基于调节肠道菌群平衡探究“慢痞消”治疗胃癌癌前病变的药效物质基础及其作用机制

To block or reverse PLGC is an effective way to prevent gastric cancer. Manpixiao, a Chinese herbal formula based on clinical experience had significant clinical efficacy in the treatment of PLGC and significantly ameliorated the gastric mucosal injury in patients and PLGC model rats. However, it is still unclarified that the pharmacodynamic basis and mechanism of Manpixiao in the treatment of PLGC. It was reported that the occurrence ,development and treatment of PLGC was closely related to intestinal flora, and the Chinese herb medicines, the composition of Manpixiao, could regulate the intestinal flora balance and improve the systemic immune function. How does Manpixiao treat PLGC by regulating intestinal flora balance? which is worth further exploration. Therefore, based on our preliminary study, set the interaction between TCM and intestinal flora as the entry point, combined with the serum medicinal chemistry, intestinal flora genomics, metabolomics and in vitro microbial culture methods, we intend to further explore the components in the blood and their biotransformation methods of the Chinese herbal medicines in the Manpixiao, and the effect of Manpixiao on the structural composition, gene function and metabolic pathway of intestinal flora in PLGC model rats, and screen the effective portions and active ingredients of Manpixiao with regulating the intestinal flora, in order to clarify the pharmacodynamic basis and mechanism of Manpixiao in treatment of PLGC. It would provide the scientific basis for its clinical application, and new idea for the research on TCM in the treatment of PLGC with the target of regulating intestinal flora balance.

阻断或逆转胃癌癌前病变（PLGC）是预防胃癌发生的有效途径。中医药经验方“慢痞消”临床治疗PLGC效果显著，能从根本上逆转患者和PLGC模型大鼠胃黏膜损伤，但其药效物质基础和作用机制尚不清楚。PLGC的发生、发展及治疗与肠道菌群密切相关，“慢痞消”组方中药能调节肠道菌群平衡，改善机体免疫功能。“慢痞消”如何通过调节肠道菌群平衡来治疗PLGC，值得进一步探究。本项目在前期工作基础上，拟以中药与肠道菌群相互作用为切入点，结合血清药物化学、肠道菌群基因组学、代谢组学和体外细菌培养学方法，进一步探究“慢痞消”组方中药经肠道菌群代谢后的血中移行成分及其生物转化方式，探究其对PLGC模型大鼠肠道菌群结构组成、基因功能和代谢通路的影响，筛选组方中调节肠道菌群的中药有效部位和有效成分，以阐明其药效物质基础和作用机制，为其临床应用提供科学依据，为以调节肠道菌群平衡为靶标的中医药治疗PLGC研究提供新思路。

胃癌前病变（PLGC）是慢性胃炎“炎癌转化”的关键阶段，在PLGC阶段进行积极有效干预，能延缓或阻断慢性胃炎“炎癌转化”，对预防胃癌发生具有重要的临床与社会意义。国医大师路志正教授以“调气养阴、活血解毒”立法，创立“慢痞消”，在缓解临床患者症状、改善胃黏膜病理改变等方面优势显著。本项目以中药与肠道菌群相互作用为切入点，结合肠道菌群基因组学、代谢组学、血清药物化学、体外细菌培养组学等方法，系统探究“慢痞消”防治PLGC的药效物质基础及其作用机制。研究发现，“慢痞消”能有效保护PLGC模型大鼠胃黏膜病理损伤，阻断慢性胃炎“炎癌转化”进程，为其临床有效治疗PLGC及预防胃癌发生提供科学实验依据。“慢痞消”能有效增加PLGC模型大鼠粪便样本菌群的多样性，有效降低大肠埃氏菌属-志贺氏菌属(Escherichia-Shigella)等致病菌的丰度，增加艾克曼菌属（Akkermansia）等益生菌的物种丰度，通过调控模型大鼠粪便样本中菌群平衡，恢复菌群代谢功能，进而发挥治疗胃癌前病变的作用。结合体外细菌培养组学方法，进一步验证“慢痞消”能通过促进嗜黏蛋白阿克曼菌(Akkermansia muciniphila，Akk菌)的增殖，以及AKK菌外膜囊泡（OMVs）分泌进而发挥抗炎活性。通过体外细胞模型、转录组学及分子生物学方法对“慢痞消”主要入血成分筛选并发现，二氢丹参酮I能显著下调MAPK10、Stathmin 1、Cdkn2a、cyclin D1、MDM2等蛋白的表达水平，上调P53、P21等蛋白表达水平，通过调控MAPK\P53信号通路，抑制MC细胞增殖，诱导其细胞凋亡，进而发挥治疗胃癌前病变的作用。.本研究从调节肠道菌群平衡、细胞分子机制的角度，全面揭示国医大师经验方防治PLGC的药效物质基础及相关作用机制，为“慢痞消”治疗胃癌前病变及新药研发提供有效支撑，为其临床用于阻断慢性胃炎“炎癌转化”、预防胃癌发生提供新思路，为以调节肠道菌群平衡为靶标的中医药治疗PLGC研究提供参考，为中药及其复方调节肠道菌群平衡的药效物质基础及其作用机制研究提供新思路。