Increased genital mucosal cytokines in Canadian women associates with increased antigen presenting cells, inflammatory metabolites, epithelial barrier disruption and the depletion of L. crispatus

Abstract Background: Cervicovaginal inflammation has been linked to negative reproductive health outcomes including acquisition of HIV, other sexually transmitted infections, and cervical carcinogenesis. While changes to the vaginal microbiome have been linked to genital inflammation, the molecular relationships between the functional components of the microbiome with cervical immunology in the reproductive tract are understudied, limiting our understanding of mucosal biology that may be important for reproductive health.Results: In this study we used a multi’-omics approach to profile cervicovaginal samples collected from 43 Canadian women to characterize host, immune, functional microbiome and metabolome features of cervicovaginal inflammation. We demonstrate that inflammation is associated with lower amounts of L. crispatus and increased levels of cervical antigen presenting cells (APCs). Proteomic analysis showed an upregulation of pathways related to neutrophil degranulation, complement, and leukocyte migration, with decreased levels of cornified envelope and cell-cell adherens junctions. Functional microbiome analysis showed reductions to carbohydrate metabolism and lactic acid, with increases of xanthine and other metabolites. Bayesian network analysis linked L. crispatus with glycolytic and nucleotide metabolism, succinate and xanthine, and epithelial proteins SCEL and IVL as major molecular features associated with pro-inflammatory cytokines and increased APCs.Conclusions: This study identified key molecular and immunological relationships with cervicovaginal inflammation, including increased APCs, bacterial metabolism, and proteome alterations that underlie inflammation. As APCs are involved in HIV transmission, parturition, and cervical cancer progression, further studies are needed to explore the interactions between these cells, bacterial metabolism, mucosal immunity, and their relationship to reproductive health.