Recent studies suggest that the gut microbiome can influence fertility and the hypothalamic-pituitary-gonadal (HPG) axis through modifications of bile acids. The overall goal of this study is to determine whether the gut microbiome’s modulation of bile acids affects reproductive function and fertility. To have a better mechanistic understanding of how bacterial bile acid modifications affect reproductive health, there is a critical need for a tool that will introduce specific bacterial biotransformations into the gut microbiome and investigate their effects on the host HPG axis. An innovation of this proposal is a new strategy that allows us to quickly and effectively knock- in a beneficial function in a sustained manner, for perpetuity, by engineering the host’s native bacteria to induce a physiological change. The candidate will use this tool to address her central hypothesis, that bile acids are key modulators of the HPG axis and fertility. In the next three years, the candidate will pursue the proposal’s central hypothesis with three specific aims. The first aim will determine how bacterial bile acid biotransformations in the gut microbiome affect fertility in both male and female mice. By using engineered native bacteria to increase bile acid deconjugation, the candidate will determine the effect of altered bile acid composition on serum sex hormones and other markers host fertility. Overall, this aim will determine if there is sexual dimorphism in microbiome modulation of bile acids and host reproductive health. In the second aim, the candidate will evaluate the effect of bile signaling modulation and reduced serum androgen levels, shown in my preliminary results, on fecundity in a cohort of male mice. This will determine whether bile acid biotransformations elicit a strong enough effect on the reproductive axis to reduce fecundity in males. The third aim will determine whether the nuclear bile acid receptor, farnesoid X receptor (FXR), is necessary for the effect of bacterial bile acid biotransformations on testosterone levels. Ultimately, this aim will determine whether this receptor is a novel therapeutic target to manipulate fertility and fecundity. The expected outcome of these studies is further clarity about the relationship between bile acid signaling and reproductive health. The positive translational impact includes the determination of whether the gut microbiome can be used to better understand, and potentially treat, male and female subfertility. The candidate is an exceptional scientist whose goal is to become an independent scientist investigating the relationship between the gut microbiome and host reproductive health. Her training goals include developing expertise in reproductive physiology, designing microbiome experiments, developing expertise in animal models of disease, learning the skills necessary to become an independent researcher, and building her professional network. To accomplish these training goals, the candid...