Influence of Vaginal Bacteria andd- andl-Lactic Acid Isomers on Vaginal Extracellular Matrix Metalloproteinase Inducer: Implications for Protection against Upper Genital Tract Infections

Abstract

We evaluated levels of vaginal extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP-8) in vaginal secretions in relation to the composition of vaginal bacterial communities and d- and l-lactic acid levels. The composition of vaginal bacterial communities in 46 women was determined by pyrosequencing the V1 to V3 region of 16S rRNA genes. Lactobacilli were dominant in 71.3% of the women, followed by Gardnerella (17.4%), Streptococcus (8.7%), and Enterococcus (2.2%). Of the lactobacillus-dominated communities, 51.5% were dominated by Lactobacillus crispatus, 36.4% by Lactobacillus iners, and 6.1% each by Lactobacillus gasseri and Lactobacillus jensenii. Concentrations of l-lactic acid were slightly higher in lactobacillus-dominated vaginal samples, but most differences were not statistically significant. d-Lactic acid levels were higher in samples containing L. crispatus than in those with L. iners (P < 0.0001) or Gardnerella (P = 0.0002). The relative proportion of d-lactic acid in vaginal communities dominated by species of lactobacilli was in concordance with the proportions found in axenic cultures of the various species grown in vitro. Levels of l-lactic acid (P < 0.0001) and the ratio of l-lactic acid to d-lactic acid (P = 0.0060), but not concentrations of d-lactic acid, were also correlated with EMMPRIN concentrations. Moreover, vaginal concentrations of EMMPRIN and MMP-8 levels were highly correlated (P < 0.0001). Taken together, the data suggest the relative proportion of l- to d-lactic acid isomers in the vagina may influence the extent of local EMMPRIN production and subsequent induction of MMP-8. The expression of these proteins may help determine the ability of bacteria to transverse the cervix and initiate upper genital tract infections.

The vaginal microbiome during pregnancy and the postpartum period in a European population

“…produce both the D- and L-lactic acid isomers60. Witkin and colleagues (2013) recently reported elevated levels of D-lactic acid in vaginal microbiomes dominated by L. crispatus and showed that an increased ratio of D- to L-lactic acid promotes the expression of vaginal extracellular matrix metalloproteinase inducer, which in turn can activate matrix metalloproteinase-8 and may subsequently alter cervical integrity61. Such studies designed to improve understanding of the functional relevance of specific vaginal community state types during pregnancy could help clarify recent conflicting reports regarding the association of the vaginal microbiome in preterm birth outcomes.…”

Cervical Microbiota Associated with Higher Grade Cervical Intraepithelial Neoplasia in Women Infected with High-Risk Human Papillomaviruses

“…Smith et al also observed that cervical microbiota clustered in six distinct community types, one of which was characterized by a predominance of L. iners (42) L. iners , discovered by Falsen et al (43) has escaped attention because it grows only on blood agar. L. iners -dominated samples have lower concentrations of D-lactic acid, which is protective against infection by pathogens (44). L. iners has also been reported to induce IL-8 secretion in vivo and thereby potentially moderate pro-inflammatory activity in the cervix which may influence CIN progression (36).…”

The Changing Landscape of the Vaginal Microbiome

“…Lactobacilli use several mechanisms to inhibit colonization by other bacteria including pathogens. Vaginal epithelial cells produce glycogen, which lactobacilli ferment, producing D- and L- lactic acid 18 . Some species produce hydrogen peroxide in vitro; however, recent studies suggest that in the hypoxic conditions that exist in the vagina, concentrations may never achieve levels that are inhibitory to other bacteria 19 .…”