绿原酸通过靶向调控罗伊氏乳杆菌内源代谢改善肥胖相关代谢紊乱的作用机制研究

肥胖在全球范围内越来越普遍，基于肥胖状态下肠道微环境的天然药物干预模式是目前减肥药物开发的热点，而口服药物在体内的吸收、代谢十分复杂。绿原酸是广泛存在于传统中草药中的多酚类酸性物质，极性较大，以致其口服吸收差、生物利用度低，因此对于绿原酸产生药理活性的原因和效果往往难以解释或归一化。本项目拟从绿原酸的肠道营养特性出发，首先基于不同动物模型，确证肠道微生物在绿原酸药效发挥中的关键作用；结合高通量测序信息以及肠道微生物体外培养体系，挖掘关键微生物；最终聚焦罗伊氏乳杆菌，基于“传统中药-微生物-宿主”三元互作阐明绿原酸如何通过靶向调控罗伊氏乳杆菌内源短链脂肪酸代谢治疗肥胖相关代谢紊乱，提出绿原酸作为新型益生元与益生菌罗伊氏乳杆菌协同促进减肥效能的新治疗策略。研究结果为中药多酚类化合物的药物微生物组学研究提供新思路。一系列针对肥胖及其并发症的治疗策略也为现代化中药的可持续发展提供可借鉴的途径。

The obesity epidemic continues all around the world. Nowadays, the model of natural products intervention based on the intestinal micro-environment is becoming a highlight for the discovery and development of anti-obesity drug. However, the absorption and metabolism of oral drugs are very complicated. Caffeoylquinic acid (CQA) is an acidic polyphenol with large polarity, exists in traditional Chinese medicine (TCM) widely, which lead to its poor oral absorption and low bio-availability. Therefore, it is difficult to explain or normalize the cause and effect of the pharmacological activity of CQA. This project intends to start from the intestinal nutritional characteristics’ perspective of CQA. Firstly, the key role of intestinal microbiota is confirmed in the anti-obesity phenotype of CQA based on different animal models. Then, we identified the key microbes by combining with high-throughput sequencing information and in vitro culture system of intestinal microbiota. Next, we focused on one of the key microbes, Lactobacillus reuteri, clarified how CQA can treat obesity-related metabolic disorders via regulation the endogenous short-chain fatty acids (SCFAs) metabolism of Lactobacillus reuteri based on "TCM-microbiota-host" interaction. Finally, we posed a novel therapeutic strategy of the synergistic effect of Lactobacillus reuteri and CQA on anti-obesity efficiency. All the results will provide a new idea for the study of natural polyphenols in pharmacomicrobiomics. What makes more sense is that, the treatment strategies for obesity and its complications will show a reference for the sustainable development of TCM modernization.