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Specific, highly complex microbial communities (microbiota), including their collective genetic material (microbiome), differ between anatomic sites of an individual (e.g., intestinal, vaginal, oral, skin) as well as between people.1 An increasing body of scientific evidence has demonstrated these microbial communities markedly influence human health. Furthermore, clinical research is demonstrating the targeted manipulation of these microbial communities with specific probiotic strains offers a promising strategy to improve and maintain health.
The vagina is a dynamic environment colonized by various microorganisms (microbes), thus, collectively referred to as the vaginal microbiota. The composition and function of the vaginal microbiota has been linked to women's health status. Microbes inhabiting the vagina are thought to provide the first line of defense in the urogenital tract. Although there is not a definitive 'normal" vaginal microbiota, current scientific knowledge has revealed that lactobacilli predominance is generally the hallmark of a healthy vaginal microbiota as high lactobacilli abundance is associated with the promotion and maintenance of vaginal microbial ecosystem balance. In 1892, Albert Döderlein, a German obstetrician and gynecologist considered one of the founders of gynecological bacteriology, first described a Gram-positive vaginal bacillus (Döderlein's bacillus) occurring in normal vaginal secretions of asymptomatic pregnant women, which was later renamed Lactobacillus. He argued that in normal vaginal secretions, Döderlein's bacilli and lactic acid produced by the bacilli were essential to keep the vagina free of pathogenic bacteria. Low numbers or absence of vaginal lactobacilli is more often associated with increased risk of bacterial vaginosis (BV), yeast overgrowth ('yeast infection"), aerobic vaginitis (AV), urinary tract infections (UTIs), and adverse obstetric outcomes (e.g., miscarriage, premature rupture of membranes (PROM), preterm birth, ventilation/respiratory distress at birth, neonatal sepsis, neonatal intensive care unit admission).2-6 Clinical research has established the therapeutic value of administering specific probiotic lactobacilli strains for the restoration and maintenance of a healthy vaginal microbiota.
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Vaginal Acidification: Lactobacilli Production of D- and L-Lactic Acid
Lactobacilli are facultative anaerobic (aerotolerant) bacteria that produce lactic acid via the fermentation of glucose.7 The vaginal lactic acid concentration is inversely associated with vaginal pH in women with a lactobacilli-dominated vaginal microbiota, indicating lactic acid is predominantly responsible for vaginal acidification.8 Production of lactic acid and vaginal acidification plays a prominent role in imparting the broad protection against other microbes associated with a lactobacilli-dominated vaginal microbiota.9 Furthermore, lactic acid reinforces lactobacilli predominance and maintenance of an acidic vaginal pH in support of a balanced microbial ecosystem with limited diversity.
Vaginal lactobacilli are the primary source of lactic acid in the vagina10,11 and only source of the D-isomer as human cells can only produce L-lactic acid, with < 15% of L-lactic acid produced by vaginal mucosal epithelial cells.11 The production of the D-lactic acid isomer by some Lactobacillus strains enhances protection against microbial invasion of the upper genital tract by supporting the integrity of the cervical external orifice of the uterus.12 The majority of preterm births result from infections caused by bacteria from the vagina that have traversed the cervix. In addition to vaginal acidification, lactic acid has been shown to directly inactivate various reproductive and urinary tract pathogens.13-15 The active microbicidal/viricidal form of lactic acid is the protonated (LAH) rather than the un-protonated lactate anion (LA-),16,17 with the latter form a function of both the concentration of total lactate (LAH + LA-) and hydrogen ions (H+)/pH.
Lactic acid may also regulate host immune responses to evoke protection against potentially pathogenic microbes within the vaginal microbiota. In the presence of a synthetic analogue of double-stranded viral RNA, lactic acid potentiates the production of protective pro-inflammatory cytokines (IL-8 and IL-1b) by vaginal epithelial cells.19 Lactic acid was shown to potentiate interleukin-23 production from innate immune cells in response to lipopolysaccharide (endotoxin), which may promote activation of T-helper type 17 subclass of T-lymphocytes in response to Gram-negative bacteria.20 Each of these activities exemplifies enhanced activation of host anti-microbial innate and acquired immunity.
Other Potential Protective Mechanisms of Vaginal Lactobacilli
In addition to lactic acid production and vaginal acidification, Lactobacilli are thought to utilize several mechanisms to inhibit pathogen colonization of the vaginal tract: co-aggregation of non-pathogens and pathogens to interfere with the infectious capacity of pathogenic species, production of biosurfactants to disrupt adhesion to the vaginal mucosa by pathogenic species, production of antimicrobial bacteriocins and hydrogen peroxide, competitive exclusion of pathogenic species via competing for nutrients and host surfaces, reinforcing the integrity of the vaginal mucosal epithelial barrier (up-regulation of tight junction proteins to limit damage caused to vaginal epithelium by inflammatory processes or pathogens), and regulation of host immune responses (production of antimicrobial peptides/proteins such as defensins, lactoferrin and lysozyme, and alkaline phosphatases, which can bind to lipopolysaccharide/endotoxin to neutralize toxicity).21
Lactobacillus Species Predominance of Vaginal Microbiota
Unlike any other anatomical site of the human body, most vaginal microbial communities (>70%) are dominated by one or more species of Lactobacillus that constitute >50% of all genetic sequences obtained. Recent studies using high-throughput 16S rRNA gene sequencing studies have shown that composition and relative abundance of vaginal microbial communities in reproductive-aged women cluster into at least five core vaginal microbiota, termed community state types (CSTs).22-24 Four of these CSTs, representing the majority (>70%) of women, are dominated by a different Lactobacillus species: L. crispatus (CSTI), L. gasseri (CSTII), L. jensenii (CSTV), and L. iners (CSTIII), whereas CSTIV is characterized by low proportions of lactobacilli and is composed of a diverse mixture of primarily strict anaerobic bacteria including species of the genera Gardnerella, Atopobium, Mobiluncus, Prevotella and other taxa in the order Clostridiales, as seen with states of BV.
Of note, L. iners is present in most women, including both healthy and those with dysbiosis/BV,4 whereas L. crispatus is typically only observed in healthy women. Ravel et al.22 observed that L. crispatus-dominated vaginal microbiota have lower vaginal pH compared to communities dominated by other species. Vaginal microbiotas dominated by L. iners have lower vaginal concentrations of D-lactic acid as L. iners lacks the gene coding for D-lactate dehydrogenase, so cannot produce this lactic acid isomer,12 which may in part mediate the higher observed frequency of BV and preterm delivery in these women.25 D-lactic acid levels were significantly higher when L. crispatus was the dominant vaginal bacterial species than when L. iners or Gardnerella dominated the vaginal microbiota.12 It has been suggested that the increased proportion of L. iners in women with BV may be due to increased tolerance of this Lactobacillus species to an elevated pH, characteristic of BV, more than other Lactobacillus species.26 In contrast, L. crispatus, L. gasseri, and L. jensenii are all producers of the D-lactic acid isomer as well as hydrogen peroxide. L. iners also does not produce antimicrobial hydrogen peroxide.
Hydrogen peroxide-producing lacto-bacilli are more likely to sustain long-term vaginal colonization, and women colonized by hydrogen peroxide-producing lactobacilli have decreased acquisition of human immunodeficiency virus (HIV) infection,27 gonorrhea,27 and BV.28 Evidence supports a vaginal microbiota dominated by Lactobacillus species other than L. iners is optimal to support vaginal health (i.e., strains of L. iners have not been considered candidates as probiotics to support women's urogenital health).29,30
Differences in the composition of these vaginal microbial communities have been observed between women of different ethnic backgrounds. Lactobacilli-dominated vaginal microbial communities (CST I, II, III, V) were observed in ~80% and ~90% of Asian and white women, respectively, but only ~60% and ~62% of Hispanic and black women, respectively.22 Over-representation of CSTIV in Hispanic and black women was associated with a higher median pH in these ethnic groups as well. Such differences in vaginal microbial communities between women of different ethnic backgrounds have been observed in other studies as well.24,31
Although CSTIV can be observed in otherwise healthy women, asymptomatic for BV, it is associated with higher Nugent scores (a Gram stain scoring system from 0 – 10 for vaginal swabs reflecting abundance of Gram-positive rods [lactobacilli] and Gram-negative variable rods and cocci [G. vaginalis, Prevotella, etc.] to diagnose BV with 0 – 3 considered normal, 4 – 6 indicative of intermediate bacterial counts, and 7 – 10 diagnostic of BV) and may be a risk factor for adverse gynecologic and obstetric outcomes.3,32,33
Pregnancy and Estrogen Promotion of Vaginal Lactobacilli
Composition of the vaginal microbiota can be dynamic and capable of rapid shifts within a short period of time (e.g., < 24 hours), although more stable in many women and during different physiologic states such as pregnancy. Vaginal microbial communities of pregnant women are more stable and have higher relative abundance of lactobacilli than non-pregnant women.34,35 The most common lactobacillus species of the vaginal microbiota observed in healthy pregnant women in the late first trimester were L. crispatus and L. gasseri (>50%), followed by L. jensenii (~20%) and L. rhamnosus (~10%), as well as combinations thereof (~10%).36
Estrogen is thought to play an important role in promoting a lactobacilli-dominated vaginal microbiota by stimulating accumulation of glycogen in the vaginal epithelial mucosa,37,38 which is thought to contribute to the increased lactobacilli predominance and stability of the vaginal microbiota observed in healthy pregnant women. Nutrient-containing vaginal secretions and glycogen-containing (as a source of glucose) vaginal epithelial cells that are sloughed and subsequently lyse are thought to be primary nutrient sources for the vaginal microbiota. Estrogen increases the volume of vaginal secretions and induces thickening of the vaginal epithelium along with glycogen accumulation, thought to support growth of glucose-fermenting lactobacilli.39 Changes in relative abundance of vaginal lactobacilli are associated with both estrogen levels and glycogen content across the various life-stages of women (e.g., pre-pubertal, pubertal/reproductive age, postmenopausal).40 Additionally, use of oral hormonal contraceptives (i.e., estrogen) and a decreased prevalence of BV has been consistently observed in epidemiological studies.41-44
Loss of Vaginal Lactobacilli: Common Factors
Various common factors are thought to influence the vaginal microbiota and have been associated with dysbiosis/BV: hygiene/intravaginal practices (douching), sexual activity (e.g., increased frequency and number of partners, lack of male circumcision/condom use), stress, smoking, and use of antibiotics/anti-fungals.3,45 Antimicrobials have been the primary therapeutic intervention utilized for the treatment of urogenital 'infections" (overgrowth of potentially pathogenic microbes) for more than four decades. Unfortunately, antimicrobial treatment of urogenital infections is often ineffective, particularly for BV; and there is a high rate of recurrent infections without preventative continuation of antimicrobial therapies. Efficacy is also diminishing with increasing development of antimicrobial resistance. The antimicrobial, metronidazole, is the most commonly used treatment for BV; however, cure rates associated with this treatment are low (as low as 61% one month post-therapy46) with a high incidence of overgrowth of potentially pathogenic bacteria following treatment.47
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