Bile acid sequestration reveals microbiome remodeling that dominates FXR signaling to shape host responses to enteric infection.

Approximately 90 million American adults are hypercholesterolemic, with an estimated 43 million individuals either already using or eligible to receive cholesterol-lowering medications, such as bile acid sequestrants. Although bile acid sequestrants have demonstrated therapeutic efficacy in lowering cholesterol levels in individuals with hypercholesterolemia, their impact on intestinal homeostasis in healthy individuals and those with enteric microbial infections remains unclear. We set out to investigate the potential effects of bile acid sequestration on mucosal immune responses and to evaluate how enteric microbial pathogens colonize the small intestine of mice in vivo. We also examined how bile acid sequestration affected intestinal microbial ecosystems before and during enteric infection. We found that bile acid sequestration increased resistance to enteric infection, and this phenotype required farnesoid X receptor (FXR) in myeloid cells. We observed significantly increased diversity and richness in the gut microbiome of mice that were administered a bile acid sequestrant that correlated with enhanced resistance to enteric infection, suggesting that bile acids may function as limiting factors for the diversity and richness of the gut microbiome in health and disease. Notably, the antibiotic-driven depletion of the gut microbiome led to significantly increased susceptibility to infection with both Giardia duodenalis and Giardia muris. Our findings reveal a previously overlooked role for bile acid sequestrants in the regulation of the gut microbiome as well as host resistance to enteric infections. Bile acid sequestration and the subsequent blockade of pathways downstream of bile acid signaling may modulate host immunity during enteric infections, potentially leading to an altered gut microbiome in individuals taking bile acid sequestrants to lower blood cholesterol.