Cellular and molecular mechanisms for bile acid regulation of intestinal immunity

胆汁酸是在肝脏中使用胆固醇作为前体合成并分泌到胃肠道中的洗涤剂样分子。胆汁酸的最佳功能是促进胃肠道对膳食脂质和维生素的消化和肠道吸收。然而，胆汁酸也作为激素，因此，有能力影响全身代谢和免疫的多个方面。胃肠道不断暴露于饮食抗原和数万亿的常驻肠道微生物。适当的肠道免疫功能对于隔离这些微生物和维持肠道功能至关重要。这是通过肠上皮屏障实现的，肠上皮屏障是由几种机制支持的多功能实体，最值得注意的是：（i）在肠内容物和组织之间构成物理屏障的粘液层，（ii）肠粘膜细胞产生免疫球蛋白，以及（iii）肠上皮细胞合成和分泌多种抗微生物肽和蛋白质（AMPP）。最近的证据表明，胆汁酸在形成肠道免疫应答中起着重要作用，尽管对肠道免疫的哪些方面响应于胆汁酸信号传导以及所涉及的分子机制知之甚少。我们实验室最近发表的工作已经确定，某些种类的天然胆汁酸刺激肠道AMPP和粘蛋白的合成，并诱导肠道免疫系统重要细胞丰度的变化，从而增强肠道的抗菌微环境。我的NSERC资助的研究项目的总体目标是了解胆汁酸在肠道免疫控制中的作用，并确定发挥作用的分子机制。这项建议的具体目标是：（1）确定胆汁酸调节肠AMPP合成的潜在机制，和（2）了解胆汁酸控制肠粘膜中免疫细胞群的存在和功能以及肠道的免疫微环境的机制。我们将利用先进的细胞和分子生物学技术，包括使用肠类器官，其在培养中复制肠上皮组织和功能的许多方面。将使用几种遗传缺陷的小鼠模型来确定特定细胞类型和分子参与胆汁酸介导的AMPP和免疫细胞群的调节。这项研究的结果对于更深入和更全面地了解维持肠道免疫和功能的基本分子机制非常重要，并将在胃肠道生物学的许多领域中具有潜在的应用。

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.