基于肠道菌群介导的黄芩苷-黄芩素平衡轴探讨黄芩抗结肠癌作用机理

Colon cancer, a kind of frequently-occurring malignant tumor of the digestive system, has become a serious threat to public health. Traditional Chinese medicines play an important role in the clinical treatment of colon cancer as an adjunctive therapy. It has been reported that intestinal bacteria is closely associated with the genesis and development of colon cancer. Therefore, the interaction of active constituents and gut microbiota might be a promising target in the study of therapy mechanisms of colon cancer. Our previous investigations have indicated that Scutellaria baicalensis is effective in the treatment of colon cancer. Base on the results above, multi-disciplinary methods, such as UPLC-MS/MS and 16S rRNA sequencing analysis, are explored to investigate the mechanism of anti-colon cancer effects of Scutellaria baicalensis on gut microbiota-mediated baicalin-baicalein balance axis. Our research would focus on the absorption and metabolism differences of baicalin-baicalein in normal and pathological conditions, elucidate the intrinsic relationship between the biotransformation of baicalin-baicalein promoted by gut microbiota and reversed regulation, and bring insights into the synergistic mechanism of these three essential factors in the balance axis. This study will be helpful for full understanding the mechanism of absorption and metabolism, bioavailability and pharmacodynamic evaluation of the active constituents of Scutellaria baicalensis, providing some scientific evidences for the treatment of colon cancer with microbial intervention.

结肠癌是一类常见的严重威胁人类健康的消化系统恶性肿瘤。中药作为辅助手段在结肠癌的临床治疗中发挥重要作用。有报道称结肠癌的发生发展过程与肠道菌群息息相关，因此中药活性成分与菌群的相互作用很可能成为研究其治疗结肠癌深层机理的重要靶点。本课题组前期研究证实黄芩是临床治疗结肠癌的有效药物。在此基础上，本项目运用UPLC-MS/MS、16S rRNA基因序列分析等技术手段，围绕“肠道菌群介导的黄芩苷-黄芩素平衡轴”假说开展黄芩抗结肠癌作用机理研究。本项目旨在对比黄芩苷-黄芩素在正常和结肠癌病理状态下的吸收代谢行为差异，阐明肠道菌群代谢驱动黄芩苷-黄芩素转化以及该转化反作用调节菌群构成的内在联系，揭示平衡轴三要素互动增效、协同抗癌的科学本质，为黄芩抗结肠癌活性成分的体内吸收代谢、生物利用度及药效评价等相关研究奠定理论基础，也为药物干预肠道菌群治疗结肠癌策略提供科学依据。

结肠癌是一种严重威胁人类健康的常见消化道恶性肿瘤。大量研究证实结肠癌的发生发展与肠道菌群关系密切。黄芩苷和黄芩素是抗结肠癌活性中药黄芩的两个重要化学成分，而肠道菌群代谢可能是影响黄芩苷-黄芩素体内过程和药效发挥的关键环节。本项目围绕“肠道菌群介导的黄芩苷-黄芩素平衡轴”这一科学假说，综合运用液质联用、16S rRNA基因测序以及菌群培养等多种技术手段，构建了黄芩苷-黄芩素在多种生物样品中的UPLC-MS/MS特征识别模式，实现了两者的快速辨识与同步测定；建立了二甲肼诱发结肠癌大鼠模型和氧化偶氮甲烷/葡聚糖硫酸钠诱发结肠癌小鼠模型，结合疾病活动指数评价、结肠肿瘤检查等方法开展了多重表征研究；比对了正常和结肠癌病理状态下黄芩苷-黄芩素吸收代谢的差异行为，肠道菌群孵育转化谱、肠吸收谱和分布特征谱均表明在结肠癌病理状态下其生物转化、吸收代谢效率有所降低；阐明了黄芩苷-黄芩素可以有效改善结肠癌病理状态的肠道菌群结构，且促进自身生物转化的互动效应，揭示了黄芩苷-黄芩素在肠道菌群作用下协同增效发挥抗结肠癌作用的核心机制，为中药干预肠道菌群治疗结肠癌策略的运用提供了研究依据。