苦味受体介导食源性苦味化合物对肠道分泌细胞功能调控的机制研究

食源性苦味物质由于其特殊的生理效应越来越受到人们关注，富含苦味化合物的食物及基于苦味活性成分的功能食品研制开发已成为大健康食品产业的新增长点。但是，关于苦味的肠道感知（苦味受体）以及肠道功效的调控机制仍有许多未知，并且由于苦味受体家族成员、苦味感知及肠道上皮细胞谱系的多样性，导致苦味受体在肠道的分布特征及生理功能尚不明确。本项目以苦味受体为切入点，以肠道类器官为研究模型，首先明确苦味受体在肠道的分布，包括肠段差、细胞谱系、性别及年龄差异性；随后应用异源表达系统和高通量钙离子成像技术确定肠道苦味受体与苦味化合物对应特征；最后以功能明确的代表性食源性苦味化合物及对应的苦味受体，借助基因敲除和苦味阻断剂，利用肥胖和肠炎症小鼠模型，系统探究苦味受体介导的功能性食物源苦味化合物肠道功能调控（包括肠道分泌细胞激活及功能调控，肠道微生物和肠道炎症调控）详细作用机制，为功能性苦味食品的开发提供科学基础。

Food-derived bitter substances are getting more and more attention because of their special physiological effects. New foods rich in bitter compounds and serving as beneficial food additives have become one of the new trends pursued by the modern health food industry, but there still many unknowns about the intestinal cognition of bitter taste (including bitter receptors) and the regulation mechanism of intestinal efficacy. Bitter taste receptor is the sensor of bitter taste perception. Whereas bitter taste receptors have been demonstrated to be expressed through the intact intestine, the distribution characteristics and precise physiological functions of bitter receptors reside in the intestine are still not clear resulting from the diversity of bitter taste receptor family members, and the complex of bitter ligand perception as well as the distribution of bitter receptors in the intestinal epithelial cell lineage. In this study, bitter taste receptors as research objective, intestinal organoid as the ex vivo model, we firstly analyze the distribution characteristics of bitter taste receptors in the intestine, including the differences between different intestinal segment, different epithelial cell lineage, gender, and age. Next, using a heterologous expression system in HEK293 cells and high-throughput calcium imaging technology to determine the corresponding characteristics between bitter taste receptors and food-derived bitter compounds. Finally, based on above results representative bitter compounds with clear intestinal function is selected, and through gene knockout and bitter blockers, using obese and intestinal inflammatory mouse models, the detailed mechanism of bitter taste receptor-mediated of intestinal functions (including intestinal secretary cell activation and function Regulation, intestinal microbial and intestinal inflammatory regulation). providing scientific guidance and potential targets for the development of functional bitter foods and diet therapy. In short, this will provide scientific guidance and potential tartest for the development of functional bitter foods and diet therapy.