基于肠道FXR/TGR5信号通路的肠道菌群调控2型糖尿病合并非酒精性脂肪性肝病肝细胞糖脂代谢的作用机制

The crosstalk between gut microbiota and bile acid homeostasis play an importance role in cholestatic liver disease, but its role in the pathological process of T2DM complicated with NAFLD is not clear. Studies showed that FXR/TGR5 signaling pathway is closely related with lipid synthesis, oxidation, absorption and transport, and our previous study found that patients with first-diagnosis of T2DM had higher liver injury suffering rate, and glucose and lipid metabolic disorder was aggravated in patients of T2DM complicated with NAFLD. Based on the literature analysis and previous experimental results, we hypothesize that dysregulation of gut microbiota-bile acid homeostasis crosstalk result in the decrease of unconjucted bile acid, which down-regulate the secretion of GLP-1 and FGF15/19 by inhibiting the intestinal FXR/TGR5 signaling pathway, leading further aggravation of the disorder of glycolipid metabolism in hepatocytes under T2DM, and ultimately accelerate the pathological process of T2DM complicated with NAFLD. Probiotics can improve glucose and lipid metabolic disorder in hepatocytes by regulating the dysregulation of gut microbiota and its signaling pathway, and played an early role in preventing and delaying the pathological process of T2DM complicated with NAFLD. The findings will provide theoretical and experimental evidence not only for the early prevention and inhibition of pathologic process, but also for drug preventive treatment of T2DM-related liver diseases.

肠道菌群-胆汁酸稳态的交互作用在胆汁淤积性肝脏疾病中发挥重要作用，而在T2DM合并NAFLD中的作用不明。FXR/TGR5通路是脂质合成、氧化、吸收及转运过程中的重要调控途径，我们前期研究发现初诊T2DM患者合并肝脏疾病风险较高，而合并二者的患者糖脂代谢紊乱进一步加剧。据此我们提出假设：肠道菌群-肠道胆汁酸交互作用失衡通过抑制肠道FXR/TGR5信号通路，下调道GLP-1和FGF15/19的分泌，加剧T2DM下肝细胞糖脂代谢紊乱而加速T2DM合并NAFLD病理进程。而益生菌则通过调节肠道菌群失衡及其调控下的信号通路，改善肝细胞糖脂代谢紊乱，发挥早期预防并延缓T2DM合并NAFLD病理进程的作用。本项目拟在临床样品、动物、细胞及分子水平研究肠道菌群失衡通过加剧肝细胞糖脂代谢紊乱加速T2DM合并NAFLD病理进程的分子调控机制，为探究糖尿病性肝脏疾病早期预防及延缓其发生发展提供新思路。

肠道微环境是导致非酒精性脂肪肝（NALFD）和2型糖尿病（T2DM）发展的潜在因素，与肠道紧密连接（TJs）密切相关。本项目研究发现高血糖诱导T2DM合并NAFLD小鼠肠道紧密连接结构的破坏，而丁酸梭菌和丁酸钠（NaB）能改善T2DM合并NAFLD下破坏的紧密连接结构，继而缓解肠道炎症。进一步的机制研究显示，NaB通过激活肠道TGR5/GLP-1信号通路改善高糖（HG）和高脂（FFA）共培养下肝细胞脂质蓄积。整体动物实验结果显示，NaB不仅能缓解db/db小鼠肝脏损伤及炎症反应，还能改善db/db小鼠肝细胞糖脂代谢紊乱。本项目分别在临床样品、分子、细胞及整体动物水平研究证实肠道紧密连接破坏通过加剧肝细胞糖脂代谢紊乱在T2DM合并NAFLD的病理进程中发挥重要作用，并阐明肠屏障破坏通过抑制肠道TGR5/GLP-1信号通路调控加速T2DM合并NAFLD肝细胞糖脂代谢紊乱的分子机制。丁酸梭菌及其代谢物丁酸可通过肠屏障结构完整性及其调控下的肠道信号通路，发挥早期预防并延缓T2DM合并NAFLD病理进程的作用。该研究揭示肠屏障结构完整性经由肠道炎症加速T2DM合并NAFLD病理进程的新机制，为探究糖尿病性肝脏疾病早期预防及延缓糖尿病性肝脏疾病提供新的思路。