The role of bile acids in the control of Paneth cells function

点击翻译按钮获取中文摘要

Bile acids are typically associated with the digestion of dietary lipids in the gastrointestinal tract. However, over the past few years, bile acids have been implicated in other biological processes. Bile acids are simultaneously present in multiple body compartments; they are produced (or reabsorbed) by the liver, incorporated into the bile and drained from the liver into the gallbladder. After storage in the gallbladder, they are discharged into the small intestine in response to feeding. About 95% of the intestinal bile acids are eventually reabsorbed by the distal small bowel epithelium and transported back to the liver through the circulation. This is a highly-controlled cycle, which is thought to be a major way to convey multiple signals that control the overall metabolical and physiological status of the body. The objective of this proposal is to study the effects of bile acids over the function of Paneth cells, a secretory cell type of the small intestine that is involved in modulating the physiological and immunological landscape of the gut. In this proposal, we plan to determine to the capacity of Paneth cells to sense and respond to bile acids, as well as to identify the molecular mechanisms involved in such sensing and response, and evaluate the effects of bile acids signaling in selected aspects of Paneth cells function, such as the synthesis and secretion of antimicrobial proteins and peptides. I have developed preliminary data suggesting that the production of antimicrobial peptides by Paneth cells is responsive to the intestinal bile acids pool. We plan to demonstrate this hypothesis using a combination of advanced genetic, biochemical, molecular and immunohistochemical techniques using experimental animal models. This proposal targets the relationship between hepatobiliary and intestinal functions, and will explore the putative connection between two apparently separated aspects of gastrointestinal physiology. This study will contribute to the understanding of the role of bile acids as hormones as well as the molecular mechanisms of Paneth cell function in the maintenance of the intestinal microenviroment.