节食富集的小鼠肠道细菌Lactobacillus murinus抗衰老的机制研究

Emerging evidences suggested that the gut microbiota plays a critical role in host aging. Our previous publication showed that gut microbiota modulated by calorie restriction contributed to attenuate the host metabolic health and extend lifespan. In our previous work, it demonstrated that a strain of Lactobacillus murinus was promoted in CR mice and causatively contributed to the attenuation of ageing-associated inflammation. In this study, we plan to regulate the abundance of Lactobacillus murinus in the mice gut by phage, CR or bacterial transplantation. Integration of gut microbiome, metabolites, host transcriptome and immunosenescence will lead to figure out the contributions of Lactobacillus murinus in the modification of metabolism and immunity by CR. Investigation the function of mutant strains in the models with Caco-2 cell, C. elegans and mice will lead to identification of putative key metabolites of Lactobacillus murinus for anti-inflammation and extending lifespan, and establishing the cross-talk pathway between this bacterium and the host. We will also investigate the effect of Lactobacillus murinus and its key metabolite on the metabolism, immunity and aging in senescence-accelerated mice. This project will generate further insights on the contribution of gut microbiota in maintaining the metabolism health of the mammal, which can help us to understand the proper mechanism of aging, and may shed light on development of probiotic or drug for anti-aging.

越来越多的证据表明，肠道菌群在衰老中有重要作用，而申请者的研究则为节食通过显著改变肠道菌群结构达致改善代谢健康和延长寿命效果的提供了新证据。在前期工作中，申请者证明了节食小鼠肠道中的优势细菌鼠乳杆菌对节食产生的健康效应有重要贡献。本课题拟利用噬菌体、节食和菌群移植调控小鼠肠道中鼠乳杆菌的丰度，对元基因组、代谢组、转录组、免疫组等数据进行整合分析，解析鼠乳杆菌在节食调控宿主免疫、代谢中的作用；构建突变菌株，在体外细胞模型、线虫模型和小鼠模型中阐明鼠乳杆菌是通过产生哪种特定产物，使得它能够抗炎、保护肠屏障从而对抗衰老有贡献，发现宿主与鼠乳杆菌活性产物进行“分子对话”的受体及通路；在快速衰老小鼠模型中研究鼠乳杆菌及其活性产物对宿主免疫、代谢以及衰老的影响。从而进一步阐述肠道菌群在哺乳动物代谢健康中的作用机制，完善对衰老机制的理解，为开发临床上能够应用的延缓衰老的益生菌或药物奠定基础。

本项目的通过动物模型全面分析了膳食结构、进食量（节食）、进食时间对肠道菌群及其代谢物的调控，发现节食塑造的肠道菌群能够减少化疗药物的毒副作用，节食富集的肠道关键细菌L. murinus能够加速慢性结肠炎恢复、与宿主糖脂代谢改善关系密切、与早衰小鼠衰老有关。揭示了节食的模式、进食时间通过调控肠道菌群影响糖脂代谢并影响宿主代谢疾病的发生发展，为临床干预老年相关代谢性疾病提供理论依据。在此基础上，我们对代谢性疾病患者进行了膳食运动的临床干预，为以菌群为靶点的个性化治疗策略提供了新途径。在包括Nature communications、mBio等国际知名期刊发表相关SCI论文9篇（标注本项目基金号）、中文核心核心期刊论文5篇（标注本项目基金号），获得两项专利授权，培养硕士生2名、博士生1名。