二氢杨梅素通过SIRT3-H3K27ac-IL22轴促进肠粘膜固有层ILC3免疫功能和维持肠粘膜屏障防治T2DM的作用及机制研究

二型糖尿病（T2DM）严重威胁人类健康，但缺乏理想防治措施。T2DM发生机制复杂，肠屏障功能下降导致的肠源性内毒素血症和机体慢性低度系统性炎症是胰岛素抵抗和T2DM发生的重要原因。3型固有淋巴样细胞(ILC3)是维持肠粘膜免疫屏障功能的关键效应细胞。课题组前期研究发现，二氢杨梅素（DHM）能有效改善胰岛素抵抗，降低肠粘膜通透性，增加ILC3效应性细胞因子IL-22表达，但该作用在SIRT3敲除小鼠体内消除。结合相关研究，课题组提出“DHM通过SIRT3-H3K27ac-IL22轴，提高ILC3免疫功能和维持肠粘膜屏障，改善内毒素血症和机体慢性炎症，防治T2DM”的科学假说。本项目拟利用高脂诱导小鼠模型，结合流式细胞术、细胞能量代谢检测等方法，阐明DHM通过SIRT3调节ILC3能量代谢表型进而增加组蛋白H3K27乙酰化修饰，促进IL22表达和分泌，维持肠粘膜屏障功能防治T2DM的作用机制。

Diabetes mellitus type 2 (T2DM) is a serious threat to human health, but without ideal strategies of prevention and therapy. The mechanism of T2DM occurrence is complex, and the intestinal barrier function disturbance and the related intestinal endotoxemia with chronic low-grade systemic inflammation are important reasons of insulin resistance and T2DM occurrence. Type 3 lymphoid cells (ILC3) play a key role in maintaining intestinal mucosal barrier. We previously found that dihydromyricetin (DHM) can improve the insulin resistance, reduce intestinal permeability and increase the expression of IL22 by ILC3. However, such effects induced by DHM were eliminated in the SIRT3KO mice. Based on the associated research, we hypothesized that DHM might prevent the occurrence of T2DM by the maintenance of intestinal mucosal barrier function through the improvement of the immunologic function of ILC3 via the SIRT3-H3K27ac-IL22 axis, leading to the ameliorated endotoxemia and chronic systemic inflammation. By use of the high fat diet-induced mice model, combined with the assays including flow cytometry and cellular energy metabolic phenotype detection, we aim to clarify the mechanisms that DHM regulates the energy metabolism phenotype of ILC3 via SIRT3, which in turn increases the acetylation of a histone H3K27, leading to the increased expression of IL22, finally maintains the intestinal barrier function and prevent T2DM occurrence.