肠道菌群及代谢产物SCFA/BCAA在迷走神经改善糖尿病心血管损伤中的作用机制研究

肠道菌群失衡导致胰岛素抵抗而增加糖尿病风险，糖尿病存在自主神经失衡（交感亢进、迷走低下）及肠道屏障功能紊乱。但迷走神经调节、肠道菌群、糖尿病心血管损伤三者内在联系尚不清楚。本课题拟研究改善迷走能否重塑肠道菌群稳态从而发挥糖尿病心血管保护的分子机制：1）利用糖尿病/高血压动物模型结合迷走干预，采用qPCR等技术分析肠道上皮细胞间紧密连接蛋白表达和肠道通透性，明确拟胆碱药对肠道屏障功能的作用；2）通过16SrRNA基因测序技术明确介导迷走神经对糖尿病代谢调节的关键驱动菌群；3）分析迷走活化对肠道菌群代谢产物短链脂肪酸（SCFA，及其介导的脂质代谢）、支链氨基酸（BCAA，及其介导的线粒体损伤）的调控机制，阐明活化迷走神经引起肠道菌群变化减轻糖尿病心血管损伤的分子机制。本研究有望为调控肠道菌群防治糖尿病及其心血管损伤提供自主神经干预的新途径和药理学治疗靶点。

Gut microbial imbalance can induce insulin resistance and increase risk and incidence of diabetes. Diabetes is associated with an autonomic imbalance characterized by sympathetic hyperactivity and diminished vagal activity, and hyperglycemia drives intestinal barrier dysfunction. However, the intrinsic relations of vagal regulation, gut microbiota, and cardiovascular injury in diabetes are not yet clear. In the present project, we will investigate the molecular mechanisms underlying cholinergic drugs regulating metabolic profile and exerting cardiovascular protection through modulating gut microbiota in diabetes. We will 1) detect intestinal epithelial tight junction protein expression and intestinal permeability using diabetes/hypertension animal models combined with vagal intervention by qPCR and other techniques, in order to determine the impact of cholinergic drugs on gut barrier function; 2) explore the microbiota-modulating effect of the cholinergic drugs by application of high-throughput 16SrRNA gene sequencing, in order to clarify the role of gut microbiota in vagal nerve-induced protective effects against diabetes; 3) explore the effects of cholinergic drugs on microbiota-derived metabolites including short chain fatty acids (SCFA, and its related lipid metabolism) and branched-chain amino acids (BCAA, and its related mitochondrial injury), in order to disclose the signal pathway of vagal nerve regulating gut microbiota and ameliorating cardiovascular injury in diabetes. This study may help to provide a new way of autonomic intervention and pharmacological therapeutic targets for the regulation of gut microbiota in the prevention and treatment of diabetes and its related cardiovascular disorders.