目的 基于大承气汤治疗大肠癌的药效，探究大承气汤干预大肠癌的代谢物靶点，明确大承气汤干预大肠癌的体内药效物质基础并揭示其作用机制。方法 以APC^Min/+转基因小鼠构建大肠癌模型，通过一般体征指标、生理生化指标及组织病理学评价动物模型及大承气汤的干预作用；利用超高效液相色谱-四级杆-飞行时间串联质谱（ultra-performance liquid chromatography-quadrupole-time of flight-tandem mass spectrometry，UPLC-Q-TOF-MS/MS）技术，表征大肠癌的代谢轮廓及生物标记物，并以此揭示大承气汤在代谢层面上干预大肠癌的作用机制；借助UPLC-Q-TOF-MS^E技术结合多种数据库表征大肠癌小鼠经大承气汤有效干预后的体内直接作用物质，通过相关性分析，挖掘与药效生物标记物高度关联的入血成分作为大承气汤干预大肠癌的药效物质基础。结果 大承气汤显著抑制了模型小鼠的肠道腺瘤数量和体积（P＜0.01），显著回调血清中肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素-10（interleukin-10，IL-10）水平（P＜0.05、0.01），对血清中γ干扰素（interferon-γ，IFN-γ）水平具有回调趋势，能够有效干预模型小鼠的组织病变。表征了47个有效状态下的体内直接作用物质，其中厚朴木脂素C、没食子酸、芦荟大黄素、芹菜素、木犀草素、橙皮素、川陈皮素等14个成分是大承气汤干预大肠癌的潜在药效物质基础。大承气汤通过改善花生四烯酸、吲哚衍生物及多种磷脂类内源性代谢物调节模型小鼠的色氨酸代谢、亚油酸代谢、花生四烯酸代谢、甘油磷脂代谢等代谢途径，从而干预大肠癌的发生发展。结论 利用方证代谢组学的理论和方法，确定了大承气汤干预大肠癌的药效物质基础，揭示了大承气汤干预大肠癌的作用机制，为大承气汤的临床精准用药及新药创制提供科学依据。

Objective To reveal the metabolic targets, and elucidate the pharmacodynamic material basis in vivo and the mechanism of Dachengqi Decoction (大承气汤) based on its effectiveness in the intervention of colorectal cancer. Methods APC^Min/+ mice were used to replicate the colorectal cancer model, the animal model and intervention effect of Dachengqi Decoction were evaluated through general physical indicators, biochemical indicators and histopathology. The ultra-performance liquid chromatography-quadrupole-time of flight-tandem mass spectrometry (UPLC-Q-TOF-MS/MS) technology was used to characterize the metabolic profile and metabolic biomarkers of colorectal cancer to reveal the intervention mechanism of Dachengqi Decoction on the metabolic level of colorectal cancer. UPLC-Q-TOF-MS^E combined with multiple databases was used to characterize the directly acting substances in vivo after effective intervention of Dachengqi Decoction in colorectal cancer mice. At last, the constituents absorbed into blood highly associated with biomarkers were identified as the pharmacodynamic material basis of Dachengqi Decoction in the intervention of colorectal cancer by correlation analysis.Results Dachengqi Decoction significantly inhibited the number and volume of intestinal adenomas in model mice (P < 0.01), significantly regulated the levels of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in serum (P < 0.05, 0.01), and showed a callback trend in interferon-γ (IFN-γ) level, thus effectively intervening the tissue lesions of model mice. A total of 47 direct effective constituents were characterized under effective states, and 14 components were significantly correlated with metabolic markers, such as magnolignan C, gallic acid, aloe emodin, apigenin, luteolin, hesperetin, nobiletin, which were the potential pharmacological substance basis of Dachengqi Decoction in the intervention of colorectal cancer. Dachengqi Decoction intervened the initiation and progression of colorectal cancer by regulating tryptophan metabolism, linoleic acid metabolism, arachidonic acid metabolism and glycerophospholipid metabolism in model mice by improving arachidonic acid, indole derivatives and various endogenous metabolites of phospholipids. Conclusion This study utilizes the theory and methods of chinmedomics to scientifically reveal the pharmacodynamic material basis and the mechanism of Dachengqi Decoction in the intervention of colorectal cancer. It provides scientific basis for the clinical precision medication and the innovative drug development of Dachengqi Decoction.

R285.5

国家自然科学基金重点项目（81830110）