Abstract

The gut microbiome plays a critical role in regulating glucose metabolism, in part by modifying host-derived metabolites such as bile acids. Bile acids, synthesized from cholesterol, are primarily involved in fat digestion but also serve as key signaling molecules influencing metabolic and physiological processes. Certain gut bacteria express bile salt hydrolases (BSHs), enzymes that modify bile acids and reduce their detergent activity. We have developed a novel approach to modulate the gut bile acid pool by engineering native bacteria to express distinct BSHs. A single oral dose of these engineered native bacteria results in long-term colonization in conventionally raised mice, reshapes the bile acid profile, and significantly improves glucose and insulin regulation.

Despite these promising findings, the mechanisms linking microbial bile acid modification to glucose homeostasis remain poorly understood. Different BSHs vary in substrate specificity and enzymatic efficiency, suggesting that even subtle differences in microbial bile acid metabolism can impact host metabolic health.

This project aims to elucidate how BSHs with distinct biochemical properties influence glucose and insulin dynamics in the host. We will also investigate the key signaling pathways, particularly bile acid-mediated mechanisms, that underlie these effects. Our goal is to uncover microbiome-driven regulatory pathways that can inform novel therapeutic strategies for type 2 diabetes.