Type 2 diabetes mellitus exacerbates vaginal group B Streptococcus colonization via impaired mucosal cytokine...

Type 2 diabetes mellitus (T2D) is a metabolic disorder that confers increased risk of microbial infections, including those caused by the opportunistic pathogen group B Streptococcus (GBS). Asymptomatic GBS vaginal carriage is a notable reservoir for infection, but the impact of T2D on the vaginal mucosa and GBS colonization is not fully understood. We employed a diet-induced mouse model of T2D to investigate the impact of diabetes on glucose availability, vaginal microbiome composition, and vaginal cytokines at baseline and in response to GBS. We observed enhanced susceptibility of diabetic mice to GBS vaginal colonization and reproductive tract dissemination. Despite experiencing hyperglycemia, diabetic mice did not exhibit elevated glucose in the reproductive tract. Regarding the vaginal microbiota, diabetic mice had minimal compositional differences, with decreased Mammaliicoccus being the only significant taxonomic variance. Vaginal cytokine profiling revealed consistently depressed cytokines in diabetic mice, beginning with KC at baseline and expanding to eight pro-inflammatory cytokines post-GBS infection. Diabetic mice exhibited decreased proportions of uterine neutrophils and, following GBS exposure, also displayed an expanded vaginal γδ T cell compartment compared with controls. Pairing cytokine observations with GBS colonization revealed a correlation between delayed vaginal IL-1α induction and persistent vaginal GBS, suggesting that vaginal cytokine deficiency may contribute to diabetic GBS phenotypes. Intravaginal supplementation with rIL-1α resolved GBS burden differences between diabetic mice and controls, confirming that deficient vaginal cytokines contribute to diabetic GBS vaginal persistence. These findings advance our understanding of diabetic vaginal mucosal susceptibility to pathogens and support the potential for immunological intervention.IMPORTANCEPeople with T2D are more susceptible to microbial infections, but there is limited understanding of the mechanisms that drive this vulnerability. One possibility is that T2D enhances the colonization of opportunistic pathogens, like GBS, in mucosal reservoirs as a precursor to infection. In this study, we used a diabetic mouse model to test whether diabetes alters the vaginal mucosa to promote GBS colonization. We found that increased vaginal GBS colonization in diabetic mice was not linked to tissue glucose availability or changes in the vaginal microbiome but instead was associated with impaired vaginal immune responses. These findings provide a foundation for translational approaches to reduce GBS persistence and dissemination in at-risk individuals.