Bile acid sequestration reveals microbiome remodeling that dominates FXR signaling to shape host responses to enteric infection
- 1Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
- 2Laboratory of Mucosal Immunology, Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
Abstract
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. Author summary: Human giardiasis is a common enteric parasitic infection that causes millions of infections globally, yet the mechanisms underlying effective parasite clearance are poorly understood. Bile acids act as key signaling molecules that shape the gut microbiome and influence immune responses. Millions of individuals with hypercholesterolemia take bile acid sequestrants to lower cholesterol, but it is still unclear how these medications affect susceptibility to intestinal infections. In the current study, we examined how bile acid sequestration modulates host defenses during Giardia infection. We found that bile acid sequestration increased the diversity of the gut microbiome and enhanced early resistance to infection in a murine model of human giardiasis. This protective effect required signaling through the bile acid receptor FXR, but not TGR5, in myeloid cells. Depleting the microbiome with an antibiotic cocktail abolished protection and made mice highly susceptible to infection, indicating that the microbiome plays a dominant role in controlling intestinal Giardia colonization. We also observed robust intestinal mast cell activation and increased inflammatory lipid mediators following infection. Together, our findings demonstrate that bile acids regulate intestinal immunity mainly by reshaping the gut microbiome. Understanding how bile acids interact with the microbiome may help guide new strategies to strengthen mucosal defenses against enteric pathogens.
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BibTeX
@article{mansouripour2026bile,
title = {{Bile acid sequestration reveals microbiome remodeling that dominates FXR signaling to shape host responses to enteric infection}},
author = {Anahita Mansouripour and Drew R. Seeger and Meredith Parmer and Peddanna Kotha and Anton M. Golovko and Mikhail Y. Golovko and Shahram Solaymani-Mohammadi},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014558},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014558},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Bile acid sequestration reveals microbiome remodeling that dominates FXR signaling to shape host responses to enteric infection
AU - Anahita Mansouripour
AU - Drew R. Seeger
AU - Meredith Parmer
AU - Peddanna Kotha
AU - Anton M. Golovko
AU - Mikhail Y. Golovko
AU - Shahram Solaymani-Mohammadi
PY - 2026
DA - 2026/09/08
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014558
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014558
AB - 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. Author summary: Human giardiasis is a common enteric parasitic infection that causes millions of infections globally, yet the mechanisms underlying effective parasite clearance are poorly understood. Bile acids act as key signaling molecules that shape the gut microbiome and influence immune responses. Millions of individuals with hypercholesterolemia take bile acid sequestrants to lower cholesterol, but it is still unclear how these medications affect susceptibility to intestinal infections. In the current study, we examined how bile acid sequestration modulates host defenses during Giardia infection. We found that bile acid sequestration increased the diversity of the gut microbiome and enhanced early resistance to infection in a murine model of human giardiasis. This protective effect required signaling through the bile acid receptor FXR, but not TGR5, in myeloid cells. Depleting the microbiome with an antibiotic cocktail abolished protection and made mice highly susceptible to infection, indicating that the microbiome plays a dominant role in controlling intestinal Giardia colonization. We also observed robust intestinal mast cell activation and increased inflammatory lipid mediators following infection. Together, our findings demonstrate that bile acids regulate intestinal immunity mainly by reshaping the gut microbiome. Understanding how bile acids interact with the microbiome may help guide new strategies to strengthen mucosal defenses against enteric pathogens.
SN - 1553-7374
ER -