Beyond association: pathogenesis models reveal ecological drivers of vaginal dysbiosis

Despite its critical importance to health, our understanding of the vaginal microbiome lags far behind other mucosal sites, reflecting both the distinct biology of the human vaginal microenvironment and the historic neglect of women's reproductive health in biomedical research. Recent investment in this area, coupled with the widespread use of high-throughput omics technologies, has greatly expanded our understanding of vaginal microbiota states and their associations with health and disease. However, associative studies that correlate community composition with clinical outcomes are limited in their ability to define causal, modifiable host-microbe relationships that support a protective microbiota. Consequently, broad probiotic strategies based on descriptive findings show limited success in restoring lasting homeostasis in the female reproductive tract. Murine infection models provide tractable systems for identifying evolutionarily conserved physiological processes that influence microbial growth. Here, we highlight studies across pathogenesis fields that leverage murine models to identify ecological factors controlling infection susceptibility in the vaginal microenvironment. Rather than treating pathogen colonization as an endpoint alone, we emphasize how genetically tractable microbes reveal the resources, barriers, and immune responses mediating microbial persistence, ascension, and inflammation. Where possible, we integrate these findings with clinical observations to assess their relevance to human reproductive health. Together, these studies illustrate how imperfect but tractable models reveal causal drivers of vaginal dysbiosis in women and help ground large-scale associative studies in a more clinically relevant way.