胆汁酸代谢对饮食诱导的肥胖型肠道菌群结构的作用机制研究

It is increasing evident that gut microbes shape the host metabolism and influence the development of obesity, providing new insights into potential mechanisms of the aetiopathogenesis of obesity. The applicant will carry out further investigations in this field, based on previous studies on gut microbiota. Currently, much emphasis is put on assessing alterations in the gut microbiota (increased abundance of Firmicutes and decreased abundance of Bacteroidetes) associated with diet-induced obesity and on clarifying how such reshaped gut microbiota mediates the development of obesity. However, important questions about why and how high-fat diets induce changes in the bacterial population remain to be elucidated. High-fat diets enhance bile acid secretion to facilitate lipid digestion, and bile acid metabolism is regulated by gut microbes. Thus, bile acid metabolism might be an important linkage of diets and the composition of gut microbiota. Here, we hypothesize that bile acid metabolism after high-fat diets is a main host factor that regulates the composition of gut microbiota in diet-induced obesity. We will conduct animal studies with bile acid metabolism intervention, to demonstrate that bile acids, especially secondary bile acids, manipulate the composition of gut microbiota. Significantly altered microbes (Firmicutes and Bacteroidetes at species levels) will be cultivated in vitro for bile acid sensitivity tests, in order to validate the findings in animal studies and elucidate the mechanisms of the regulation effect of bile acid metabolism on the composition of gut microbiota. This mechanistic study will provide a better understanding in the diet-bile acids-gut microbiota-obesity axes and raise prospect for diagnosis, treatment and prevention in obesity.

肠道菌群是近年肥胖机制研究的热点，申请人基于对肠道菌群代谢的多年研究基础开展本项目。现有报道集中于饮食诱导的肥胖个体肠道中厚壁菌门丰度升高而拟杆菌门丰度下降，该肥胖型肠道菌群结构影响糖脂代谢和能量摄取。然而，宿主饮食是如何调控形成肥胖型菌群结构，却少有研究。高脂饮食刺激胆汁酸分泌，肠道细菌同时参与胆汁酸代谢，因此，胆汁酸可能是饮食和肠道菌群间的潜在桥梁。本项目的科学假说为“胆汁酸代谢是调控饮食诱导的肥胖型肠道菌群结构的关键因素”。项目将对实验动物进行胆汁酸代谢干预，通过胆汁酸谱和肠道菌元基因组学数据结果，证明胆汁酸特别是细菌代谢的次级胆汁酸能够调控肠道菌群结构；挖掘作用于肠道菌的关键胆汁酸和肥胖型肠道菌结构中的关键菌种；进一步通过体外细菌培养实验考察菌种对胆汁酸的敏感性，阐释体内作用机制。本项目的实施有望阐明饮食对肠道菌群的影响，为肥胖的机制研究和临床治疗提供新的思路和手段。

肠道菌群是近年肥胖机制研究的热点，现有报道集中于饮食诱导的肥胖个体肠道中厚壁菌门丰度升高而拟杆菌门丰度下降，然而，宿主饮食是如何调控形成肥胖型菌群结构，尚不清楚。高脂饮食刺激胆汁酸分泌，肠道细菌同时参与胆汁酸代谢，因此，胆汁酸可能是饮食和肠道菌群间的潜在桥梁。本项目的科学假说为“胆汁酸代谢是调控饮食诱导的肥胖型肠道菌群结构的关键因素”。本项目主要通过构建高脂饮食干预的肥胖小鼠模型来观察胆汁酸和肠道菌群的互作，进一步通过胆汁酸和肠道菌随着饮食干预的变化规律、添加和剥夺胆汁酸实验，阐明胆汁酸是饮食诱导形成肥胖型肠道菌群结构的关键因素。为了研究胆汁酸和肠道菌群的互作是否在饮食干预的模型中普遍存在，研究进一步考察了其他饮食干预方式（禁食、能量限制）对肠道菌群和代谢物特别是胆汁酸的调控作用研究。在此基础上，研究对代谢物-肠道菌群的相关性分析方法进行了开发和创新。本研究饮食和肠道菌群的互作关系提供有力依据，为肥胖的机制研究和临床治疗提供新的思路和手段。