Not all vaginal microbiomes are equal: functional context shapes immune landscapes

Taxonomic classification alone fails to capture the ecological and functional diversity of vaginal microbiomes, particularly those dominated by <i>Gardnerella</i> species. Using the expanded VIRGO2 gene catalog, we developed the vaginal inference of subspecies and typing algorithm (VISTA), a novel ortholog-based framework that defined metagenomic subspecies and 25 metagenomic community state types (mgCSTs), including six distinct <i>Gardnerella</i>-dominated profiles. The mgCSTs exhibit marked differences in species composition, functional gene content, transcriptional activity, and host immune responses. These findings reveal that <i>Gardnerella</i> predominance does not uniformly equate to dysbiosis and underscore the importance of functional context in shaping host-microbiome interactions. VISTA provides scalable classifiers and an interactive application to support mechanistic studies of vaginal microbiome function and its implications for reproductive health.IMPORTANCEThe vaginal microbiome plays a central role in reproductive and gynecologic health, yet its functional diversity and ecological organization remain poorly understood. Traditional 16S rRNA approaches provide only a partial view of this complexity, overlooking the strain-level variation that often determines microbial behavior and host outcomes. By applying metagenomic sequencing and scalable computational modeling, we developed the vaginal inference of subspecies and typing algorithm, a framework that defines gene-based subspecies and community state types across diverse populations. These classifications reveal new insights into the genomic and ecological foundations of vaginal community structure and offer a standardized resource for comparative and translational microbiome research. This work establishes the foundation for functionally informed diagnostics and precision interventions targeting women's reproductive health.