基于“微生物-肠-脑轴”探讨乳杆菌通过多巴胺调控糖脂代谢的分子机制

肥胖已成为21世纪威胁人类健康最严重的疾病之一。已知肥胖的形成与肠道微生物、糖脂代谢紊乱密切相关。快节奏的生物方式容易引起昼夜饮食节律的改变，影响肠道菌群节律，扰乱生物钟，导致糖脂代谢紊乱。前期研究中，申请者发现肠道乳杆菌与昼夜饮食节律密切相关，部分肠道乳杆菌丰度与血清多巴胺、甘油三酯、血糖呈显著正相关关系，干预多巴胺的外周节律可诱导糖代谢紊乱。这一发现揭示肠道乳杆菌诱导的多巴胺节律变化可能是饮食节律变化诱发糖脂代谢紊乱的关键环节。本研究拟采用宏转录组、代谢组等现代生物学技术，通过离体实验研究不同肠道乳杆菌的多巴胺合成，通过在体实验研究乳杆菌对大鼠肠道微生态及宿主多巴胺节律的影响，探讨肠道乳杆菌对多巴胺受体干预大鼠糖脂代谢、胰岛素抵抗、外周生物钟及能量内稳态的影响，明确多巴胺节律在肠道乳杆菌调节糖脂代谢中的作用机制，为肥胖、糖尿病等代谢类疾病的防治提供新的思路及策略。

Obesity has become one of the most serious diseases threatening human health in the 21st century. It is known that the formation of obesity is closely related to the gut microbiota and disorders of glycolipid metabolism. The fast-paced lifestyle is easy to cause the change of circadian diet rhythm, affect circadian rhythm of gut microbiota, disturb the body clock and lead to disorder of glycolipid metabolism. In the previous study, we found that intestinal Lactobacillus was closely related to circadian dietary rhythm. The abundance of some intestinal Lactobacillus was significantly positively related to the content of dopamine, triglyceride and blood sugar in serum. Interfering of peripheral rhythm of dopamine can induce the disorder of glucose metabolism. These results suggest that the change of dopamine rhythm induced by intestinal Lactobacillus may be the key point of glycolipid metabolism disorders induced by the change of dietary rhythm. In this study, meta-transcriptomics, metabolomics and other modern biological techniques will be used to analyze the dopamine synthesis of Lactobacillus in vitro and the effects of Lactobacillus on intestinal microecology and dopamine rhythm of rats in vivo, and explore the effects of intestinal Lactobacillus on glycolipid metabolism, insulin resistance, circadian clock and energy homeostasis of rats of with blocking of dopamine receptor. These results may help to provide new ideas and strategies for the prevention and treatment of metabolic diseases, such as obesity and diabetes.