基于肠源性SCFAs-GPCR43/41通路探讨铁皮石斛超微粉抗“肥甘醇酒”致代谢性高血压的机制

With the change of lifestyle, the metabolic hypertension (MH) has become the principal part of hypertension, and its prevention and treatment demand is great. Improper diet could cause the decrease of gut derived short chain fatty acids (SCFAs), which could active G protein coupled receptors (GPCRs), therfore, weakened the improvement of gastrointestinal function, metabolism and blood pressure, which easily lead to the development of MH. Dendrobium officinale is a commonly used "Strengthened enterogastric function" medicine, which had the exact effect on improvement of gastrointestinal function, lowering blood pressure, and improving metabolic abnormalities, etc, but wheather the effect and mechanism of Dendrobium officinale on anti-metabolic hypertension based on improvment of SCFAs are not clear. Dendrobium officinale ultramicro powder (DOP) is regarded to improve the hypertension may be related to improve the gastrointestinal function, increase the intestinal SCFAs, activate the GPCR43/41-mediated glycolipid metabolism and vascular protective effect. Prepare MH rat model by feeding with alcohol and high fat&sugar diet. Meanwhile, based on focusing the DOP effect on increasing its SCFAs content and improving gastrointestinal pathophysiology, glucose and lipid metabolism and blood pressure. From the point of produce of SCFAs and transporting into blood to explain mechanism of DOP on increase the intestinal SCFAs content, with analysis of the correlation between the activation of SCFAs-GPCR43 and the improvement of glycolipid metabolism, and mainly from the activation of SCFAs-GPCR41 pathway to clarify DOP antihypertensive mechanism. This study provides a new entry point for study of prevention mechanism and treatment of metabolic hypertension.

随着生活方式改变，代谢性高血压（MH）已为高血压主体，防治需求大。饮食不节致短链脂肪酸（SCFAs）含量降低，使其通过G蛋白偶联受体（GPCRs）介导的胃肠功能、代谢和血压等改善作用减弱，而易致MH。铁皮石斛改善胃肠功能、降血压和调节代谢异常等作用确切，但其通过增加SCFAs而发挥抗MH的作用及机制尚不明确。我们认为铁皮石斛超微粉（DOP）“厚肠胃”改善胃肠功能，从而改善“肥甘醇酒”致MH，其机制可能与增强“SCFAs-肠道菌群-肠”互作，增加肠源性SCFAs，激活SCFAs-GPCR43/41有关。拟采用过食“肥甘醇酒”致MH大鼠，在以SCFAs为核心的DOP抗MH整体药效评价的基础上；从SCFAs生成、转运角度阐述DOP增加SCFAs含量；分析激活SCFAs-GPCR43与改善糖脂代谢的相关性；并主要从激活SCFAs-GPCR41，阐明DOP降压机制。为防治MH的机理研究提供新切入点。

代谢性高血压（MH）已为高血压主体。饮食不节等致短链脂肪酸（SCFAs）-G蛋白偶联受体（GPCRs）通路介导的改善胃肠功能、代谢和血压等作用减弱，而易致MH。本项目在前期研究基础上，按计划建立了拟人“过食肥甘醇酒”和L-NAME诱导型MH大鼠模型，采用微循环动态可视化观察、16SrRNA测序、脂质代谢组学等技术创新性系统研究了MH模型大鼠肠道病理生理指标体系，发现L-NAME诱导型高血压模型大鼠同样具有MH的肠道病理生理变化和脂质代谢紊乱等特征，并探讨其脂肪酸代谢酶异常和肠道菌群紊乱等相关的发病机理，丰富了MH动物模型；评价了铁皮石斛超微粉具有降血压和改善代谢异常的药效作用，分析明确了铁皮石斛“厚肠胃”与其改善MH的相关性；并进一步结合离体主动脉环实验和抑制剂、抗生素干预等评价，以“SCFAs”为核心（生成、转运），首次系统阐释了铁皮石斛超微粉增强“SCFAs-肠道菌群-肠”互作，激活肠-血管轴SCFAs-GPCR41/43通路，改善血管内皮功能，降低“过食肥甘醇酒”MH模型大鼠血压的分子作用机制。.发表SCI论文2篇（JCR 1区2篇）；申请国家发明专利1项；培养出站博士后1人，完成了项目全部的研究内容和任务指标。本研究进一步丰富铁皮石斛“厚肠胃”的现代科学内涵，为铁皮石斛防治代谢性高血压的机制深入研究提供新的切入点，并为铁皮石斛大健康产品的开发提供参考。