The human vaginal microbiota: from clinical medicine to models to mechanisms

Abstract

The composition of the vaginal microbiota is linked to numerous reproductive health problems, including increased susceptibility to infection, pregnancy complications, and impaired vaginal tissue repair; however, the mechanisms contributing to these adverse outcomes are not yet fully defined. In this review, we highlight recent clinical advancements associating vaginal microbiome composition and function with health outcomes. Subsequently, we provide a summary of emerging models employed to identify microbe-microbe interactions contributing to vaginal health, including metagenomic sequencing, multi-omics approaches, and advances in vaginal microbiota cultivation. Last, we review new in vitro, ex vivo, and in vivo models, such as organoids and humanized microbiota murine models, used to define and mechanistically explore host-microbe interactions at the vaginal mucosa.

Figure 1.. Current and proposed models to study host-microbe and microbe-microbe interactions at the vaginal mucosa.

Upper left) In vitro host-microbe interactions are most frequently studied with well-characterized immortalized vaginal epithelial cell lines, but vagina-on-a-chip and murine vaginal organoid models possess multiple cell types, offering more granular study of host-microbe interactions. We propose human-derived vaginal epithelial organoids as a further advancement. Upper right) Cultivation-independent models for microbe-microbe interactions generally constitute functional predictions from 16S rRNA gene amplicon sequencing to determine bacterial taxonomic presence and abundance within communities, or whole genome sequencing for bacterial, fungal, archaeal, and viral taxonomy and identification of individual microbial genes. Cultivation-dependent models are generally limited to batch cultivation in bacteriological media, but co-culture with vaginal cell lines may improve retention of fastidious but clinically relevant bacteria. We propose continuous flow cultivation of vaginal microbial communities as a further advancement to characterize microbe-microbe interactions. Lower right) The most common in vivo model is the conventional microbiota mouse, which possesses complex tissue/organ systems and a complete immune system. The humanized gut microbiota mouse adds to these strengths by possessing a more human-like vaginal microbiota for improved translational study of human host interactions with vaginal microbes. We propose a humanized vaginal microbiota mammalian model as a further advancement. Figure Created with BioRender.com