lactic acid is more effective
than acidity alone as a microbicide against HIV or against pathogens such as Neisseria gonorrhoeae
(38, 60). Exposure to gram-negative bacteria, in the presence of lactic acid, is believed to have
stimulatory effects on the host innate immune defense system (120). A recent study using in
vitro colonization of vaginal epithelial cell monolayers with common bacteria such as L. crispatus,
Prevotella bivia,andAtopobium vaginae demonstrated that these key vaginal bacteria appear to
regulate the epithelial innate immunity in a species-specific manner (32).
L. crispatus was previously thought to be one of the most common species of lactobacilli in the
vagina (5). However, the application of the culture-independent method has identified L. iners,
an organism that is difficult to cultivate and does not grow on traditional culture media, as the
most prevalent vaginal bacterial species (30, 122). In these studies, vaginal microbiota of 42%
(17) and 66% (123) of the reproductive-age women sampled were dominated by L. iners. A recent
large-scale cross-sectional study of 396 healthy asymptomatic women revealed that L. iners was
detected in 83.5% of the subjects and dominated 34.1% of the communities analyzed (86), and
that L. crispatus,L. gasseri,andL. jensenii were present in 64.5, 42.9, and 48.2% of the subjects
and dominated in 26.2, 6.3, and 5.3% of the samples, respectively (86). This large study showed
that vaginal bacterial communities that had similar species composition and abundance could be
classified into five groups, which are referred to as community state types (Figure 1). The four
community state types dominated by Lactobacillus spp. represented 73% of the samples, which
supports the prevailing view that Lactobacillus spp. are important members of vaginal microbiota.
The remaining 27% represented communities that lacked significant numbers of Lactobacillus spp.
but instead were composed of a diverse array of facultative or strictly anaerobic bacteria. Interest-
ingly, the distribution of Lactobacillus spp.–dominated community state types varies significantly
among individuals with different ethnic backgrounds (86, 123, 124). White and Asian women are
more likely than Hispanic and Black women to have vaginal communities dominated by lacto-
bacilli (86). When a Lactobacillus species is present, vaginal communities of Hispanic and Black
women are more often dominated by L. iners (86). The study also noted a higher average pH in
Black and Hispanic women, 4.7 and 5.0 respectively, compared to 4.4 and 4.2 for Asian and White
women. This observation supports the hypothesis that host factors may play an important role in
determining vaginal microbial community composition and structure.
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Lactobacillus iners
Lactobacillus crispatus
Lactobacillus gasseri
Lactobacillus jensenii
Prevotella
Megasphaera
Sneathia
Atopobium
Streptococcus
Dialister
Lachnospira
Anaerococcus
Peptoniphilus
Eggerthella
Finegoldia
Rhodobaca
Anaerotruncus
Ureaplasma
Mycoplasma
Aerococcus
Parvimonas
Staphylococcus
Corynebacterium
Veillonella
Lactobacillus vaginalis
Community
state types
pH
Nugent score
0
20
40
60
80
100
Taxon
abundance (%)
Community groups
II
II
III
III I
IV
IVV
II III I IVV 4.0–4.5
pH
4.6–5.0
5.1–5.5
>5.5
0–3
Nugent score
4–6
7–10
a
b
Figure 1
Heatmap of percentage abundance of microbial taxa found in the vaginal microbial communities of 394 reproductive-age women.
(a) Complete linkage clustering of samples based on species composition and abundance in communities defining five community state
types (CST I–V). (b) Nugent scores and pH measurements for each of the 394 samples. Adapted from Reference 86.
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1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
00.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Gardnerella vaginalis HMP9231 (Mbp)
a
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
Gardnerella vaginalis
409–05 (Mbp)
b
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Gardnerella vaginalis HMP9231 (Mbp)
0
0.2
0.4
0.6
0.8
1
Less similarity to
more similarity
Gardnerella vaginalis
ATCC 14019 (Mbp)
Figure 2
Whole-genome comparative analysis of Gardnerella vaginalis using BLAST score ratio analysis. A protein match between two genomes
is represented by a point plotted using the genomic coordinate of both matched proteins as xand ycoordinates. The level of protein
sequence similarity is represented by the color of the points (see scale at right). (a) High degree of protein similarity and synteny are
observed between G. vaginalis strains HMP9231 and ATCC 14019. (b) Lack of synteny and low degree of protein similarity are
observed between G. vaginalis strains HMP9231 and 409-05. The vertical blue bar highlights a set of syntenic genes that is unique to
the G. vaginalis HMP9231 genome and is not present in the other two genomes.
These findings highlight potential differences in the protective capabilities of vaginal Lacto-
bacillus species. Statistically significant differences have been observed in the ability of different
Lactobacillus species to lower pH between different community state types. L. crispatus–dominated
communities are able to acidify the vaginal milieu to pH 4.0; communities dominated by other
species achieved pH ranging from 4.4 to 5.0 (86). Although Lactobacillus spp. drive these processes,
other community members can contribute by either producing or utilizing lactic acid. Moreover,
it is anticipated that strains of the same species will also demonstrate genomic differences that
will result in specific physiological and biochemical traits. Previous comparative genomic analyses
have identified a high level of genetic diversity and varied metabolic potential of closely related
bacterial species or strains of the same species. For example, Escherichia coli strains can vary by as
much as 25% in their gene content (79), and strains of the same serovars of Salmonella enterica can
vary by more than 20% (61). Much of the variation occurs in the form of large genomic islands
or lineage-specific regions that may be involved in adaptation to the host microenvironment (10,
82). No comparative genomic studies of vaginal Lactobacillus spp. have been reported. However, in
Figure 2 we show strains of Gardnerella vaginalis, which is commonly found in the vaginal micro-
biota and associated with bacterial vaginosis (73, 116), can differ by 31% in gene content and gene
order (synteny). Advanced knowledge of genetic variation among Lactobacillus species (or strains)
may provide further insight into their functional potential, which may have significant implica-
tions for health and diseases. Because of species-level or strain-level genomic heterogeneity, the
analysis of 16S rRNA gene sequences, though taxonomically informative, is not able to identify
functional differences without considerable speculation, and attempts to infer the function of any
bacterial community knowing only “who is there” should be made with caution.
Lactobacillus Species’ Antimicrobial Substances Production
Vaginal Lactobacillus species produce antimicrobial compounds in addition to lactic acid, including
target-specific bacteriocins (2, 6) and broad-spectrum hydrogen peroxide (28, 43). Bacteriocins
are proteinaceous, bactericidal substances synthesized by bacteria that have a narrow spectrum of
activity (53). Their antimicrobial activity is usually based on permeabilization of the target cell
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membrane (81). In the vagina, bacteriocins could play a major role in fending off the growth of
nonindigenous or pathogenic organisms (26). Many Lactobacillus spp. produce hydrogen peroxide
in vitro under aerobic conditions, which could inhibit colonization of potential pathogenic bacteria
in vivo (43, 48, 112). However, the vagina is virtually an anaerobic environment wherein dissolved
oxygen levels are low. Therefore, it is unlikely that significant amounts of hydrogen peroxide
are produced and accumulate to a toxic level. Further, a recent study showed that physiologi-
cal concentrations of hydrogen peroxide have no detectable effect on 17 BV-associated bacteria
(BVAB) under anaerobic growth conditions and the presence of vaginal fluid can actually block its
antimicrobial activity (80). In addition, it appears that high concentrations of hydrogen peroxide
are even more toxic to vaginal Lactobacillus than to BVAB (80). Interestingly, some Lactobacillus
species, such as L. iners, fail to produce hydrogen peroxide. This feature has been used to differen-
tiate beneficial versus nonbeneficial vaginal Lactobacillus isolates (5), and it has been suggested that
hydrogen peroxide–producing vaginal Lactobacillus spp. are more likely to be protective against
acquisition of BV (43). Given the information summarized above, it is more likely that in vitro
hydrogen peroxide production is not a significant factor in preventing the emergence of disease-
causing organisms; however, it could be a surrogate marker for other yet unknown biochemical
or physiological traits. Overall, this work suggests that lactic acid, not hydrogen peroxide, is more
likely to contribute to the protective role of vaginal microbiota.
Other Types of Vaginal Microbiota
Recent studies have found that 20–30% of asymptomatic, otherwise healthy women harbor vaginal
communities that lack appreciable numbers of Lactobacillus but include a diverse array of faculta-
tive or strictly anaerobic bacteria that are associated with a somewhat higher pH (5.3–5.5) (86,
122–124). This proportion of communities can reach 40% among Black and Hispanic women
(86). These microbiota include members of the genera Atopobium,Corynebacterium,Anaerococ-
cus,Peptoniphilus,Prevotella,Gardnerella,Sneathia,Eggerthella,Mobiluncus,andFinegoldia, among
others (52, 86, 115, 122–124). These findings challenge the common wisdom that the occur-
rence of high numbers of lactobacilli and a vaginal pH of <4.5 are synonymous with “normal” and
“healthy.” Previous studies have hypothesized non-Lactobacillus-dominant vaginal microbiota may
be nonetheless able to maintain functional vaginal ecosystems by preserving lactic acid produc-
tion and possibly other important functions (36, 86, 122). Many underappreciated microorganisms,
such as members from Atopobium,Streptococcus,Staphylococcus,Megasphaera,andLeptotrichia,are
capable of homolactic or heterolactic acid fermentations (89, 122). The highly diversified micro-
bial community may have accommodated functional redundancy, allowing for the function of the
ecosystem to persist in the face of perturbations (117). In the absence of symptomology, these
types of vaginal bacterial communities might be considered normal and healthy, even though the
composition of these communities closely resembles those associated with symptomatic BV.
BACTERIAL VAGINOSIS
BV is a highly prevalent vaginal disorder in reproductive-age women, but its diagnostics and
treatment are disappointingly ineffective. BV is often vaguely characterized as the disruption of
the equilibrium of the normal vaginal ecosystem.
The Bacterial Vaginosis Enigma
BV is the most frequently cited cause of vaginal discharge and malodor, and it is the most common
vaginal condition of reproductive-age women, resulting in millions of health care visits annually
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Nugent-score BV:
BV that is diagnosed
based on Nugent
Gram stain test;
symptomology is not
taken into account
in the United States alone (99). In a cross-sectional study of reproductive-age women in 2001,
the National Health and Nutrition Examination Survey found that the prevalence of BV in the
United States was 29.2% (59). BV is an independent risk factor for the acquisition of STIs (19, 69,
83, 118), the acquisition and transmission of HIV (20–22, 69, 103, 105), the development of pelvic
inflammatory disease (76), as well as for reproductive tract and obstetric sequelae (37, 39, 49, 71,
72). Numerous investigations have identified factors that increase a woman’s risk for BV. Men-
strual blood, a new sexual partner, vaginal douching, smoking, and lack of condom use are among
the strongest risk factors for BV (9, 15, 44, 45, 51, 57, 75, 95, 119). In general, these suspected
factors often manifest themselves as relatively minor risks in clinical studies, and many women
without the above risk factors have BV. In most women, the symptoms of BV resolve on their
own without intervention (58). When necessary, the treatment of BV typically includes antibi-
otics such as metronidazole (oral tablets or topical vaginal gel) or clindamycin vaginal cream (121).
However, recurrence of BV after treatment is common: Fifteen to 30% of women have symp-
tomatic BV 30 to 90 days following antibiotic therapy; 70% of patients experience a recurrence
within nine months (13, 62, 101). Strategies for managing recurrent BV are not standardized
(100), and because the etiology of BV remains unknown, the causes of relapse remain unclear
(13, 97).
The confusion about BV stems in part from the subjective diagnostic criteria used. In clinical
settings, BV is commonly diagnosed on the basis of the clinical criteria described by Amsel et al.
(4), wherein three of the following four symptoms must be evident: (a) a homogenous, white,
noninflammatory discharge that smoothly coats the vaginal walls; (b) the presence of clue cells
(squamous epithelial cells covered with adherent bacteria) on microscopic examination; (c) a vagi-
nal fluid pH over 4.5; and (d) a fishy odor of vaginal discharge before or after addition of 10%
KOH (potassium hydroxide). The reliability of the Amsel criteria has been subject to debate, par-
ticularly in reference to pregnancy, given the increased vaginal discharge that is often experienced
by pregnant women, and to the variation of pH depending on how and where samples are taken
(41). However, not all symptoms are observed in every case (56), and because the diagnosis is
subjective, controversy persists about the definition of BV. The sensitivity and specificity of the
Amsel criteria are 70% and 94%, respectively (93), when compared to another diagnostic assay,
the Nugent Gram stain score, which is used in research and laboratories. In these settings, BV
is traditionally diagnosed by scoring a Gram-stained vaginal smear using the criteria defined by
Nugent et al. (77). The Nugent score reflects the relative abundance of large gram-positive rods
(lactobacilli), gram-negative rods and cocci, gram-variable rods and cocci (e.g., G. vaginalis,Pre-
votella,Porphyromonas,andPeptostreptococcus), and curved gram-negative rods (Mobiluncus). This
technique permits assessment of relative numbers of bacterial morphotypes and other cellular
elements, allowing for a rough evaluation of bacterial load, as well as the presence of polymor-
phonuclear leukocytes, candidal spores, fungal hyphae, and sperm. It is based on a linear scale
ranging from 0 to 10. A score of 0–3 is normal, 4–6 is intermediate, and 7–10 is considered BV.
Although the Nugent criteria are commonly used to assess BV, the scoring of specimens can be
subjective. Nonetheless, with a sensitivity of 89% and specificity of 83% (93) compared to Amsel
criteria, the Nugent Gram stain test remains the preferred diagnostic tool (41, 59), and it can be
performed on self-collected vaginal smears (74), thus facilitating longitudinal field-based studies
(14, 94). Interestingly, as much as 50% of all women with BV (as defined by Nugent score) are
asymptomatic (4), which led to the use of the term Nugent-score BV (85). It is unclear whether
these women are truly without symptoms or whether the symptoms were poorly recognized or
underreported. The meaning and implications of asymptomatic BV are not known. Even so, and
because of growing concern for the complications linked to BV, there is a practice of treating
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asymptomatic disease under certain circumstances, such as prior to a hysterectomy procedure or
in women at high risk for preterm birth (121).
Complex Etiology of Bacterial Vaginosis
Despite decades of research, attempts to find a single causative agent for BV have failed. Con-
sequently, Koch’s postulates are not fulfilled, in which the etiologic agent is both necessary and
sufficient to cause disease and should not be found in subjects without disease (29, 35). Indeed,
there is growing evidence that BV is characterized, and perhaps caused, by disruption of the vaginal
ecosystem, which is reflected in alterations to the composition and structure of vaginal microbial
communities, such that the numbers of lactic-acid-producing bacteria are decreased and the di-
versity and numbers of strictly anaerobic bacteria are increased, including species of Gardnerella,
Atopobium,Mobiluncus,andPrevotella, as well as other taxa of the order Clostridiales (34). The vaginal
microbial community composition associated with BV is somewhat similar to the community state
type described above that is found in asymptomatic healthy women that lack a significant number
of Lactobacillus species. Culture-independent methods have identified potentially BV-associated
bacteria (BVAB) that could not be identified by traditional culture-based methods (31, 34). BVAB
are distantly related to known species of the phyla Actinobacteria and Firmicutes. However, the
significance of these findings remains unclear, as it is not known whether these microorganisms
are pathogens that cause BV or whether they simply are opportunistic organisms that take ad-
vantage of the temporarily higher pH environment and thus increase in numerical dominance.
Overall, these molecular studies have shown that the diversity, composition, and relative abun-
dances of microbial species in the vagina vary dramatically in both normal, healthy women and
women presenting with BV. These diverse organisms accumulate to form different communities,
or profiles, which support the hypothesis that BV is not a single entity, but a syndrome linked to
various community types that cause somewhat similar physiological symptoms. This suggests that
a yet unknown common community function may account for BV and the differing responses to
antibiotic therapies.
However, because these studies often rely on a single sample collected from women presenting
to their physician with symptomatic BV, it is not possible to elucidate the causes of BV (microbi-
ological, biochemical, molecular, or behavioral) without access to samples collected prior to the
diagnosis and during the events leading to BV. Prospective longitudinal studies, in which samples
are collected frequently along with detailed behavioral metadata, are necessary to understand the
causes of BV. Such information is expected to suggest methods to identify women who are at risk
of acquiring symptomatic BV, to identify new targets for intervention and prevention strategies,
and to enable development of more accurate diagnostic criteria.
RETHINKING NORMAL AND HEALTHY
The paradigm that healthy women are always colonized with high numbers of Lactobacillus species
(46, 48) has previously been challenged as discussed above. Although numerous studies have shown
that women with abundant Lactobacillus species do not have BV, the corollary that women whose
vaginal communities have few or no Lactobacillus species have BV is faulty logic. Unfortunately, the
commonly used diagnostic criteria (both Amsel and Nugent), wherein the degree of healthiness
is in part assessed by scoring the abundance of Lactobacillus morphotypes, tends to overdiagnose
BV. This could account at least partly for the reported high incidence (as high as 42%; 56) of
so-called asymptomatic BV in reproductive-age women, as defined by a positive Nugent score
and no reported vaginal symptoms. It could also explain a portion of BV treatment failures and
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Stability:
the capability of an
ecosystem to resist
change in the face of
disturbance
apparent recurrences of BV (33). To better understand symptomatic BV, its causes, and the
factors predisposing or triggering the condition, it is essential to apply molecular analyses of
vaginal communities to a statistically significant number of women sampled longitudinally and
prospectively in order to define the diversity and dynamics of the vaginal ecosystem in the general
populace. These studies would help us better understand what constitutes normal and healthy
vaginal microbiota and the fluctuations that commonly occur in normal and healthy communities.
As suggested by Marrazzo et al. (67), only by using such approaches will we be able to change and
refine the definition, etiology, and epidemiology of BV.
The fine line that separates a normal and healthy vaginal microbiota from one that is abnormal
and unhealthy is further complicated by potential confusion between health and the predisposition
to diseases such as STIs, and by the lack of a complete understanding of the functional intricacies
of the host and its vaginal microbiota. It is difficult to envision the evolutionary processes that led
to a vaginal microbiota with the sole function of protecting the host from STIs, mainly because only
a small proportion of women have been or are exposed to STI pathogens. Interestingly, humans
are among the very few mammals with a vaginal microbiota often dominated by Lactobacillus spp.,
and with such a low pH. Hence, it appears that other yet unknown functions must have driven the
composition of the human vaginal microbiota. For example, one potential function could relate
to immune stimulation or microbial protection of the newborn in the first days of life. Without
more knowledge of these functions, one might consider separating the concept of health from the
concept of resistance to STIs. That said, it is essential to understand the factors that increase the
risks of acquiring STIs and the community types that might be more susceptible to infection. It is
conceivable that from time to time a dynamic system such as the vaginal microbiota might enter
states (defined by their composition or their function) that would increase the risk of infection.
The frequency and duration of these states might represent better predictors of risk of infection
than the abundance of a single community member or a given microbial community profile.
With knowledge of the factors driving these dynamics and a better understanding of the func-
tion of the vaginal microbiota, novel prevention strategies could be developed to lower the risks.
These strategies might include driving the maintenance of more protective and highly functional
vaginal microbiota, or possibly using more personalized probiotics or prebiotic mixtures. In addi-
tion, these risks are at play only when a woman has the potential to be exposed to the pathogens.
If exposure is not likely (perhaps through the practice of celibacy or monogamy), it might not be
appropriate to define the healthiness of a woman’s vaginal microbiota by factors associated with
their predisposition to infections. Hence, a new thinking would involve dissociating the concept
of normal and healthy vaginal microbiota from that of predisposition to STIs. A healthy vaginal
microbiota could then be defined as a microbial community with a functional output that is ad-
equately beneficial to the host and not solely defined by its composition, and this function could
be provided by several kinds of vaginal communities. In this context, different types of vaginal
microbiota could be considered healthy in the absence of symptoms, with or without lactobacilli,
while having differing degrees of predisposition to infections by sexually transmitted pathogens.
Temporal Dynamics of Vaginal Communities
To date most studies of vaginal microbiology have employed cross-sectional designs in which
samples are obtained from individuals at a single time point or with long intervals between sampling
times (weeks or months). Although these studies have provided important information on the
species composition of vaginal communities, they yield little insight into the normal temporal
dynamics of these bacterial communities within individuals and do not provide an estimate of
community stability. Daily fluctuations in the composition of the vaginal microbiota have been
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Microbiome:
microbial community
gene content
previously documented by microscopy (16, 44, 55, 95). Even more recently, a longitudinal study
conducted by our group described the temporal dynamics of vaginal community composition
in 32 healthy reproductive-age women sampled twice weekly over a 16-week period (36). The
study showed that some communities changed markedly over a short period, whereas others
were relatively stable, including communities lacking a significant number of Lactobacillus spp.
(Figure 3). In an effort to model the dependence of vaginal bacterial community stability on
the time in the menstrual cycle and other time-varying factors, menses was identified as having
the most negative effect on stability, along with the type of communities and sexual activity to
a lesser extent. On the other hand, time periods of the menstrual cycle corresponding to a high
level of estrogen or estrogen and progesterone were associated with higher stability. This study
highlights the great potential of prospective longitudinal studies to elucidate the cause and etiology
of multifactorial diseases such as BV compared with studies that often rely on a single sample
collected from women presenting with symptomatic BV. Longitudinal study designs, in which
samples are collected frequently along with detailed behavioral metadata, would afford access to
samples collected prior to the diagnosis and during the events leading to BV. The knowledge
gained from such studies is expected to elucidate factors that govern this dynamic ecosystem, to
forecast symptomatic BV susceptibility, and to enable the development of innovative diagnostic,
intervention, and prevention strategies.
Toward a System-Level Understanding of the Vaginal Ecosystem
Although comprehensive molecular community surveys have provided a great deal of information
about the composition of the vaginal microbiota, its role and the intrinsic dynamics that drive
its interaction with its host are still unknown. In order to have translational impact on women’s
health, it is essential to develop an understanding of healthy and disease states that includes
knowledge of the functional characteristics of the vaginal microbiota and the types of vaginal
microbiota that can provide the needed functions. For example, the notion of an enterotype in
the gut microbiome is defined not by the presence of a core set of organisms, but by a core set of
available conserved genes that are involved in critical metabolic pathways (7, 86, 108, 109). This
notion is informative for subject stratification, but it is still limited to an understanding of the
functional potential of a microbial community, and not of its true function and benefit to the host.
State-of-the-art -omics technologies combined with a statistical modeling framework offer
an opportunity to develop a systems-level understanding of the vaginal ecosystem by measuring
biological components of a system to derive functional modules that reflect specific phenotypic
traits. This could be accomplished by using a multilevel approach based on (a) metagenomics
to catalog the relative abundance of all microbial and, to some extent, human genes and their
polymorphisms, and the functional potentials and their degree of redundancy; and (b) metatran-
scriptomics and metaproteomics to assess levels of differential expression of microbial and host
genes in healthy and disease states or in response to various perturbations. This multilevel ap-
proach would also provide insight into the functional interaction between the vaginal microbiota
and the host by using metabolomics to characterize the products of ecosystem-level physiological
processes and metabolic output. Predictive statistical models used in a systems biology framework
could be used to integrate these various datasets and to quantitatively assess critical biological
processes, environmental conditions, or behaviors associated with healthy states, as well as disease
initiation, progression, and symptomatology (40, 63, 68, 78). The goal of these efforts would be to
develop a systems-level understanding of the molecular events that promote health or lead to dis-
ease, and to spur the development of novel diagnostic screens and enable more holistic prevention
and treatment regimens.
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Lactobacillus iners
Atopobium
Lactobacillus jensenii
Prevotella
Aerococcus
Escherichia
Megasphaera
Gemella
Coriobacteriaceae.3
Lactobacillus gasseri
Peptoniphilus
Enterobacter
Streptococcus
Lactobacillus crispatus
Lactobacillus iners
Lactobacillus otu5
Lactobacillales.2
Lactobacillus jensenii
Lactobacillus gasseri
Staphylococcus
Lactobacillus otu3
Lactobacillus vaginalis
Lactobacillus otu4
Atopobium
Prevotella
Lactobacillus iners
Parvimonas
Sneathia
Peptoniphilus
Gardnerella
Mobiluncus
Peptostreptococcus
Aerococcus
Lactobacillus gasseri
Lactobacillus otu4
Streptococcus
Lactobacillus iners
Corynebacterium
Staphylococcus
Finegoldia
Dermabacter
Prevotella
Bidobacterium
Microbacterium
Escherichia
0
20
40
60
80
100
1234567891011121314150
Time (weeks)
Phylotype relative
abundance (%)
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
Time (weeks)
Phylotype relative
abundance (%)
0
20
40
60
80
100
1234567891011121314150
Time (weeks)
Phylotype relative
abundance (%)
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 1011121314150
Time (weeks)
Phylotype relative
abundance (%)
a
b
c
d
Figure 3
Temporal dynamics of vaginal bacterial communities in women sampled twice weekly over 16 weeks.
Interpolated bar plot of the relative abundance of phylotypes from four subjects (a–d ) with different
community dynamics profiles. Color key for each phylotype is shown at the top of each graph.
382 Ma ·Forney ·Ravel
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MI66CH18-Ravel ARI 8 August 2012 16:26
CONCLUDING REMARKS
The dynamics of vaginal bacterial communities during the menstrual cycle, and the dramatic
changes associated with transitions between the physiological stages of a woman’s life span, from
the first week of life to puberty, reproductive years, and menopause, are a reflection of the interplay
of the mutualistic relationship between the vaginal microbiota and its human host. The ever-
changing yet finely tuned vaginal ecosystem is a result of adaptive coevolutionary processes that
integrate many different aspects such as sexual hormone levels, features of host physiology, and
composition and functional output of the vaginal microbiota. Study of the systems-level temporal
dynamics of the vaginal ecosystem and its functional output will contribute to our understanding
of what truly constitutes normal and healthy. The application of the modern -omics technologies
to the study of the vaginal ecosystem is expected to translate to better diagnostics and improved
personalized treatments.
SUMMARY POINTS
1. The development of culture-independent community surveys has greatly advanced our
understanding of the composition and structure of vaginal microbiota.
2. Lactobacillus species dominate vaginal microbiota in most normal and healthy women.
However, an appreciable proportion of asymptomatic, otherwise healthy individuals have
vaginal microbiota that lack significant numbers of Lactobacillus spp. and harbor a diverse
array of facultative and strictly anaerobic microorganisms, challenging the conventional
wisdom that the presence of lactobacilli equates to normal and healthy vaginal microbiota.
3. Neither clinical criteria (using either the Amsel or the Nugent scoring systems) nor
community composition and structure can fully explain symptomatic BV, which appears
to be a multifactorial clinical syndrome with complex and still unknown etiologies.
4. The concept of normal and healthy vaginal microbiota is difficult to define without a
complete understanding of its true function(s) and its effect on host physiology. One
might envision separating the concept of normal and healthy from predisposition to
diseases such as STIs.
FUTURE ISSUES
1. Study of the vaginal ecosystem using prospective and frequent sampling study design
allows the analysis of samples collected before, during, and after a disease event.
2. There is a need to further characterize the true function of the vaginal microbiota in the
context of vaginal health to better understand disease.
3. The role of host genotype in community assembly, composition, and dynamics requires
further examination.
4. A systems-level model of the vaginal ecosystem should be developed in order to charac-
terize the functional interaction between the vaginal microbiota and the host.
5. It is expected that future effort should be made to translate current knowledge to the de-
velopment of personalized preventive or curative regimens (based on vaginal community
types), including probiotics and prebiotics.
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DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
This work was supported by the National Institute of Allergies and Infectious Diseases, National
Institutes of Health (grant numbers U19 AI084044, UO1 AI070921, and UH2 AI083264).
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Annual Review of
Microbiology
Volume 66, 2012 Contents
A Fortunate Journey on Uneven Grounds
Agnes Ullmann pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp1
Memories of a Senior Scientist: On Passing the Fiftieth Anniversary
of the Beginning of Deciphering the Genetic Code
Peter Lengyel pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp27
Yeast ATP-Binding Cassette Transporters Conferring
Multidrug Resistance
Rajendra Prasad and Andre Goffeau pppppppppppppppppppppppppppppppppppppppppppppppppppppppp39
‘Gestalt,’ Composition and Function of the
Trypanosoma brucei Editosome
H. Ulrich G¨oringer ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp65
Physiology and Diversity of Ammonia-Oxidizing Archaea
David A. Stahl and Jos´e R. de la Torre ppppppppppppppppppppppppppppppppppppppppppppppppppppp83
Bacterial Persistence and Toxin-Antitoxin Loci
Kenn Gerdes and Etienne Maisonneuve ppppppppppppppppppppppppppppppppppppppppppppppppppp103
Activating Transcription in Bacteria
David J. Lee, Stephen D. Minchin, and Stephen J.W. Busby ppppppppppppppppppppppppppp125
Herpesvirus Transport to the Nervous System and Back Again
Gregory Smith pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp153
A Virological View of Innate Immune Recognition
Akiko Iwasaki ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp177
DNA Replication and Genomic Architecture in Very Large Bacteria
Esther R. Angert pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp197
Large T Antigens of Polyomaviruses: Amazing Molecular Machines
Ping An, Maria Teresa S´aenz Robles, and James M. Pipas pppppppppppppppppppppppppppppp213
Peroxisome Assembly and Functional Diversity
in Eukaryotic Microorganisms
Laurent Pieuchot and Gregory Jedd ppppppppppppppppppppppppppppppppppppppppppppppppppppppp237
vi
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Microbial Population and Community Dynamics on Plant Roots and
Their Feedbacks on Plant Communities
James D. Bever, Thomas G. Platt, and Elise R. Morton ppppppppppppppppppppppppppppppppp265
Bacterial Chemotaxis: The Early Years of Molecular Studies
Gerald L. Hazelbauer pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp285
RNA Interference Pathways in Fungi: Mechanisms and Functions
Shwu-Shin Chang, Zhenyu Zhang, and Yi Liu pppppppppppppppppppppppppppppppppppppppppp305
Evolution of Two-Component Signal Transduction Systems
Emily J. Capra and Michael T. Laub ppppppppppppppppppppppppppppppppppppppppppppppppppppp325
The Unique Paradigm of Spirochete Motility and Chemotaxis
Nyles W. Charon, Andrew Cockburn, Chunhao Li, Jun Liu,
Kelly A. Miller, Michael R. Miller, Md. A. Motaleb,
and Charles W. Wolgemuth ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp349
Vaginal Microbiome: Rethinking Health and Disease
Bing Ma, Larry J. Forney, and Jacques Ravel pppppppppppppppppppppppppppppppppppppppppppp371
Electromicrobiology
Derek R. Lovley ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp391
Origin and Diversification of Eukaryotes
Laura A. Katz pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp411
Genomic Insights into Syntrophy: The Paradigm
for Anaerobic Metabolic Cooperation
Jessica R. Sieber, Michael J. McInerney, and Robert P. Gunsalus ppppppppppppppppppppppp429
Structure and Regulation of the Type VI Secretion System
Julie M. Silverman, Yannick R. Brunet, Eric Cascales, and Joseph D. Mougous ppppppp453
Network News: The Replication of Kinetoplast DNA
Robert E. Jensen and Paul T. Englund pppppppppppppppppppppppppppppppppppppppppppppppppppp473
Pseudomonas aeruginosa Twitching Motility: Type IV Pili in Action
Lori L. Burrows ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp493
Postgenomic Approaches to Using Corynebacteria as Biocatalysts
Alain A. Vert`es, Masayuki Inui, and Hideaki Yukawa pppppppppppppppppppppppppppppppppp521
Index
Cumulative Index of Contributing Authors, Volumes 62–66 ppppppppppppppppppppppppppp551
Errata
An online log of corrections to Annual Review of Microbiology articles may be found at
http://micro.annualreviews.org/
Contents vii
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... In this study, we conducted initial functional characterization of urinary lactobacilli from seven species under uniform conditions. Three of those species (eight strains) are from the abundant and frequently identified species in the female urinary tract: L. crispatus, L. gasseri and L. jensenii (Ma et al., 2012;Komesu et al., 2020;Neugent et al., 2022). While lactobacilli inhabiting other ecological niches have been previously studied, urinary lactobacilli have not previously been characterized, despite their potential for direct interactions with uropathogens and potential clinical implications regarding urinary tract infections. ...
Article
Full-text available
The human urinary microbiome is thought to affect the development and progression of urinary tract infections (UTI), particularly recurrent UTIs in aging populations of women. To understand the possible interactions of urinary pathogens with commensal bacteria inhabiting the aging bladder, we conducted an initial functional assessment of a representative set of urinary lactobacilli that dominate this niche in postmenopausal women. We created a repository of urinary bladder bacteria isolated via Enhanced Quantitative Urinary Culture (EQUC) from healthy postmenopausal women, as well as those with a culture-proven recurrent UTI (rUTI) diagnosis. This repository contains lactobacilli strains from eight different species. As many other lactobacilli are known to inhibit human pathogens, we hypothesized that some urinary lactobacilli will have similar abilities to inhibit the growth of typical uropathogens and thus, provide a link between the urinary microbiome and the predisposition to the rUTI. Therefore, we screened the urinary lactobacilli in our repository for their ability to inhibit model uropathogens in vitro. We observed that many urinary isolates strongly inhibit model strains of gram-negative Escherichia coli and Klebsiella pneumoniae but demonstrate less inhibition of gram-positive Enterococcus faecalis. The observed inhibition affected model strains of uropathogens as well as clinical and multidrug-resistant isolates of those species. Our preliminary analysis of inhibition modes suggests a combination of pH-dependent and cell-dependent inhibition. Overall, inhibition strongly varies among species and strains of urinary lactobacilli. While the strength of the inhibition is not predictive of health outcomes in this limited repository, there is a high level of species and strain diversity that warrants future detailed investigations.
... Although the CVM is composed of different microbe communities, it is highly dominated by the genus Lactobacillus (Lactobacillus crispatus, Lactobacillus iners, Lactobacillus gasseri, or Lactobacillus jensenii) [171,172]. In addition to maintaining tissue homeostasis [173] and a local pH lesser than 4.5 [174], lactobacilli adhere to epithelial cells by forming microcolonies and serve as a barrier to protect the genital environment from infectious pathogens [175], counteracting bacterial vaginosis, yeast infections, and sexually transmitted diseases (STDs) [176,177]. The imbalance of the CVM triggers abnormal cell proliferation, chronic inflammation, genome instability, STDs, premature births, and cancers of the vaginal tract [40, [178][179][180]. ...
Article
Full-text available
Advancement in the development of molecular sequencing platforms has identified infectious bacteria or viruses that trigger the dysregulation of a set of genes inducing the epithelial–mesenchymal transition (EMT) event. EMT is essential for embryogenesis, wound repair, and organ development; meanwhile, during carcinogenesis, initiation of the EMT can promote cancer progression and metastasis. Recent studies have reported that interactions between the host and dysbiotic microbiota in different tissues and organs, such as the oral and nasal cavities, esophagus, stomach, gut, skin, and the reproductive tract, may provoke EMT. On the other hand, it is revealed that certain microorganisms display a protective role against cancer growth, indicative of possible therapeutic function. In this review, we summarize recent findings elucidating the underlying mechanisms of pathogenic microorganisms, especially the microbiota, in eliciting crucial regulator genes that induce EMT. Such an approach may help explain cancer progression and pave the way for developing novel preventive and therapeutic strategies.
... The composition of the female genital tract microbiota is influenced by numerous factors, including age, pH in vagina, hormonal secretions, the menstrual cycle, contraceptives, antibiotic use, and sexual activity (Prince et al., 2015;Nasioudis et al., 2017). Lactobacillus, the dominant bacterium in the vagina of women during pregnancy (Dominguez-Bello et al., 2010;Ma et al., 2012), can bind to the surface of vaginal epithelial cells to prevent the attachment of other microorganisms in the vagina. It can not only produce lactic acid by decomposing glycogen in the vagina to maintain a stable pH, but also kill intracellular microorganisms by inducing the autophagy of vaginal epithelial cells (Witkin and Linhares, 2017). ...
Article
Full-text available
The distribution of the microbiome in women with advanced maternal age (AMA) is poorly understood. To gain insight into this, the vaginal and gut microbiota of 62 women were sampled and sequenced using the 16S rRNA technique. These women were divided into three groups, namely, the AMA (age ≥ 35 years, n = 13) group, the non-advanced maternal age (NMA) (age < 35 years, n = 38) group, and the control group (non-pregnant healthy women, age >35 years, n = 11). We found that the alpha diversity of vaginal microbiota in the AMA group significantly increased. However, the beta diversity significantly decreased in the AMA group compared with the control group. There was no significant difference in the diversity of gut microbiota among the three groups. The distributions of microbiota were significantly different among AMA, NMA, and control groups. In vaginal microbiota, the abundance of Lactobacillus was higher in the pregnant groups. Bifidobacterium was significantly enriched in the AMA group. In gut microbiota, Prevotella bivia was significantly enriched in the AMA group. Vaginal and gut microbiota in women with AMA were noticeably different from the NMA and non-pregnant women, and this phenomenon is probably related to the increased risk of complications in women with AMA.
... All of these microorganisms make up the vaginal microbiota and colonise in a dynamic environment [95]. Though each woman exhibits a different vaginal microbiota community, those with Lactobacillus as the dominant member are more often associated with healthy vaginal homeostasis [96]. ...
Article
Full-text available
Vulvovaginal candidiasis (VVC) is a prevalent gynaecological disease characterised by vaginal wall inflammation that is caused by Candida species. VVC impacts almost three-quarters of all women throughout their reproductive years. As the vaginal mucosa is the first point of contact with microbes, vaginal epithelial cells are the first line of defence against opportunistic Candida infection by providing a physical barrier and mounting immunological responses. The mechanisms of defence against this infection are displayed through the rapid shedding of epithelial cells, the presence of pattern recognition receptors, and the release of inflammatory cytokines. The bacterial microbiota within the mucosal layer presents another form of defence mechanism within the vagina through acidic pH regulation, the release of antifungal peptides and physiological control against dysbiosis. The significant role of the microbiota in maintaining vaginal health promotes its application as one of the potential treatment modalities against VVC with the hope of alleviating the burden of VVC, especially the recurrent disease. This review discusses and summarises current progress in understanding the role of vaginal mucosa and host immunity upon infection, together with the function of vaginal microbiota in VVC.
... Regarding the oral route of administration, it is critical to consider the viability of the probiotics strains under high concentrations of gastric acid and bile salts as well as the time lactobacilli can reach and colonize the vagina, which appear to be different person to person [53]. Marcotte et al. [43] illustrated that the efficacy of probiotics was consistent with the short-term efficacy of antibiotics and that the long-term efficacy of probiotics significantly prevented BV recurrence [54,55]. e results of several trials have shown that pre/probiotics combined with metronidazole (12 trials; 994 populations) or clindamycin (3 trials; 350 populations) are more efficient in reducing BV recurrence rate compared to metronidazole or clindamycin alone. ...
Article
Full-text available
Background: Bacterial vaginosis (BV), caused by an imbalance in the vaginal microbiota, can be treated and prevented by probiotics. Pregnant women with BV can experience premature labor and spontaneous abortions. Probiotics and prebiotics promote the proliferation of beneficial microorganisms, alter the composition of the vaginal microbiota, and prevent intravaginal infections in postmenopausal women. In addition to reducing infection symptoms, pre/probiotics can also help prevent vaginal infections. Materials and methods: A systematic review was conducted on studies from 2010 to 2020 to determine the efficacy of pre/probiotics on the treatment of BV in pregnant and nonpregnant women. The databases Medline, Scopus, Embase, and Google Scholar were systematically searched using the following keywords: "bacterial vaginosis," "probiotics," "prebiotics," and "synbiotics." Results: A total of 1,871 articles were found in the initial search, and 24 clinical trials were considered eligible. In studies comparing the effects of pre/probiotics and placebos with or without antibiotic therapy in patients with BV, significant differences in clinical outcomes were observed. Probiotics reduced the levels of IL-1β and IL-6, as well as the overall Nugent score and Amsel's criteria for restitution of a balanced vaginal microbiota. In addition, probiotics can reduce the vaginal colonization of Group B streptococci among pregnant women. In subjects treated with probiotics, BV cure rates were higher than those in subjects treated with antibiotics. There were no additional adverse events. Conclusion: Pre/probiotic regimens, when used for BV treatment, are usually safe and can exhibit long-term and short-term benefits. In order to prove the benefits of pre/probiotics in BV treatment, additional high-quality research is required.
... In addition to microorganisms within the gut, microorganisms in other niches may profoundly influence host physiology [122][123][124][125] . This includes microorganisms on external surfaces and mucosal sites, and also tissue-resident microorganisms 126 . ...
Article
Microorganisms within the gut and other niches may contribute to carcinogenesis, as well as shaping cancer immunosurveillance and response to immunotherapy. Our understanding of the complex relationship between different host-intrinsic microorganisms, as well as the multifaceted mechanisms by which they influence health and disease, has grown tremendously—hastening development of novel therapeutic strategies that target the microbiota to improve treatment outcomes in cancer. Accordingly, the evaluation of a patient’s microbial composition and function and its subsequent targeted modulation represent key elements of future multidisciplinary and precision-medicine approaches. In this Review, we outline the current state of research toward harnessing the microbiome to better prevent and treat cancer. There exists tremendous opportunity to target microorganisms in the gut and other niches to help treat or even prevent cancer. This Review outlines how microbial targeting could become a pillar of personalized cancer care over the next 5 to 10 years.
... Vaginal taxa from the mother have also been found to transiently colonize the child's fecal and airway microbiota [22]. Vaginal microbiota communities are typically dominated by Lactobacillus species [23,24], specifically L. iners, L. crispatus, L. gasseri, or L. jensenii; yet, significant differences are seen between North American women from different ethnic groups (White, Black, Hispanic, and Asian) [25]. When a misbalance in vaginal microbiota occurs, such as a lower abundance of Lactobacillus, bacterial vaginosis is likely to occur-resulting in unwanted perinatal outcomes, including preterm birth (e.g. ...
Article
Full-text available
The intestinal microbiota plays a crucial role in health and changes in its composition are linked with major global human diseases. Fully understanding what shapes the human intestinal microbiota composition and knowing ways of modulating the composition are critical for promotion of life-course health, combating diseases, and reducing global health disparities. We aim to provide a foundation for understanding what shapes the human intestinal microbiota on an individual and global scale, and how interventions could utilize this information to promote life-course health and reduce global health disparities. We briefly review experiences within the first 1,000 days of life and how long-term exposures to environmental elements or geographic specific cultures have lasting impacts on the intestinal microbiota. We also discuss major public health threats linked to the intestinal microbiota, including antimicrobial resistance and disappearing microbial diversity due to globalization. In order to promote global health, we argue that the interplay of the larger ecosystem with intestinal microbiota research should be utilized for future research and urge for global efforts to conserve microbial diversity.
Article
Background: in recent years, many studies were carried out to explore the role of vaginal microbiota in HPV infections and cervical intraepithelial neoplasia (CIN) progression. The aim of this study was to conduct a review of the literature to analyze the interaction between the vaginal microbiota, the CIN, and the immunological response. Methods: we performed a literature search, considering papers published between November 2015 and September 2021. Results: despite significant evidence suggesting a role of vaginal microbiota in the pathogenesis of HPV-related lesions, some studies still struggle to demonstrate this correlation. However, the vaginal microbiota of HPV-positive women shows an increased diversity, combined with a reduced relative abundance of Lactobacillus spp. and a higher pH. In cervical dysplasia progression, a strong association is found with new bacteria, and with the deregulation of pathways and hyperexpression of cytokines leading to chronic inflammation. Conclusions: in HPV progression, there is a strong correlation between potential biomarkers, such as Sneathia and Delftia found in community state types IV and II, and chronic inflammation with cytokine overexpression. Better analysis of these factors could be of use in the prevention of the progression of the disease and, eventually, in new therapeutic strategies.
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