Identifying Ecological Drivers of Dysbiosis in the Female Reproductive Tract

University Of California At Davis, Davis CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Dysbiosis in the female reproductive tract (FRT) occurs when unknown ecological factors in the vaginal microenvironment drive the expansion of suboptimal bacterial communities that contribute to disease. Our understanding of the host and microbial-derived factors that contribute to FRT dysbiosis is limited, and as such we lack effective strategies for restoring vaginal homeostasis in at-risk women. Aerobic vaginitis occurs when enteric opportunists such as Escherichia coli subvert the dominance of glycogen fermenting commensals to expand in the FRT, causing severe inflammation and tissue atrophy. The host-derived factors that drive the bloom of facultative anaerobes in the FRT during aerobic vaginitis are unclear, but risk factors include hormonal changes during pregnancy, menopause, etc. We and others have observed that mice in specific reproductive phases (estrus and metestrus) are highly susceptible to vaginal E. coli colonization suggesting hormonal-driven changes in the FRT may influence pathogen susceptibility in mice. Our preliminary findings show that estrogen alters vaginal epithelial cell metabolism, reduces epithelial hypoxia, and drives a respiration-dependent bloom of E. coli that induces subsequent inflammation in the FRT. From these findings, I hypothesize that hormone-induced metabolic reprogramming of the host epithelium towards aerobic glycolysis increases luminal oxygenation of the vaginal tract, allowing E. coli to outcompete fermenting anaerobes and induce an inflammatory response that perpetuates chronic aerobic vaginitis. Here, I propose to use genetically tractable uropathogenic E. coli (UPEC) in combination with specialized animal and tissue culture models to identify the specific host and bacterial metabolic pathways that contribute to aerobic vaginitis. In AIM1, we will determine how host cell metabolism controls vaginal community composition during homeostasis. In AIM2, we will use UPEC to identify host and microbial metabolic pathways that facilitate the bloom of facultative anaerobes during vaginal dysbiosis. In AIM3, we will explore how UPEC ecosystem engineering facilitates persistent colonization of the female reproductive tract during aerobic vaginitis. Together, these studies will provide much-needed insight into the factors that influence vaginal health and disease and reveal new therapeutic targets for supporting women’s reproductive health. The support of this K99/R00 Pathway to Independence award will facilitate the training necessary to achieve these aims, including training in advanced microbiome techniques, specialized conventional and gnotobiotic mouse models, and further career development. With the combined support of an outstanding mentorship team and the world-class technical and intellectual resources available at UC Davis, the proposed scientific aims and training objectives will form the foundation for an independent research program aimed at uncovering the ecological drivers of dysbiosis in the FRT.