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Abstract
Bacterial vaginosis (BV) is a gynecologic disorder characterized by a shift in cervicovaginal microbiota from Lactobacillus spp. dominance to a polymicrobial biofilm composed of diverse anaerobes. We utilized a well-characterized human three-dimensional cervical epithelial cell model in conjunction with untargeted metabolomics and immunoproteomics analyses to determine the immunometabolic contribution of three members of the Veillonellaceae family: Veillonella atypica, Veillonella montpellierensis and Megasphaera micronuciformis at this site. We found that Veillonella spp. infections induced significant elevation of polyamines. M. micronuciformis infections significantly increased soluble inflammatory mediators, induced moderate levels of cell cytotoxicity, and accumulation of cell membrane lipids relative to Veillonella spp. Notably, both V. atypica and V. montpellierensis infections resulted in consumption of lactate, a key metabolite linked to gynecologic and reproductive health. Collectively our approach and data provide unique insights into the specific contributions of Veillonellaceae members to the pathogenesis of BV and women’s health.
Highlights
Human mucosae are colonized by diverse and dynamic bacterial communities that impact health and homeostasis or contribute to disease states, depending on the compositional nature of the communities[1]
We found that M. micronuciformis induced significant cytotoxicity at all tested multiplicities of infection (MOI) (6.65%, 7.96%, and 13.63%) to cervical epithelial cell monolayers (P = 0.0291, P = 0.0041, and P < 0.0001 respectively); cervical epithelial cytotoxicity induced by M. micronuciformis infections was still modest at the highest MOI
Since Veillonella and Megasphaera spp. are predicted to harbor genes encoding lactate dehydrogenase (LDH)[48,49], we assessed the cytotoxicity using crystal violet staining (Supplementary Fig. 1). These results were consistent with LDH activity data with respect to cell viability measurements, indicating that potential bacterial LDH activity did not impact these data
Summary
Human mucosae are colonized by diverse and dynamic bacterial communities that impact health and homeostasis or contribute to disease states, depending on the compositional nature of the communities[1]. Overgrowth of diverse anaerobic bacteria and depletion of Lactobacillus spp. is characteristic of bacterial vaginosis (BV) in the cervicovaginal microenvironment[4,5]. Our group and others have developed a hypothetical model suggesting that early colonizers, such as Gardnerella vaginalis and Prevotella bivia, establish biofilm scaffolds over the cervicovaginal epithelium and exhibit low pro-inflammatory properties[4,6]. This model proposes that as the biofilm matures, Lactobacillus spp. become less abundant and secondary colonizers associate with the biofilm, which results in inflammation[4]. As Lactobacillus spp. are depleted, BV-associated bacteria produce polyamines that result in increased pH4
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