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Abstract
Bacterial vaginosis (BV) is an enigmatic polymicrobial condition characterized by a depletion of health-associated Lactobacillus and an overgrowth of anaerobes. Importantly, BV is linked to adverse gynecologic and obstetric outcomes: an increased risk of sexually transmitted infections, preterm birth, and cancer. We hypothesized that members of the cervicovaginal microbiota distinctly contribute to immunometabolic changes in the human cervix, leading to these sequelae. Our 3D epithelial cell model that recapitulates the human cervical epithelium was infected with clinical isolates of cervicovaginal bacteria, alone or as a polymicrobial community. We used Lactobacillus crispatus as a representative health-associated commensal and four common BV-associated species: Gardnerella vaginalis, Prevotella bivia, Atopobium vaginae, and Sneathia amnii. The immunometabolic profiles of these microenvironments were analyzed using multiplex immunoassays and untargeted global metabolomics. A. vaginae and S. amnii exhibited the highest proinflammatory potential through induction of cytokines, iNOS, and oxidative stress-associated compounds. G. vaginalis, P. bivia, and S. amnii distinctly altered physicochemical barrier-related proteins and metabolites (mucins, sialic acid, polyamines), whereas L. crispatus produced an antimicrobial compound, phenyllactic acid. Alterations to the immunometabolic landscape correlate with symptoms and hallmarks of BV and connected BV with adverse women’s health outcomes. Overall, this study demonstrated that 3D cervical epithelial cell colonized with cervicovaginal microbiota faithfully reproduce the immunometabolic microenvironment previously observed in clinical studies and can successfully be used as a robust tool to evaluate host responses to commensal and pathogenic bacteria in the female reproductive tract.
Highlights
Bacterial vaginosis (BV) is the most common vaginal infection among premenopausal women worldwide with an estimated annual economic cost of $4.8 billion[1]
The analysis using metabolomic data derived from 3D cervical models infected with L. crispatus, single BV-associated bacteria (BVAB) species, the polymicrobial community, and uninfected controls resulted in excellent predictive accuracy (93.75%), when compared to the random chance of 12.5% (Fig. 4)
We tested the hypothesis that members of the cervicovaginal microbiota distinctly contribute to inflammation and metabolic responses in the vagina and cervix, which contribute to disease
Summary
Bacterial vaginosis (BV) is the most common vaginal infection among premenopausal women worldwide with an estimated annual economic cost of $4.8 billion[1]. The analysis using metabolomic data derived from 3D cervical models infected with L. crispatus, single BVAB species, the polymicrobial community (consisting of four BVAB), and uninfected controls resulted in excellent predictive accuracy (93.75%), when compared to the random chance of 12.5% (Fig. 4). Putrescine and Nacetylputrescine levels were not impacted by any tested bacteria (Fig. 6c) Succinate, another metabolite elevated in women with BV, was elevated following infections with P. bivia (4.5-fold, p = 0.0003, q = 0.006) and the polymicrobial community (2.7-fold, p = 0.004, q = 0.02). Colonization with G. vaginalis and the polymicrobial community resulted in significant depletion of sialic acid (2.4-fold, p = 0.006, q = 0.08 and 1.6-fold, p = 0.03, q = 0.09, respectively), suggesting G. vaginalis may use this metabolite as a potential energy source Overall, this analysis demonstrated unique metabolic contributions of tested clinical isolates of common BVAB species. We demonstrated additive interactions of BVAB in the multispecies consortium (a microbiological characteristic of BV), which may lead to pathophysiological changes in the cervical epithelium
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