Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii

Background : 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. Methods : Transmission electron microscope assay, pathological and biochemical analysis were applied to identify 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 inhibition role of celastrol on intestinal FXR. Fxr -knockout mice and inhibitors or agonists of FXR were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii . Results : The present study shown that co-treatment with triptolide?+?celastrol (from Tripterygium wilfordii ) could induce intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies identified that celastrol expected to be a novel intestinal FXR inhibitor. 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 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 duodenal JNK pathway. Conclusions : The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, which hinted that celastrol should be included in the quality marker system of Tripterygium wilfordii preparation. Determining the mechanism of FXR-JNK axis in intestinal bleeding was expected to become an additional therapeutic target for the treatment of gastrointestinal hemorrhage diseases. This study provides a new idea for the quality standard system of Tripterygium wilfordii and the treatment of gastrointestinal injury.

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