基于VDR/肠道菌群/肠黏膜屏障轴探讨大承气汤防治肠源性内毒素血症的作用和机制研究

Intestinal endotoxemia (IETM) is a result of a large amount of intestinal endotoxin (LPS) being absorbed into the blood due to the destruction of the intestinal mucosal barrier.So far, there is no specific treatment for IETM. It is confirmed that intestinal mucosal barrier is affected by the interaction between intestinal vitamin D receptor (VDR) and intestinal flora; Dachengqi Decoction, which is the main prescription for Yang ming fu shi syndrome, can significantly promote functional recovery and reduce mortality in patients with IETM. Our previous study showed that Dachengqi Decoction can promote the expression of VDR, improve the intestinal mucosal barrier, and alleviate the inflammatory injury caused by IETM. In the present study, we take the VDR molecule as the starting point. Firstly, we aim to clarify the mechanism of VDR molecules influencing IETM through intestinal bacterial/endotoxin translocation; secondly, we intend to investigate the effect of abnormal expression of VDR molecules on intestinal flora and intestinal mucosal barrier during the development of Yang ming fu shi sydrome in the pathogenesis of IETM; finally, we plan to confirm that Dachengqi Decoction can regulate intestinal flora through the intestinal VDR, thereby improve intestinal mucosal barrier function. Based on the combination of syndrome and disease differentiation, and guided by the theory "the lung and the large intestine are interior-exteriorly related" and the theory "interlinked communicant of liver and large intestine", this project is promising to provide new strategies for prevention and treatment of IETM.

肠源性内毒素血症（IETM）是肠黏膜屏障破坏使内毒素（LPS）大量吸收入血的结果，迄今无特效治疗方法。研究证实，肠组织维生素D受体（VDR）与肠道菌群相互作用影响肠黏膜屏障；治疗阳明腑实证的代表方大承气汤能明显促进IETM患者脏器功能恢复，降低病死率。我们前期研究发现，大承气汤可促进肠组织VDR表达，改善肠黏膜屏障功能，减轻IETM炎症损伤。本课题以VDR为切入点，首先明确VDR分子通过肠道细菌/内毒素移位对IETM的影响机理；其次研究IETM发病过程中产生阳明腑实证时，VDR分子的异常表达对肠道菌群和肠黏膜屏障的影响；最后确证大承气汤通过肠道VDR调节肠道菌群，从而改善肠黏膜屏障功能。本项目立足于病证结合和辨证论治的思想，以中医“肺与大肠相表里”、“肝与大肠相通”理论为指导，将为防治IETM提供新的思路。

肠源性内毒素血症（IETM）是肠黏膜屏障破坏使内毒素（LPS）大量吸收入血的结果，迄今无特效治疗方法。研究证实，肠组织维生素D受体（VDR）与肠道菌群相互作用影响肠黏膜屏障；治疗阳明腑实证的代表方大承气汤能明显促进IETM患者脏器功能恢复，降低病死率。本课题结合分子生物学，从体内及体外两方面，在蛋白、基因表达的层面，探讨大承气汤的作用机制。研究中通过建立IETM模型，确定阳明腑实证病理特征的客观化指征，验证了大承气汤可通过调控VDR/肠道菌群/肠黏膜屏障轴来改善肠源性内毒素血症。同时通过siRNA技术对VDR进行敲减，发现VDR是脓毒症肠屏障损伤的可能关键靶点之一，并证实大承气汤有效成分大黄素可通过VDR/ Nrf2 /HO-1信号通路中改善脓毒症肠屏障损伤，减轻体内和体外的炎症和氧化应激反应。为IETM的防治提供新的思路，也为中医“肺与大肠相表里”、“肝与大肠相通”理论赋予科学依据和物质基础。