基于食管菌群对TLR4/PAR2/TRPV1通路影响探讨活血通降法治疗反流性食管炎机制

反流性食管炎（RE）伴有弱酸反流及内脏高敏感者，病程迁延反复为难治病种。中医活血通降法疗效有优势，但机制不明。我们前期国自然研究发现，该法具有良好黏膜保护作用，其机制与降低黏膜MC数目及TPS表达等相关。近年研究证实：RE存在食管菌群紊乱，其程度与食管炎症呈正相关。紊乱的菌群通过LPS-TLR4通路活化MC，释放TPS，进而激活PAR2，加重黏膜免疫炎症。PAR2为炎症通路关键蛋白，可被弱酸刺激表达增加，同时与TRPV1具有协同作用，导致内脏高敏感。本项目基于前期研究及新进展，提出假说：活血通降法治疗RE是通过调理食管菌群、进而调节TLR4/MC-TPS-PAR2免疫炎症通路，修复（包括弱酸反流导致）食管黏膜炎症，以及调控PAR2与TRPV1协同作用，改善内脏高敏感。拟建立RE大鼠模型，采用中西药分组干预，结合体外细胞水平研究，验证中药对食管菌群及上述炎症通路的影响，深化该法的疗效机制。

Reflux esophagitis(RE) patients with weak acid reflux and visceral hypersensitivity have poor response to regular treatment. The Huoxue Tongjiang Formula was effective in the therapy of RE, but the mechanism was not clear. Our previous research showed that Huoxue Tongjiang Formula protects mucosal by reducing the MC number and the TPS level. Recent studies showed that there was disorder of esophageal microbiome in RE patients, and the disorder degree of esophageal microbiome of the RE patients is positively correlated with esophageal inflammation. The disordered microbiome could induce release of TPS by the activated LPS-TLR4 pathway and mast cell, resulting the activation of PAR2 and mucosal immune inflammation. Weak acid stimulation increased the expression of PAR2, a key protein of inflammation pathway. The synergistic effect of TRPV1 and PAR2 resulted in visceral hypersensitivity. So we hypothesize that Huoxue Tongjiang Formula treat RE by regulating the esophageal microbiome and TLR4/MC-TPS-PAR2 pathway. And it could repair esophageal mucosal inflammation, improve visceral hypersensitivity and regulate the level PAR2 to cooperate with TRPV1. In this study we will use the rat model and cell experiments in vitro with traditional Chinese and Western medicine treatment to examine the efficacy of traditional Chinese medicine in regulating esophageal microbiome and relative pathways. And we’ll research the mechanism of Huoxue Tongjiang Formula treatment furtherly.