基于“肠道菌群调控宿主能量代谢”关系研究黄芪多糖防治肥胖的机理

Obesity is one of the most challenges in the 21st century. However, we are still lacking safe and effective anti-obesity drugs to date. Obesity is directly caused by imbalance of energy metabolism, and gut microbiota plays important role in modulating host energy homeostasis. Meanwhile, the dysreguation of gut microbiota is highly correlated with Spleen-qi deficiency syndrome, which is regarded as the main pathogenesis of obesity in TCM. As a result, obesity is characterized by three inter-correlated properties, i.e dysregulation of gut microbiota, imbalance in energy metabolism, and Spleen-qi deficiency syndrome. According to the theory of ‘obesity treatment by targeting on Spleen’ in TCM, and the clinical anti-obesity evidence of Fangji Huangqi Decoction, a classical TCM formula, we first validated the anti-obesity effect of Fangji Huangqi Decoction and its main component, the aqueous extract of Huangqi, and Astraglus polysaccharides (APS), the main effective part of Huangqi. Our results indicated that both the whole formula and the aqueous extract of Huangqi had similar anti-obesity effect in high-fat diet fed mice. Moreover, our results indicated that the anti-obesity effect of APS was associated with modulation on gut microbiota in mice. In the current project, our principal objective is to elucidate the underlying mechanism of the anti-obesity effect of APS. Based on our preliminary results, we hypothesized the axis of “APS-gut microbiota-microbial metabolites-energy metabolism” underlying the anti-obesity effect of APS. This study will not only reveal the anti-obesity mechanism of APS by modulating gut microbiota and host energy metabolism homeostasis, but also highlight the importance of gut microbiota in modulating host metabolism of other herb-derived polysaccharides, provide scientific evidence for research and development of herb-derived polysaccharides in obesity therapy. It will also identify the relationship between gut microbiota and activity of traditional medicines with invigorating Spleen and supplementing Qi character, as well as enriching the scientific content of Spleen-qi deficiency syndrome in TCM.

肥胖是当今人类所面临的严峻挑战，仍缺乏安全、有效的治疗药物。肥胖的直接病因是机体能量代谢失衡，而肠道菌是宿主能量代谢平衡的重要调节者。肠道菌群失调与中医学的脾气虚证具有高度的相关性，后者也是肥胖的重要病机，因而形成了肥胖的‘肠道菌群失调、能量代谢失衡与脾气虚证’三种紧密依存的特征。根据肥胖的‘从脾论治’中医思想，我们依据报道的防己黄芪汤的临床减肥证据，验证了该复方，及黄芪水提物与黄芪多糖（APS）的减肥作用，并观察到APS的减肥作用与调节肠道菌有关。本项目将重点研究APS通过肠道菌，调节宿主能量代谢，发挥减肥作用的机理，提出 “APS-肠道菌-菌群代谢物-能量代谢”关系轴假说。该研究将揭示肠道菌介导APS调控宿主能量代谢分子网络的机理，并将为其它植物多糖作用机理的研究，以及在防治肥胖的产品开发上提供科学依据，促进对健脾益气类中药药效与调控肠道菌关系的认识， 丰富中医脾气虚证的现代科学内涵。

肥胖是当今人类所面临的严峻挑战。肥胖的直接病因是机体能量代谢失衡，而肠道菌是宿主能量代谢平衡的重要调节者。肠道菌群失调与中医学的脾气虚证具有高度的相关性，后者也是肥胖的重要病机，因而形成了肥胖的“肠道菌群失调、能量代谢失衡与脾气虚证”三种紧密依存的特征。根据肥胖的“从脾论治”中医思想，我们依据报道的防己黄芪汤的临床减肥证据，验证了该复方中黄芪来源的黄芪多糖（Astragalus polysaccharides, APS）的减肥作用，并观察到APS的减肥作用与调节肠道菌有关，提出了APS通过调节肠道菌群与宿主代谢进而发挥其减肥作用的科学假说。通过本项目的研究，我们证实了APS的减肥作用依赖于其对肠道菌群的调节，并且发现APS干预能够明显增加动物体内的短链脂肪酸（SCFA）的水平，尤其是乙酸的含量。利用血清非靶向代谢组学技术，我们发现APS干预能够明显调节肥胖小鼠的整体代谢，并首次发现了一种小分子代谢物2-羟基丁酸（2-HB）在APS干预下显著上升，体内外的研究证实APS增加的2-HB能够改善胰岛素抵抗，调节脂肪酸代谢,2-HB可能是APS调节机体及肠道菌群代谢所产生的功能性小分子代谢物，参与了APS发挥减肥，改善胰岛素抵抗，调节脂代谢等功能。此外，利用肝脏转录组学分析，我们发现了肝脏腺苷A1(Adora1)在高脂饮食喂养动物中显著上调，而APS干预显著抑制了其表达，提示了APS发挥减肥以及改善脂肪肝的效应可能与下调Adora1受体有关。综上所述，本项目的研究证实了APS的减肥作用依赖于对动物肠道菌群的调节，发现了小分子代谢物2-HB和乙酸可能是APS发挥脂代谢调节的关键途径之一，并且，肝脏Adora1受体很可能是APS改善高脂喂养小鼠肝脏脂质代谢的关键靶标。该研究揭示了APS通过调节肠道菌群与机体代谢，调节肝脏特定分子靶标的作用，为下一步深入研究APS等植物多糖对代谢性疾病的防治作用机制提供了重要实验依据，加深了对健脾益气类中药药效与调控肠道菌关系的认识，丰富了中医脾气虚证的现代科学内涵。