Vaginal epithelial dysfunction is mediated by the microbiome, metabolome, and mTOR signaling

Bacterial vaginosis (BV) is characterized by depletion of Lactobacillus and overgrowth of anaerobic and facultative bacteria, leading to increased mucosal inflammation, epithelial disruption, and poor reproductive health outcomes. However, the molecular mediators contributing to vaginal epithelial dysfunction are poorly understood. Here we utilize proteomic, transcriptomic, and metabolomic analyses to characterize biological features underlying BV in 405 African women and explore functional mechanisms in vitro. We identify five major vaginal microbiome groups: L. crispatus (21%), L. iners (18%), Lactobacillus (9%), Gardnerella (30%), and polymicrobial (22%). Using multi-omics we show that BV-associated epithelial disruption and mucosal inflammation link to the mammalian target of rapamycin (mTOR) pathway and associate with Gardnerella, M. mulieris, and specific metabolites including imidazole propionate. Experiments in vitro confirm that type strain G. vaginalis and M. mulieris supernatants and imidazole propionate directly affect epithelial barrier function and activation of mTOR pathways. These results find that the microbiome-mTOR axis is a central feature of epithelial dysfunction in BV. [Display omitted] •Dysbiotic vaginal bacteria modify key signaling networks in the host including mTOR•mTOR signaling activation associated with both clinical Nugent BV and molecular BV•Epithelial barrier disruption is modulated through metabolites and bacterial products•The host-microbiome axis involving mTOR links to inflammation and barrier disruption Berard et al. find a key cellular central signaling network, mTOR, that associates with host inflammation and epithelial barrier disruption in women with a dysbiotic vaginal microbiome and bacterial vaginosis (BV). This network, as well as barrier disruption, is directly modulated by bacterial products and BV-associated metabolites in vitro.