α-亚麻酸通过调节肠道菌群-胆汁酸轴改善2型糖尿病血脂异常的机制研究

Dyslipidemia is an independent risk factor for atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Alpha-linolenic acid (ALA) is helpful to improve dyslipidemia in T2DM, but its mechanism has not been elucidated. The gut microbiota-bile acids axis is a new target in the mechanism study of metabolic diseases. Our previous research observed that the ameliorative effect of ALA on dyslipidemia in T2DM was related to intestinal bacteria involved in bile acid modification. Our hypothesis is that ALA ameliorate type 2 diabetic dyslipidemia by regulating gut microbiota, altering bile acids composition, activating farnesoid X receptor (FXR) and inhibiting fatty acid synthesis. This project will establish the model of type 2 diabetic dyslipidemia in KKAy mice, and determine the optimum dose of ALA in improving type 2 diabetic dyslipidemia. Then, the gut microbiota regulating mechanism of type 2 diabetic dyslipidemia alleviated by ALA will be investigated using antibiotic interruption and fecal transplantation. Finally, the bile acids-FXR pathway will be explored through overexpression and interference with FXR. These results will not only help finding a new way for ALA to improve the lipid metabolism through the interaction between gut microbiota and host in type 2 diabetic dyslipidemia, but also help providing scientific evidence for the development of type 2 diabetic nutritional interventions targeting gut microbiota-bile acids axis.

血脂异常是2型糖尿病（T2DM）患者动脉粥样硬化的独立危险因素。ɑ-亚麻酸（ALA）有助于改善T2DM血脂异常，但其作用机制仍未阐明。肠道菌群-胆汁酸轴是代谢性疾病机制研究的新靶标。申请人前期研究发现ALA改善T2DM血脂异常效应与修饰胆汁酸的肠道细菌有关，因此推测ALA通过调节肠道菌群，改变胆汁酸构成，激活法尼醇X受体（FXR），抑制脂肪酸合成，改善T2DM血脂异常。本项目拟首先利用KKAy小鼠建立T2DM血脂异常模型，确定ALA改善T2DM血脂异常的适宜剂量；然后通过抗生素干扰和粪菌移植实验，探究肠道菌群在ALA改善T2DM血脂异常中的作用；最后应用腺相关病毒过表达和干扰FXR，明确胆汁酸-FXR途径在ALA改善T2DM血脂异常中的作用。研究结果不仅有助于发现ALA通过肠道菌群与宿主互作改善T2DM脂代谢的新途径，而且将为制定靶向肠道菌群-胆汁酸轴的T2DM营养干预措施提供科学依据。

血脂异常是2型糖尿病（T2DM）患者动脉粥样硬化的独立危险因素。ɑ-亚麻酸（ALA）有助于改善T2DM血脂异常，但其作用机制仍未阐明。肠道菌群-胆汁酸轴是代谢性疾病机制研究的新靶标。申请人前期研究发现ALA改善T2DM血脂异常效应与修饰胆汁酸的肠道细菌有关，因此推测ALA通过调节肠道菌群，改变胆汁酸构成，改善T2DM血脂异常。本项目首先通过粪菌移植实验，确定肠道菌群对T2DM血脂异常的影响；其次，分析ALA对T2DM血脂异常、肠道菌群及胆汁酸的干预作用，探究TLR4/MyD88途径调控糖脂代谢机制；最后，给予益生菌和脱氧胆酸干预，验证调节肠道菌群和胆汁酸对T2DM血脂异常的影响。结果发现，T2DM小鼠肠道菌群增加对照小鼠甘油三酯、总胆固醇和低密度脂蛋白胆固醇，对照小鼠肠道菌群降低T2DM小鼠低密度脂蛋白胆固醇；ALA降低T2DM小鼠甘油三酯和低密度脂蛋白胆固醇，增加高密度脂蛋白胆固醇、乳杆菌属和脱氧胆酸，抑制TLR4/MyD88依赖性途径的激活，减少炎症因子分泌，缓解糖脂代谢紊乱；益生菌降低T2DM小鼠甘油三酯，脱氧胆酸减少T2DM小鼠甘油三酯和低密度脂蛋白胆固醇。研究结果不仅有助于发现ALA通过肠道菌群与宿主互作改善T2DM脂代谢的新途径，而且将为制定靶向肠道菌群-胆汁酸轴的T2DM营养干预措施提供科学依据。