肠Tuft细胞的苦味受体Tas2R138促进Th2型免疫应答的机制研究及其药物调控

The incidence of obesity with multiple serious complications is increasing markedly, which threat human life safety. Clinical treatment of obesity and related metabolic disorders is faced with many limitations. Therefore, new strategies and targets are urgently needed for long-term treatment of obesity. Recently, gut immunity has been the focus in immunology, which also plays an important role in obesity. It has been shown that IL-25 (Interleukin-25) is a critical cytokines in the maintenance of the balance of gut immunity and obesity treatment. In recent 3 years, the intestinal taste-chemosensory cells, Tuft cells, were identified as the sole intestinal source of IL-25, and IL-25 is the key molecular for its immune activity. Our previous study found that STAT6 might be the transcription factor of IL-25, and Tas2R138, the highly expressed bitter taste receptor in Tuft cells might be the upstream regulatory factor of STAT6-IL-25. The present study will focus on the mechanism of taste-chemosensing effect on immunity modulation in Tuft cells and elucidate the novel function of Tuft cells and bitter taste signaling in gut immunity and obesity, glucose and lipid metabolism disorder. This project will also discuss the possibility of Tas2R138-IL-25 signaling in intestinal Tuft cells being a potential target in treating obesity, glucose and lipid metabolism disorders. Accordingly, this research will provide new strategies for modulating gut immunity and theoretical basis for developing candidate agents in clinical treatment of gut immunity-related disease.

肥胖及其伴随的各种并发症严重危害人类生命安全，临床治疗肥胖及相关代谢异常疾病面临诸多局限。肠道免疫是国内外的研究热点，其在肥胖及相关代谢异常疾病中扮演重要角色。肠源性IL-25是肠道Th2型免疫应答关键的细胞因子，在维持肠道免疫平衡中发挥重要作用，可显著改善肥胖症状。肠感觉细胞—Tuft细胞被认为是肠源性IL-25的唯一来源。我们发现STAT6很有可能是IL-25重要的转录因子，肠Tuft细胞表面的苦味受体Tas2R138介导的苦味信号可能是STAT6-IL-25的上游调控因素。本项目拟通过体内外实验验证并阐明肠Tuft细胞内味觉-免疫之间的确切调控机制，并通过肥胖模型进一步考察肠Tuft细胞及其苦味信号在肥胖进程中的作用及机制。本课题将基于此研究肠Tuft细胞中Tas2R138-IL-25信号成为治疗肥胖等疾病新靶标的可能性，为药物的开发提供理论基础。

肠道免疫在肥胖及相关代谢异常疾病中扮演重要角色。肠源性IL-25可通过ILC2/Th2细胞轴上调肠道2型免疫应答，在维持肠道免疫平衡中发挥重要作用，并可显著改善肥胖症状。Tuft细胞被认为是肠源性IL-25的唯一来源。因此，靶向肠tuft细胞，调控肠道免疫，是治疗肥胖的潜在策略。肠tuft细胞表面存在多种化学感受器，如苦味受体Tas2Rs等，且肠道旋毛虫的感染可通过激活tuft细胞表面苦味受体信号通路，上调tuft细胞的功能。为了验证tuft细胞表面苦味受体对肠道免疫及肥胖的调控作用，我们采用小檗碱为研究工具药物。小檗碱口服生物利用度极低，不易被肠道吸收，但是口服小檗碱显著改善肥胖，且这一作用可被苦味受体拮抗剂部分取消；同时，口服小檗碱能够显著上调肠道tuft细胞的数目，激活苦味受体信号及促进IL-25的分泌，上调肠道2型免疫应答的同时下调1型免疫应答反应。以上数据提示，小檗碱靶向肠tuft细胞表面苦味受体信号通路，激活tuft细胞功能，调控肠道免疫稳态，最终缓解肥胖。此外，我们在项目研究过程中发现，tuft细胞表面存在多种苦味受体，且在肠道中可能并不完全特异性存在于肠tuft细胞中。为了对肠tuft细胞功能及调控方式有更加细致准确的判断，我们后期通过对小肠上皮细胞单细胞测序结果重新分析并验证，发现FFAR3在肠tuft细胞中特异性高表达，且FFAR3与tuft细胞功能之间的关系未见研究报道。因此，我们根据FFAR3的结合特点，筛选出色氨酸肠道代谢产物-吲哚丙酸（IPA），发现IPA可以靶向tuft细胞表面FFAR3受体，激活tuft细胞功能，上调肠道2型免疫反应，抑制肥胖所引起的肠道炎症，改善肠道通透性，从而抑制肥胖的发生发展。本项目的研究成果发现肠tuft细胞中苦味受体/FFAR3受体是治疗肥胖的潜在治疗靶标，为药物的开发提供理论基础。