醋杆菌经Toll通路对果蝇代谢性学习记忆的调控作用研究

As with the growth of social economy, diabetes has become a serious public health problem. Thus, how to maintain the "healthy" eating habits has been a critical problem of diabetes prevention. As an important animal model, drosophila has been widely used in the studies of metabolic disorders. In previous study, we found that the drosophila could form a diet memory based on different caloric content in the training through different caloric food. Maintaining this kind of memory could help the fruit fly reduce high-calorie food intake in order to maintain the metabolic homeostasis, which was conferred as the "metabolic learning memory". In contrast, when overexposing to high-calorie food, this kind of memory would attenuate, accompanying with glucose and lipid disorders, lower Acetobacter abundance and changes of Toll signaling pathway expression. So, searching the influencing and protective factors of metabolic learning memory became our next research goal. In recent years, a large number of studies have found that Acetobacter participated in mediating diet behavior, which inspired us to explore the relationship between Acetobacter and metabolic learning memory. Our team intended to establish an Acetobacter drosophila model to explore the changes of metabolic learning and memory and on this basis, we wanted to analyze the possible role of Toll signaling pathway in it by over-expressing or inhibiting Toll signaling pathway related genes. In all, we hope this study could help to better explain the mechanism of metabolic learning and memory formation and provide new ideas in prevention of diabetes through diet behavior.

随着社会经济增长，糖尿病已成为严重的公共卫生问题之一；如何维持“健康”饮食习惯是其预防的重要手段。果蝇作为重要的模式生物，已广泛被应用于代谢研究中。申请者前期研究发现，通过交互热量食物训练，果蝇形成一种对不同热量食物的学习记忆，维持这一记忆有助于果蝇主动降低高热量食物摄取、进而达到体内代谢平衡，即“代谢性学习记忆”。当长期暴露高热量食物后，这种饮食记忆会逐渐减弱，伴随糖脂代谢紊乱、肠道益生菌醋杆菌丰度下降及Toll通路表达改变。基于此，寻找代谢性学习记忆形成的机制及保护因素成为我们下一研究重点。近年研究发现醋杆菌参与调控饮食行为，这启发我们探讨醋杆菌与代谢性学习记忆的关系。本课题组拟通过建立醋杆菌果蝇模型，分析其代谢性学习记忆的变化；并在此过程进一步抑制或过表达肠道Toll通路相关基因以探讨Toll通路的介导作用，进而找出调控代谢性学习记忆的新靶点，为饮食行为预防糖尿病提供新思路。

代谢性疾病是与人类进食习惯密切相关的一组疾病，其中肠道菌群起至关重要的作用。高热量的进食习惯导致肠道菌群发生改变，随之而来的细菌异位、肠道通透性改变、内毒素血症及全身性低度炎症都会促进体内代谢水平的紊乱，同时也伴随认知功能的差异。果蝇作为生命科学领域中重要的模式生物，因其清晰的遗传背景及与哺乳动物在生理生物学和神经系统机能方面的相似性，越来越被广泛地应用于基础研究。本研究利用果蝇作为模式生物建立高热量喂养模型，观察经过高糖饮食喂养后，发现果蝇的学习记忆能力与对照组相比明显下降，不同饮食环境下生长的果蝇肠道菌群结构组成变化显著。同时还发现高糖饮食诱导的亲代果蝇学习记忆降低和肠道菌群的变化在子代果蝇中同样存在。在此基础上，通过16S rRNA 测序技术和细菌靶向代谢分析筛选出高糖组与对照组的差异菌株及其主要短链脂肪酸，进一步将细菌和短链脂肪酸回饲给高糖组子代果蝇，发现其降低的学习记忆能力能够在一定程度上被恢复，其作用机制可能借助于脑内多巴胺水平的调控。本研究在一定程度上为饮食影响代谢及认知功能研究提供了新思路。