Type 2 diabetes (T2D) mellitus is a chronic metabolic disease that afflicts over 500 million people worldwide
and causes nearly 1.5 million deaths each year. Diabetics are hospitalized at a more frequent rate and have
more expensive hospital visits compared to the general population. Current antibiotic-based treatments for
infection contribute to the global rise in antimicrobial resistance and cause dysbiosis of the endogenous
microbiome, leading to an adverse susceptibility to pathogens. Thus, additional strategies to prevent and cure
bacterial infection are desperately needed. The vaginal microbiome is a key reservoir for pathogen
dissemination to the urinary tract and a guardian against translocation to distant body sites by maintaining
epithelial integrity and controlling inflammation. Group B Streptococcus (GBS) is a bacterium that is frequently
detected in the vaginal microbiome without symptoms, but it is also an under-reported cause of aerobic
vaginitis. In the diabetic population, which is 95% type 2 diabetics, GBS causes invasive disease in ~6,000
diabetic women annually and disproportionately causes urinary tract infections. However, neither the T2D
vaginal microbiome nor its influence on diabetic susceptibility to this pathogen have been studied. Previous
research suggest that the gut microbiome can respond to metabolic disease; in some cases diabetes is
associated with enrichment of opportunistic pathogens in the gut or dysbiotic gut bacteria that are vulnerable to
pathogens. In the context of pregnancy, gestational diabetes is associated with enriched abundance of
opportunistic pathogens in the vaginal microbiome. This proposal aims to understand whether metabolic
disease impacts the vaginal microbiome outside of pregnancy and whether microbiota mediate diabetic
susceptibility to GBS. We hypothesize that T2D patients will have an altered microbiome and metabolite
composition and an inflammatory cytokine profile, and that diabetic-derived communities will be less protective
against GBS and concurrently inflict damage and inflammation on the host epithelium. This hypothesis will be
tested by the following specific aims: 1) Define homeostatic characteristics of the vaginal microenvironment in
T2D, and 2) Characterize T2D vaginal microbiome interactions with GBS and mediation of pathogen-host
interactions. To complete these aims, innovative approaches such as miniature bioreactor cultivation and
human vaginal stem-cell derived organoids will be used. The research will provide the applicant with training in
organoid models, transcriptomics and metabolomics, and whole genome and 16S analysis, while building upon
the applicant’s experience with the miniature bioreactor model. This training will take place at Baylor College of
Medicine with mentorship from leading experts in metabolic disease, host-microbe interactions, human
microbiome, and both proposed model systems, miniature bioreactors and organoids. This research will
identify components of the vaginal microenvironment that influence diabetic susceptibility to GBS infections
and provide new tools for targeted therapeutic alternatives to antibiotics.