基于肠道微生态及其分子信使短链脂肪酸调节的制何首乌改善胰岛素抵抗机制研究

Our previous researches indicated that Polygoni Multiflori Radix Praeparata (PMRP) displayed great activity on alleviation of insulin resistance (IR). Regulation of intestinal microecology and its signal molecule, short chain fatty acids (SCFA), may play vital role in this activity. However, the detailed mechanism remains unclear. In this research, we will try to reveal its mechanism from the regulation of the intestinal microbial metagenomics and its biological information molecules. This project plans to reveal the alternations on species abundance, functional gene abundance and metabolic pathway of intestinal microecology via metagenomics technology. Abundance fluctuation of microbial community that produced SCFA before and after treatment will be compared. Concentrations of SCFA in intestinal, hepatic portal venous blood and peripheral blood, will be accurately determined by high throughput solid phase extraction-gas chromatography. Comprehensive evaluations of structure and function of the pancreas, insulin sensitivity of the peripheral tissue, lipolysis inhibition and glucose utilization rate will be carried out. This research will provide scientific evidences for PMRP on the treatment of IR, according to the basic theory and principle in traditional Chinese medicine system. Moreover, more scientific basis for the application of traditional Chinese medicine in treatment of IR will be contributed.

申请人前期工作发现制何首乌能显著缓解胰岛素抵抗（IR），且该活性可能与其对肠道微生态及其分子信使短链脂肪酸（SCFA）的调节相关，然而具体机制尚不明确。本项目拟通过分析肠道微生物宏基因组及其分子信使引起的代谢功能调节开展制何首乌对胰岛素抵抗的治疗机理研究：通过宏基因组分析制何首乌给药与SCFA产生菌的相关性，揭示制何首乌对IR状态下肠道微生态物种丰度、功能基因丰度及代谢通路等的影响；利用高通量固相萃取-气相色谱法评价肠道微生态变化对肠道、肝门静脉及外周血中SCFA含量的影响；利用中药药理学、分子生物学方法评价制何首乌对SCFA激活其受体后对胰岛素分泌、外周组织葡萄糖利用率、脂肪组织脂解抑制等胰岛素敏感性的影响。项目拟阐明制何首乌在“标本兼治，扶正祛邪”治则下改善胰岛素抵抗的科学内涵，为中医药疗法在胰岛素抵抗相关疾病治疗中发挥更大的作用提供科学依据。

本项目通过分析肠道微生物宏基因组及其分子信使引起的代谢功能调节开展制何首乌对胰岛素抵抗的治疗机理研究。通过宏基因组分析制何首乌给药与SCFA产生菌的相关性，揭示制何首乌对IR状态下肠道微生态物种丰度、功能基因丰度及代谢通路等的影响；利用高通量固相萃取-气相色谱法评价肠道微生态变化对肠道、肝门静脉及外周血中SCFA含量的影响；利用中药药理学、分子生物学方法评价制何首乌对SCFA激活其受体后对胰岛素分泌、外周组织葡萄糖利用率、脂肪组织脂解抑制等胰岛素敏感性的影响。.制何首乌总多糖和TSG可以通过调节肠道微生态多样性及其功能，并通过调节参与机体糖代谢的关键靶蛋白GPR43和p-AMPK发挥调节机体血糖、增强胰岛素敏感性的作用进而改善胰岛素抵抗。项目阐明制何首乌在“标本兼治，扶正祛邪”治则下改善胰岛素抵抗的科学内涵，为中医药疗法在胰岛素抵抗相关疾病治疗中发挥更大的作用提供科学依据。