雷公藤广泛用于治疗类风湿性关节炎，该疾病常伴有严重的胃肠道损伤。雷公藤引起胃肠道损伤的分子机制尚未阐明。通过透射电子显微镜、病理学和生化分析评估肠道出血。代谢组学检测血清和肠道的代谢变化。通过体内（时间依赖性效应和剂量反应性）和体外（双荧光酶报告基因系统、DRATs、分子对接、HepG2细胞和小肠器官样物）研究，确定零肽酯对肠道法尼酰X受体（FXR）信号传导的抑制作用。利用FXR敲除小鼠和FXR拮抗剂和激动剂评估雷公藤引起的肠道出血中FXR的作用。 联用雷公藤三酮和零肽酯（来自雷公藤）导致小鼠肠道出血。代谢组学分析表明，零肽酯抑制肠道FXR信号传导，并进一步分子研究揭示零肽酯是一种新型的肠道FXR拮抗剂。在FXR敲除小鼠或预处理FXR药理学抑制剂的野生型小鼠中，单独应用雷公藤三酮可激活十二指肠JNK途径并导致肠道出血，其病理特征与联用雷公藤三酮和零肽酯获得的特征相似。最后，联用雷公藤三酮和零肽酯引起的肠道出血可以通过FXR或肠道限制FXR激动剂的下调十二指肠JNK途径得到有效缓解。 雷公藤三酮和零肽酯之间的协同效应通过对FXR-JNK轴的调节促成了由雷公藤引起的胃肠道损伤，提示零肽酯应纳入雷公藤制剂评估的质量标准体系。确定FXR-JNK轴在肠道出血中的机制有助于发现进一步治疗胃肠道出血性疾病的靶点。本研究为治疗胃肠道疾病中雷公藤的质量评价提供了新的标准。 © 2023. Elsevier GmbH出版。

Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular mechanism underlying the gastrointestinal injury of Tripterygium wilfordii are yet to be elucidated.Transmission electron microscopy, and pathological and biochemical analyses were applied to assess intestinal bleeding. Metabolic changes in the serum and intestine were determined by metabolomics. In vivo (time-dependent effect and dose-response) and in vitro (double luciferase reporter gene system, DRATs, molecular docking, HepG2 cells and small intestinal organoids) studies were used to identify the inhibitory role of celastrol on intestinal farnesoid X receptor (FXR) signaling. Fxr-knockout mice and FXR inhibitors and agonists were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii.Co-treatment with triptolide + celastrol (from Tripterygium wilfordii) induced intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies revealed that celastrol was a novel intestinal FXR antagonist. In Fxr-knockout mice or the wild-type mice pre-treated with pharmacological inhibitors of FXR, triptolide alone could activate the duodenal JNK pathway and induce intestinal bleeding, which recapitulated the pathogenic features obtained by co-treatment with triptolide and celastrol. Lastly, intestinal bleeding induced by co-treatment with triptolide and celastrol could be effectively attenuated by the FXR or gut-restricted FXR agonist through downregulation of the duodenal JNK pathway.The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, suggesting that celastrol should be included in the quality standards system for evaluation of Tripterygium wilfordii preparations. Determining the mechanism of the FXR-JNK axis in intestinal bleeding could aid in the identification of additional therapeutic targets for the treatment of gastrointestinal hemorrhage diseases. This study also provides a new standard for the quality assessment of Tripterygium wilfordii used in the treatment of gastrointestinal disorders.Copyright © 2023. Published by Elsevier GmbH.