肠道多形拟杆菌通过Treg细胞调控糖脂代谢的机制研究

Intestinal microbiota has become an important factor in the regulation of glucose and lipid metabolism. In previous study, we found Bacteroides thetaiotaomicron (BT) can alleviate the disorder of glucose and lipid metabolism, but the mechanism is still unclear. Treg cells are closely related to B. thetaiotaomicron and metabolic diseases. B.thetaiotaomicron can induce the production of peripheral Treg cells. On the other hand, chronic inflammation is an important cause of insulin resistance within obesity. Treg cells in adipose tissues can inhibit chronic inflammation and regulate insulin receptor signaling. Therefore, exploring the immune regulation process of Treg cells in metabolic diseases has important implications for transformation studies. In this study, a multi-omics association analysis combining cohort study and mouse model was used to analyze the characteristics of Intestinal B. thetaiotaomicron-Treg cell-Glycolipid metabolism in obese people. After that, phenotypic analysis of Treg cells after B.thetaiotaomicron transplantation will be performed to clarify the effect of B.thetaiotaomicron on Treg cells in the regulation of metabolic process. Finally, Treg-related deficient mice, effector blockade and other means will be used to elucidate the mechanism of Treg cells-mediated B.thetaiotaomicron regulation of glycolipid metabolism. In conclusion, this study will explore B.thetaiotaomicron-mediated regulation mechanism of chronic inflammation and glycolipid metabolism via Treg, and provide a theoretical basis for new clinical intervention for glycolipid metabolic diseases.

肠道菌群已成为糖脂代谢稳态调节的重要因素，本团队前期研究中已筛选到多形拟杆菌（BT菌）可改善糖脂代谢紊乱，但其作用机制尚不清楚。Treg细胞和肠道BT菌、代谢疾病密切相关。BT菌可诱导Treg细胞产生；而肥胖发病过程中，慢性炎症是胰岛素抵抗的重要诱因，脂肪组织Treg可抑制慢性炎症，调节胰岛素受体信号。因此，探究BT菌改善代谢疾病过程中Treg的免疫调节作用对转化研究有重要启示。本研究拟通过人群联合小鼠模型的多组学关联分析，解析代谢肥胖人群中肠道BT菌-Treg细胞-糖脂代谢调控特征；之后，拟通过BT菌移植结合免疫细胞表型功能分析，明确BT菌调控代谢过程中对Treg细胞的影响；最后，通过Treg缺陷鼠、效应分子阻断等手段，阐明Treg细胞介导BT菌调节糖脂代谢的作用机制。综上，本研究将探讨BT菌通过Treg调节慢性炎症和糖脂代谢的生物学机理，为糖脂代谢疾病临床干预新方案提供理论依据。

肠道菌群已成为糖脂代谢稳态调节的重要因素，免疫细胞介导的组织慢性炎症与糖脂代谢密切相关，而肠道菌群和免疫细胞在代谢疾病发生中的具体调控关联尚未建立。本课题关注肠道菌群和内脏脂肪Treg之间的调控关联，首先基于单细胞测序分析比较SPF小鼠和肠道菌群清除小鼠脂肪免疫细胞分布变化，发现菌群清除后脂肪Treg数量显著降低，并通过流式细胞术在蛋白水平对该表型完成确认。接下来通过单抗生素筛选模型发现万古霉素敏感菌是维持脂肪Treg数量的关键菌群，进一步关联分析发现脂肪Treg数量和产短链脂肪酸菌正相关，通过短链脂肪酸喂水补充可逆转万古霉素处理后的Treg减少。SPR实验证明短链脂肪酸和PPARγ可直接结合，且缺陷PPARγ后短链脂肪酸对Treg的作用消失，提示肠道产短链脂肪酸菌通过短链脂肪酸-PPARγ-Treg轴特异性调控内脏脂肪Treg，进而调节内脏脂肪的免疫代谢微环境。该发现提示高纤饮食干预或直接短链脂肪酸补充可能通过提高脂肪Treg数量帮助机体改善代谢并抵御脂肪组织慢性炎症。