Bile acid sequestrants modulate microbiome diversity and host immunity during enteric microbial infection 2254635

Abstract Introduction Approximately 90 million American adults are hypercholesterolemic, with an estimated 43 million either using or eligible for cholesterol-lowering therapies such as bile acid sequestrants. Beyond their role as end-products of cholesterol catabolism, bile acids regulate diverse biological processes in both intestinal and extra-intestinal organs. Increasing evidence highlights their crucial role in maintaining intestinal homeostasis under both physiological and pathological conditions. While bile acid sequestrants effectively reduce serum cholesterol, their impacts on intestinal homeostasis in healthy individuals and during enteric infections remain unclear. Methods In this study, we investigated how bile acid sequestration influences mucosal immune responses and the ability of enteric microbial pathogens to colonize the small intestine in vivo. We further examined the effects of sequestration on intestinal microbial communities before and during infection. Results Our results provide clear evidence that bile acids act as limiting factors in restricting microbiome diversity and richness. Mice administered a bile acid sequestrant exhibited significantly enhanced microbial diversity and richness, which correlated with increased resistance to enteric infection. This protective effect suggesting that enhanced microbial ecosystem diversity is a key driver of resistance. As expected, the antibiotic-driven microbiome depletion caused increased susceptibility to Giardia infection. Together, these findings reveal a previously underappreciated role of bile acid sequestrants in shaping the intestinal microbiome. Conclusion By altering bile acid signaling and downstream pathways, sequestration not only lowers cholesterol but also modulates host immunity during enteric infections. These insights may have important implications for patients taking bile acid sequestrants as part of cholesterol-lowering therapy. Funding Source This study was financially supported by a startup fund (20344-8015) from the Department of Biomedical Sciences, School of Medicine and Health Sciences, the University of North Dakota; a Dean’s Meritorious Pilot Grant, School of Medicine and Health Science Topic Categories Mucosal and Regional Immunology (MUC)