Association between statin use, the vaginal microbiome, and Gardnerella vaginalis vaginolysin-mediated cytotoxicity

Abstract

BackgroundBacterial vaginosis (BV) is the leading dysbiosis of the vaginal microbiome. The pathways leading towards the development of BV are not well understood. Gardnerella vaginalis is frequently associated with BV. G. vaginalis produces the cholesterol-dependent cytolysin (CDC), vaginolysin, which can lyse a variety of human cells and is thought to play a role in pathogenesis. Because membrane cholesterol is required for vaginolysin to function, and because HMG-CoA reductase inhibitors (statins) affect not only serum levels of cholesterol but membrane levels as well, we hypothesized that statins might affect the vaginal microbiome.MethodsTo investigate the relationship between use of the statins and the vaginal microbiome, we analyzed 16S rRNA gene taxonomic surveys performed on vaginal samples from 133 women who participated in the Vaginal Human Microbiome Project and who were taking statins at the time of sampling, 152 women who reported high cholesterol levels but were not taking statins, and 316 women who did not report high cholesterol. To examine the effect of statins on the cytolytic effect of vaginolysin, the cholesterol-dependent cytolysin (CDC) produced by Gardnerella vaginalis, we assessed the effect of simvastatin pretreatment of VK2E6/E7 vaginal epithelial cells on vaginolysin-mediated cytotoxicity.ResultsThe mean proportion of G. vaginalis among women taking statins was significantly lower relative to women not using statins. Women using statins had higher mean proportions of Lactobacillus crispatus relative to women with normal cholesterol levels, and higher levels of Lactobacillus jensenii relative to women with high cholesterol but not taking statins. In vitro, vaginal epithelial cells pretreated with simvastatin were relatively resistant to vaginolysin and this effect was inhibited by cholesterol.ConclusionsIn this cross-sectional study, statin use was associated with reduced proportions of G. vaginalis and greater proportions of beneficial lactobacilli within the vaginal microbiome. The negative association between statin use and G. vaginalis may be related to inhibition of vaginolysin function.

Interaction of Gardnerella vaginalis and Vaginolysin with the Apical versus Basolateral Face of a Three-Dimensional Model of Vaginal Epithelium

“…VLY mediates lactate dehydrogenase release only when exposed to the basolateral face. Previous studies indicate that VLY induces cytopathogenic changes in vaginal epithelial cells cultured as monolayers and lactate dehydrogenase (LDH) release (64). We extended these findings through the analysis of cytotoxicity in a threedimensional model of the vaginal epithelium.…”

“…Expression and purification of recombinant VLY. E. coli strain BL21(DE3) CodonPlus/pRIPL (Agilent technologies) was previously transformed with an isopropyl-␤-D-thiogalactopyranoside (IPTG)-inducible, vlycontaining pET32XT vector (64). One-liter cultures were grown to exponential phase (optical density at 600 nm [OD 600 ] of 0.5) and induced with 1 mM IPTG for 2 h, and the bacteria were collected by centrifugation.…”

Prospects of NSAIDs administration as double-edged agents against endometrial cancer and pathological species of the uterine microbiome

“…As mentioned, CD59 is overexpressed in many types of tumors, including breast cancer. 49 Abdelmaksoud et al 50 observed a dose-dependent reduction of G. vaginalis and normalizing the level of Lactobacillus spp. in vaginal flora after treatment with statins, known as lipid-decreasing mediators.…”

Protocol for systematic review and meta-analysis: impact of statins as immune-modulatory agents on inflammatory markers in adults with chronic diseases

“…Statins are reported to have a great effect on vaginal microbiome via reduced proportions of Gardnerella vaginalis and increased proportions of beneficial lactobacilli. 49 In addition, statins diminished the risk of infections in patients with type 2 diabetes. 50 Inversely, in patients with dementia statin, therapy was associated with increased risk of infection.…”