Antimicrobial and immune modulatory effects of lactic acid and short chain fatty acids produced by vaginal microbiota associated with eubiosis and bacterial vaginosis

Abstract

Lactic acid and short chain fatty acids (SCFAs) produced by vaginal microbiota have reported antimicrobial and immune modulatory activities indicating their potential as biomarkers of disease and/or disease susceptibility. In asymptomatic women of reproductive-age the vaginal microbiota is comprised of lactic acid-producing bacteria that are primarily responsible for the production of lactic acid present at ~110 mM and acidifying the vaginal milieu to pH ~3.5. In contrast, bacterial vaginosis (BV), a dysbiosis of the vaginal microbiota, is characterized by decreased lactic acid-producing microbiota and increased diverse anaerobic bacteria accompanied by an elevated pH>4.5. BV is also characterized by a dramatic loss of lactic acid and greater concentrations of mixed SCFAs including acetate, propionate, butyrate, and succinate. Notably women with lactic acid-producing microbiota have more favorable reproductive and sexual health outcomes compared to women with BV. Regarding the latter, BV is associated with increased susceptibility to sexually transmitted infections (STIs) including HIV. In vitro studies demonstrate that lactic acid produced by vaginal microbiota has microbicidal and virucidal activities that may protect against STIs and endogenous opportunistic bacteria as well as immune modulatory properties that require further characterization with regard to their effects on the vaginal mucosa. In contrast, BV-associated SCFAs have far less antimicrobial activity with the potential to contribute to a pro-inflammatory vaginal environment. Here we review the composition of lactic acid and SCFAs in respective states of eubiosis (non-BV) or dysbiosis (BV), their effects on susceptibility to bacterial/viral STIs and whether they have inherent microbicidal/virucidal and immune modulatory properties. We also explore their potential as biomarkers for the presence and/or increased susceptibility to STIs.

Keywords: bacterial vaginosis; lactic acid; lactobacilli; metabolites; microbiome; short chain fatty acids; vaginal microbiota.

Figure 1

The vaginal environment during alternative states of eubiosis and BV. (A) During eubiosis, lactic acid-producing bacteria acidify the vaginal milieu pH <4.5 (average ~3.5) with lactic acid as the predominant metabolite. Lactic acid potently inactivates STIs while lactic acid-producers, such as Lactobacillus, generate a non-inflammatory environment. (B) During BV, the vaginal environment has a lower redox potential conducive to the growth of diverse anaerobic bacteria and higher bacterial load. The concentration of mixed SCFAs and amines also increase and is accompanied by loss of vaginal acidity pH >4.5. The diverse anaerobic bacteria generate virulence factors which compromise epithelial barrier integrity, degrade mucin and generate a pro-inflammatory environment.

Figure 2

Protonated lactic acid exists in equilibrium with the un-protonated lactate anion, which is determined by the acid dissociation constant (pK_a 3.9). In healthy asymptomatic women of reproductive age with low vaginal pH, lactic acid predominates which is the microbicidal and virucidal form with immune modulatory activity. In contrast, the lactate anion, which does not have microbicidal or virucidal activity, predominates in women with bacterial vaginosis with a neutral vaginal pH.