Modulation of dysbiotic vaginal complications by cervical mucus revealed in linked human vagina and cervix chips

Abstract

Background The cervicovaginal mucus which coats the upper surface of the vaginal epithelium is thought to serve as a selective barrier that helps to clear pathogens, however, its role in modulating the physiology and pathophysiology of the human vagina is poorly understood. Bacterial vaginosis (BV), a common disease of the female reproductive tract that increases susceptibility to sexually transmitted infections, pelvic inflammatory disease, infertility, preterm birth, and both maternal and neonatal infections is characterized by the presence of a wide array of strict and facultative anaerobes, often including Gardnerella vaginalis. Objective To assess the role of cervical mucus in preventing dysbiosis-associated complications and preserving vaginal health. Study Design: To better understand the role of cervicovaginal mucus in vaginal health, we used human organ-on-a-chip (Organ Chip) microfluidic culture technology to analyze the effects of cervical mucus produced in a human Cervix Chip and then transferred to a human Vagina Chip BV model. Both chips are lined by primary human organ-specific (cervical or vaginal) epithelium interfaced with organ-specific stromal fibroblasts. Results Our data show that mucus-containing effluents from Cervix Chips protect Vagina Chips from inflammation and epithelial cell injury caused by co-culture with a dysbiotic microbiome containing G. vaginalis. Proteomic analysis of proteins produced by the Vagina Chip following treatment with the Cervix Chip mucus also revealed a collection of differentially abundant proteins that may contribute to the vaginal response to a dysbiotic microbiome, which could represent potential diagnostic biomarkers or therapeutic targets for the management of BV. Conclusions This study highlights the importance of cervical mucus in controlling human vaginal physiology and pathophysiology, and demonstrates the potential value of Organ Chip technology for studies focused on the health and diseases of the female reproductive tract.