Cellular and molecular mechanisms for bile acid regulation of intestinal immunity

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Bile acids are detergent-like molecules synthesized in the liver using cholesterol as the precursor and secreted into the gastrointestinal tract. The best-recognized function of bile acids is to facilitate the digestion and intestinal absorption of dietary lipids and vitamins in the gastrointestinal tract. However, bile acids also act as hormones and hence, have the ability to influence multiple aspects of whole body metabolism and immunity.***The gastrointestinal tract is constantly exposed to dietary antigens and trillions of resident commensal microorganisms. Proper intestinal immunological function is critical to segregate those microorganisms and maintain the functionality of the gut. This is achieved by the intestinal epithelial barrier, a multifunctional entity supported by several mechanisms, most notably: (i) a mucus layer that poses a physical barrier between the intestinal content and tissue, (ii) the production of immunoglobulins by cells of the intestinal mucosa and (iii) the synthesis and secretion of multiple antimicrobial peptides and proteins (AMPP) by cells of the intestinal epithelium. Recent evidences suggest that bile acids play significant roles in shaping intestinal immune responses although very little is known about what aspects of intestinal immunity are responsive to bile acid signaling as well as the molecular mechanisms involved. ***Recently published work from our laboratory has established that some species of natural bile acids stimulate the synthesis of intestinal AMPP and mucins, and induce changes in the abundance of important cells of the intestinal immune system, resulting in an enhancement of the antimicrobial microenvironment of the gut. The general objective of my NSERC-funded research program is to understand the role of bile acids in the control of intestinal immunity and determine the molecular mechanisms at play. The specific objectives of this proposal are: (1) to determine the mechanisms underlying bile acid regulation of intestinal AMPP synthesis, and (2) to understand the mechanisms by which bile acids control the presence and function of immune cell populations in the intestinal mucosa and with it, the immunological microenvironment of the gut.***For our studies, we will utilize advanced techniques of cellular and molecular biology including the use of intestinal organoids, which replicate in culture many aspects of the organization and function of the intestinal epithelium. Several mouse models of genetic deficiencies will be used to determine the involvement of specific cell types and molecules in the bile acid-mediated regulation of AMPP and immune cell populations. The results from this research will be important to gain a deeper and more integrated understanding of the basic molecular mechanisms that sustain intestinal immunity and function and will have potential applications in many areas of gastrointestinal biology.