Bile acid-dependent intestinal immune regulation

About This Grant

Project Summary Bile acids (BAs) have emerged as a rich and important source of immunoregulatory metabolites in the intestines. Yet current views of BAs are incomplete. Reductionist studies administering single BAs to cells or mice, while useful for informing basic BA physicochemical properties, engender ‘1 BA = 1 function’ models that have limited relevance to the vastly more complex physiology that underpins BA metabolism and signaling in vivo. Our goals are to quantify intestinal BA pools in mice, understand how and why they change during intestinal inflammation, and map their interactions with host intestinal cells and receptors. Recognizing that intestinal BA pools are formed and dynamically regulated by endocrine-like signaling connections between the liver (where BAs are made), ileum (where most BAs are absorbed) and colonic microbiota (where most BAs are metabolized), we developed an integrated methods set to interrogate the size, complexity, regulation and function of intestinal BA pools in mice. We validated these approaches in mice that lack the ileal BA reuptake transporter, Asbt/Slc10a2, and that harbor robust and predictable differences in BA metabolism. We also established new computational models, calibrated to in vivo datasets, that offer quantitative insights into the independent inputs that hepatic synthesis, ileal absorption and microbial metabolism each contribute to the establishment and maintenance of enterohepatic BA pools. New preliminary data suggest that Crohn’s disease-like ileitis, which arises spontaneously in human Crohn’s disease patients and TnfARE/+ mice, alters BA circulation and metabolism in ways that ultimately produce a smaller and more pro-inflammatory BA pool. We hypothesize that aberrant ileal BA absorption is triggered by cytokine-driven Asbt downregulation in enterocytes prior to overt histopathology and is a distinctive feature of ileitis in mice and humans Once produced, we posit the ileitis-associated BA pool propagates immune dysfunction and ileitis by disturbing the balance of pro- vs. anti-inflammatory NR ligands available to T cells. We test these hypotheses through two inter-related, but not inter-dependent, aims. We expect these studies will have broad and lasting impacts in the field, both by generating fundamental new insights into the regulation of BA homeostasis, and by yielding actionable new paradigms in the understanding and treatment of human Crohn’s disease.