Gut Microbiome Steroid Hormone Metabolism in Inflammatory Disease

About This Grant

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) is characterized by chronic relapsing intestinal inflammation with unpredictable flares that significantly impair patient quality of life. The gut microbiome plays a central role in IBD pathogenesis, yet specific mechanisms linking gut bacteria to inflammatory processes remain poorly defined. Glucocorticoids function as critical mediators in IBD both as endogenously produced anti-inflammatory molecules that help maintain mucosal homeostasis and as exogenously administered therapeutic agents for managing acute flares. This proposal investigates a novel bacterial pathway that enzymatically converts active glucocorticoids to inactive metabolites in the gut microbiome. Our preliminary data demonstrate that steroid- metabolizing bacterial enzymes are significantly enriched in IBD patient microbiomes compared to healthy controls, suggesting a potential contribution to disease pathogenesis. We hypothesize that microbial inactivation of glucocorticoids disrupts anti-inflammatory signaling and exacerbates intestinal inflammation. To test this hypothesis, we will employ gnotobiotic mouse models with genetically defined bacterial strains that either possess or lack glucocorticoid-metabolizing capability, evaluating their impact in the presence or absence of therapeutic glucocorticoid treatment. This exploratory research aims to investigate a potential novel mechanistic link between microbial modulation of host endocrine signaling and inflammation, which may ultimately inform the development of microbiome-based diagnostics and therapeutic approaches for inflammatory digestive diseases.