长链n-3多不饱和脂肪酸通过肠道菌群对CMPF代谢的影响及机制研究

The association between long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) and glucose metabolism and related mechanism are not clear. Prior studies suggested that the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) was significantly increased after LC n-3 PUFA intervention, and high dosage CMPF could impair beta-cell function, while moderate dosage could improve insulin sensitivity. Clarification of the effect of LC n-3 PUFA on CMPF metabolism is key for the understanding of effect of the LC n-3 PUFA on glucose metabolism, among which gut microbiota may play an important role. The present project aims to use human cohort study to investigate the association between erythrocyte n-3 PUFA, serum CMPF and gut microbiota, and explore the role of gut microbiota in the n-3PUFA-CMPF association. In addition, an animal experiment will be conducted to explore the CMPF metabolism in the body in response to LC n-3PUFA intake, and to demonstrate the role of gut microbiota in the effect of LC n-3PUFA on CMPF metabolism. We will further explore the role of gut microbiota and CMPF in the LC n-3 PUFA-glucose metabolism relationship. Our study will be important for the nutritional prevention and treatment of metabolic diseases caused by abnormal glucose metabolism.

长链n-3多不饱和脂肪酸（PUFA）与糖代谢的关系及背后的机制尚不清楚。血液呋喃脂肪酸代谢物3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）在长链n-3PUFA干预后显著升高，高浓度CMPF会破坏胰岛功能而中等浓度CMPF则能改善胰岛素敏感性。肠道菌群可能在长链n-3PUFA对CMPF和糖代谢的影响机制中发挥重要作用。本项目拟利用人群队列研究探索长链n-3PUFA及CMPF与肠道菌群的前瞻性关联、发现与CMPF密切相关的肠道菌群种类。同时本项目拟利用动物实验，通过长链n-3PUFA干预小鼠，分析确定长链n-3PUFA干预后CMPF在体内的形成机制，深入阐释肠道菌群在长链n-3PUFA影响CMPF代谢过程中的作用及相关机制，探索肠道菌群和CMPF代谢在长链n-3PUFA作用于糖代谢过程中所起的作用。本研究对于糖代谢异常导致的代谢性疾病的营养防治有重要的理论价值。

长链n-3多不饱和脂肪酸（PUFA）与糖代谢的关系及背后的机制尚不清楚。血液呋喃脂肪酸代谢物3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）在长链n-3PUFA干预后显著升高，高浓度CMPF会破坏胰岛功能而中等浓度CMPF则能改善胰岛素敏感性。肠道菌群可能在长链n-3PUFA对CMPF和糖代谢的影响机制中发挥重要作用。本项目建立了人群血清样本CMPF检测方法并完成了来自1639位志愿者共3625份样本的CMPF含量检测。在队列研究中，我们发现红细胞n-3 PUFA与血清CMPF显著正相关；红细胞n-3 PUFA与CMPF一致性地与较低的2型糖尿病发病风险相关；CMPF部分介导了长链n-3多不饱和脂肪酸与2型糖尿病的关联。肠道微生物组学揭示了与长链n-3 PUFA与CMPF相关的肠道微生物特征，主要包括Clostridium、Haemophilus和Streptococcus。利用抗生素处理小鼠模型，我们明确了肠道菌群对于n-3 PUFA升高CMPF的潜在作用。我们的研究成果为糖代谢异常导致的代谢性疾病的营养防治提供了新的靶点与思路，具有重要的理论价值。