肠道共生拟杆菌通过氨基酸代谢调节肥胖及能量代谢机制研究

Evidence that the gut microbiota contributes to the development of obesity is accumulating. Hence, characterization of the gut microbiota in obesity and identification of microbial therapeutic targets are highly warranted. However, at strain level, the specific bacteria that could regulate obesity and the underlying mechanism is still not known. Using deep metagenomic sequencing in lean and young obese Chinese individuals, we have identified gut microbial species associated with obesity, of which species from bacteroides significantly decreased in obese individuals while increased after weight-loss surgery. The abundance of bacteroides species was negatively associated with body weight, fat content and circulating amino acids. Further animal experiments explored the causal relationship between species from bacteroides with obesity and fat content. Based on these key findings, in the present project, we will use germ-free mice, diet-induced and genetic obese mouse models and follow-up cohorts, to investigate the role of three species from bacteroides (Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides intestinalis) in energy balance and the development of obesity; to explore the their role in regulating amino acid metabolism; and to elucidate the underlying mechanism how bacteroides regulate amino acid metabolism thereby regulating obesity. This study will provide better understanding of the causal relationship between certain bacteria strains /metabolites and obesity, and identify new therapeutic targets for obesity intervention.

大量研究表明，肠道菌群与肥胖发生密切相关，是新的肥胖干预靶点，然而目前我们在菌株水平对肠道共生菌调节肥胖发生的作用及机制仍所知甚少。申请人前期人群研究发现多个肥胖肠道共生菌，其中三株拟杆菌在肥胖人群显著下降，减重手术后回升，且丰度与体重、体脂、糖脂水平、血清氨基酸水平显著负相关，并通过动物实验建立其与肥胖发生的初步因果关联（Nat Med 2017）。本课题将在这些前期研究基础上，借助肥胖人群队列结合动物模型继续探索三个候选菌株（多形拟杆菌、单形拟杆菌、肠型拟杆菌）的作用：① 探究三种拟杆菌单菌株以及三菌株生态互作对能量代谢和体重的调节作用；② 阐述拟杆菌调节氨基酸代谢功能；③ 探究拟杆菌通过氨基酸代谢物影响肥胖的具体机制。在肠道菌群研究从“整体关联”迈入“菌株-代谢物-表型因果关系”以及“生态互作致病机理研究”领域取得突破，并发现减肥单菌株或多个共生互作菌株，为肥胖干预提供新方法。

本项目利用肥胖-对照人群队列以及重度肥胖减重手术干预队列，明确肥胖相关核心菌改变，锁定拟杆菌多个菌种与体重调节、糖脂代谢存在显著相关性，为后续进行益生菌功能研究奠定基础。利用无菌动物、抗生素清菌小鼠证明多形拟杆菌调节肥胖、能量代谢以及肠粘膜屏障作用，建立丙酸生成关键酶突变菌株，证明其产丙酸缺陷，并证明突变菌株促进GLP1分泌、促进肠道杯状细胞分化、肠粘膜屏障功能的缺陷。从而证实多形拟杆菌-丙酸代谢途径调节肠道激素、肠粘膜屏障功能、改善代谢的作用机制。建立中国人粪便来源多形拟杆菌、阿克曼氏菌菌株，并证明功能，为后续进行自主知识产权的益生菌药物研发提供菌株资源。证明雄激素通过调节肠道菌群和循环谷氨酰胺和 Gln/Glu 比率来恶化葡萄糖稳态，从而导致不同性别之间葡萄糖代谢的差异。为认知糖尿病发生过程中男、女性别间不同的病理生理基础、糖尿病治疗尤其是为缓解男性高代谢风险提供了新的思路和靶点。