基于Lgr5+肠干细胞及Th淋巴细胞互作用探讨葛根芩连汤治疗T2DM的作用机制

2型糖尿病（T2DM）作为慢性低水平炎症性疾病，与肠道黏膜屏障受损密切相关。最新研究表明，糖尿病患者体内肠道菌群紊乱，造成以Lgr5+肠干细胞及Th淋巴细胞亚群互作用失调为基础的肠黏膜屏障功能受损，诱发机体炎症反应是导致T2DM的关键环节。项目前期临床和实验研究表明，葛根芩连汤是治疗T2DM的有效方剂，能够富集黏膜修复相关益生菌，激活肠道黏膜免疫，调控细胞因子表达，改善胰岛素抵抗。然而其是否通过调控Lgr5+肠干细胞及Th淋巴细胞亚群而发挥作用仍不明确。本研究通过动物实验与细胞实验相结合，以中药有效单体复方为干预手段，通过肠外类器官培养、单细胞转录组学测序等技术，筛选并验证葛根芩连汤干预后，对Lgr5+肠干细胞及Th淋巴细胞亚群数量和功能相关信号通路和关键转录因子的影响，明确其治疗T2DM的细胞分子机制。以期通过本项目的示范性研究，为中医药防治2型糖尿病的生物学基础提供新的研究思路及模式

Type 2 diabetes (T2DM) is closely related to intestinal mucosal barrier damage as a chronic low-level inflammatory disease. Recent research have shown that the disorder of diabetic patients’ intestinal microbiota caused the impaired intestinal mucosal barrier based on the interaction of Lgr5 + intestinal stem cells and Th lymphocyte subsets, then induced excessive inflammatory response plays the key role for T2DM. Our clinical research and animal experiments have shown that Gegen Qinlian Decoction is an effective prescription for the treatment of T2DM, which can enrich the probiotics associated with mucosal repair, activate intestinal mucosal immunity, regulate cytokine expression, and alleviating insulin resistance. However, whether it is through regulating the interaction of LGR5 + intestinal stem cells and lymphocyte subsets is still unclear. In this study, through the combination of animal experiments and cell experiments and the intervention of active pharmaceutical ingredient of traditional Chinese medicine, we will screen and verify the key mutative signaling pathways and transcription factors of Lgr5+ intestinal stem cells and Th lymphocyte subsets. To clarify the cellular and molecular mechanisms underlying the Chinese   medicine treatment on type 2 diabetes through the intestinal Organoids culture, single-cell transcriptomics sequencing and other techniques. Through the demonstration research of this project, we expect to provide new research ideas and models for the biological basis of TCM prevention and treatment of type 2 diabetes.