丁酸通过上调脂肪酸氧化代谢促进iTreg细胞分化的作用和机制研究

饮食习惯与肠道免疫稳态间的关系是免疫学、细胞生物学等多领域共同关注的前沿问题。近年研究显示，备受“健康饮食”青睐的膳食纤维经肠道微生物发酵产生的丁酸具有组蛋白去乙酰化酶抑制剂功能，能够通过上调核心转录因子Foxp3的转录促进肠道iTreg细胞分化，降低炎症性肠病的风险。值得注意的是，iTreg的分化还依赖于脂肪酸氧化（FAO）代谢的建立。我们的前期工作表明，丁酸除了具有组蛋白去乙酰化酶抑制剂功能，还能够通过直接上调FAO关键酶CPT1的活性促进FAO，进而帮助iTreg完成分化，缓解小鼠肠炎症状。本项目拟以现有工作为基础，从分子、细胞和个体水平探究①丁酸对脂肪酸代谢以及iTreg分化的影响；②丁酸调控FAO的分子机制；③FAO调节iTreg细胞分化的作用机制。这项研究的顺利完成，将会帮助我们开启iTreg功能调控的代谢视角，为机体免疫稳态调节以及肠炎疾病防控提供重要的实验依据和分子靶点。

The connection between diet and immune homeostasis in gut has been a long-standing interest for scientists from different fields, including immunology and cell biology. In recent years, butyrate derived from dietary fiber, an essential component of balanced diet, has been shown to function as histone deacetylase (HDAC) inhibitor and promote iTreg cell differentiation both in mouse and human by enhancing Foxp3 transcription. As a consequence, the risk of inflammatory bowel disease (IBD) was reduced. It is known that iTreg differentiation associates with metabolic reprogramming and the establishment of fatty acid oxidation (FAO) appears to be necessary. Our data revealed that butyrate directly improved the enzymatic activity of CPT1, which is a key rate-limiting enzyme in FAO, to facilitate the metabolic reprogramming required for iTreg differentiation. Importantly, this previously unappreciated role of butyrate in the control of FAO is independent of its HDAC inhibitor function. Our preject aims to dissect the regulation of iTreg differentiation by butyrate at molecular, cellular and individual level, and illustrate 1) impact from butyrate on fatty acid metabolism associated with iTreg differentiation; 2) mechanism for iTreg differentiation regulated by butyrate; 3) mechanism by which FAO regulates iTreg differentiation. Revisiting iTreg differentiation through a metabolic angle may proide us with valuable evidence and potential target for the regulation of immune homeostasis as well as the intervention of human IBD.