Bile acid control of commensal-specific immune responses

The National Institute of Allergy and Infectious Diseases awarded Dartmouth-Hitchcock Clinic a cooperative agreement of $561,873 on July 24, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct research on bile acid control of commensal-specific immune responses.

The funded research investigates how bile acids—gastrointestinal metabolites with dual roles in lipid absorption and cell signaling—dynamically engage nuclear receptors and GPCRs to modulate mucosal immune cell function and inflammation. The project examines how bile acid pools are remodeled during commensal organism colonization, specifically investigating segmented filamentous bacteria (SFB) colonization in the ileum and its effects on anti-inflammatory TH17 cell induction and interleukin-10 production. The research maps novel and competitive bile acid–nuclear receptor interactions that occur at physiological bile acid concentrations in the ileum and become dysregulated during Crohn's disease-like ileitis, with the goal of tuning activities of immunoregulatory nuclear receptors. The team employs quantification and manipulation tools for enterohepatic bile acid pools in vitro and in vivo.

Work is performed in Lebanon, New Hampshire. The period of performance extends from July 24, 2026, through May 31, 2031.

Abstract

Bile acids (BAS) are essential gastrointestinal (GI) metabolites with dual roles in lipid absorption and cell signaling, including in immune cells. Both 'primary' BAS-synthesized in hepatocytes-and 'secondary' BA species and metabolites, produced via GUT microbial metabolism, dynamically engage host nuclear receptors (NRS) and gpcrs following their intestinal absorption to modulate mucosal immune cell function and inflammation. However, current efforts to understand BA-dependent immune regulation center on functions of individual BA species and lack physiological grounding as IT relates to BA enterohepatic circulation. This overlooks the composite nature of complex endogenous BA pools that interface with mucosal immune cells in situ and does not consider how the size or complexity of endogenous BA pools might be influenced by microbial colonization or infection of the intestines. Our team has developed a unique set of tools and expertise that enable quantification and manipulation of enterohepatic BA pools in vitro and in vivo. Using these systems, we have found that colonization of the model mouse commensal organism, segmented filamentous bacteria (SFB), in the ileum-the sole and dedicated site of active intestinal BA absorption-acutely remodels the pool of BAS which circulates enterohepatically through the ileal mucosa. Our team has previously shown that SFB induce a unique anti-inflammatory population of commensal-specific TH17 cells in the ileum. Our new data indicate that BAS produced in response to SFB colonization contribute directly to the induction of these TH17 cells and to establishment of their anti-inflammatory phenotype, including IL-10 production. We have also mapped a series of novel and competitive BA-NR interactions that occur at physiological BA concentrations in the ileum, are dysregulated during crohn's disease-like ileitis and tune activities of key immunoregulatory NRS, including rorɣt and pparɣ, expressed in ileal TH17 and myeloid cells, respectively. Building off these insights, our goal is to elucidate how microbiota-driven shifts in enterohepatically cycling BA pools impact commensal-specific immune responses necessary for intestinal homeostasis. Using SFB as a model, our hypothesis is that commensal colonization of the ileum reprograms host hepatic BA biosynthesis to establish an enterohepatic BA pool in the ileal mucosa that direct development of tolerogenic TH17 cells through modulation of pparɣ and rorɣ signaling in macrophages and t cells, respectively. This hypothesis will be pursued through two complementary, but not inter-dependent, aims, and the results will elucidate how dynamically regulated BA-NR circuits balance tolerogenic VS. Inflammatory functions during commensal-specific t cell responses. More broadly, we anticipate our studies will lay the foundation for rationally designing novel BA-based therapeutic strategies to promote intestinal immune tolerance and restore homeostasis in settings of enteric infectious or inflammatory diseases, including inflammatory bowel diseases (ibds).