The role of Lactobacilli in lactic acid production and vaginal acidification
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 colonised 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 defence 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 gynaecologist considered one of the founders of gynaecological 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), pre-term 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.
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 vagina 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.10,11 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-), with the latter form a function of both the concentration of total lactate (LAH + LA-) and hydrogen ions (H+)/pH.16-18 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.
In addition to lactic acid production and vaginal acidification, Lactobacilli are thought to utilise several mechanisms to inhibit pathogen colonisation 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 neutralise toxicity).21
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