The Role of Bile Salt Hydrolase in Glucose Metabolism

Significance to VA: Diabetes affects 25% of Veterans receiving VA care, making it a leading cause of blindness, end-stage renal disease, and amputations in this population. Despite advances in pharmacologic treatments like GLP-1 receptor agonists, many Veterans continue to experience poor glycemic control, and the prevalence of diabetes is rising. With an annual economic burden of $412.9 billion, diabetes accounts for one in four U.S. healthcare dollars, and even more for VA Healthcare dollars, underscoring the urgent need for novel, durable therapeutic strategies. Bile acids, traditionally recognized for their role in lipid digestion, also regulate glucose homeostasis through signaling pathways involving FXR and TGR5. The gut microbiome modifies bile acids, linking microbial metabolism to host glucose regulation, yet the mechanisms remain poorly understood. This project will investigate how bacterial bile acid transformations influence glucose metabolism, providing critical insights into microbiome-driven metabolic regulation. By identifying novel therapeutic targets, this work has the potential to improve diabetes management and reduce the burden of disease among Veterans. Innovation and Impact: This project is highly innovative because it leverages engineered native bacteria to introduce specific bile acid-modifying functions into the gut microbiome, allowing precise mechanistic studies of microbiome-host interactions. Our novel approach circumvents limitations of traditional microbiome research by enabling functional, long-term manipulation of gut bacteria in vivo. By defining how bacterial bile acid metabolism influences glucose homeostasis, this work has the potential to revolutionize microbiome-based therapies, leading to novel interventions that harness the gut microbiome to improve metabolic health in Veterans. If successful, this research will lay the foundation for new therapeutic strategies targeting bile acid pathways to enhance glucose control and mitigate metabolic disease progression. Specific Aims: Over the next four years, we will pursue three specific aims. (1) Test the hypothesis that bacteria expressing bile salt hydrolases with different bile acid modulation properties differentially improve host glucose homeostasis. Ultimately, this aim will help us determine how bacterial bile acid modifications affect the expression of host glucoregulatory genes. (2) Test the hypothesis that bacterial bile acid deconjugation regulates glucose homeostasis through the TGR5 bile acid receptor. Overall, this aim will help us determine the influence of TGR5 signaling in mediating the glucoregulatory effects of bacterial bile acid deconjugation. (3) Test the hypothesis that high-fat diet-induced perturbations to the luminal environment affect the host metabolic response to bacterial bile acid deconjugation. Ultimately, this study will define the conditions under which microbial modification of bile signaling can be leveraged as a therapeutic strategy for diabetes. Methodology: We will use a combination of engineered native bacteria (a novel method to functionally manipulate the gut microbiome) and animal models of type 2 diabetes. Among the techniques use metabolic phenotyping, transcriptomics, and targeted metabolomics to determine how bacterial bile acid modifications influence glucose homeostasis. The study will employ wild-type and knockout mouse models to assess receptor- specific effects, and a diet-induced obesity model to evaluate the impact of overnutrition. Outcomes will include glucose tolerance tests, insulin sensitivity assays, bile acid composition analysis, and gut microbiome sequencing to establish causal links between microbial bile acid transformations and host metabolic regulation. Path to Translation/Implementation: The results from this study will provide a mechanistic foundation for microbiome-based therapeutic strategies targeting bile acid metabolism in T2D. If successful, this approach could lead Project Number: 2I01RD001332-05 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Amir Zarrinpar | Institution: VA SAN DIEGO HEALTHCARE SYSTEM, SAN DIEGO, CA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 ENDA-L (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11291493