The Conversion of Evodiamine-induced Hepatotoxicity into a Therapeutic Effect on Colonitis: Insight from the Liver-Gut Axis Mediated by PPAR/NF-κB/ZO-1/caspase-3 Pathway

Background Evodiamine (EVO) exerts promising therapeutic potential in treating Ulcerative Colitis (UC). However, application in clinical practice is constrained by concerns regarding potential hepatotoxicity. Understanding the mechanisms behind EVO's hepatotoxic effects and its therapeutic benefits is therefore essential to enhance its safe and effective application in clinical practice. Purpose This study aimed to elucidate how the gut-liver axis homeostasis regulates the EVO-induced hepatotoxicity and its therapeutic effects on UC. Methods An integrated experimental strategy utilizing cell, zebrafish, and murine was implemented to assess the hepatotoxic effects of EVO. Transcriptomic and metabolomic analyses in vitro and targeted bile acids (BAs) metabolism studies in vivo were conducted to understand the overall response profile and the underlying mechanisms of hepatotoxicity. Furthermore, the expression patterns of proteins along the gut-liver axis were evaluated under various physiological conditions to identify the relationships contributing to the alleviative effects of UC on EVO-induced hepatotoxicity and the therapeutic effect of EVO on UC. Results High-dose EVO treatment was found to be associated with notable hepatotoxic effects in both in vitro cell models and normal in vivo animals, primarily manifested through disturbances in BAs metabolism, inflammatory responses, and apoptosis. In contrast, in UC models, EVO administration not only effectively improved intestinal structural damage and functional impairments, but also demonstrated minimal hepatotoxicity. Mechanism studies documented that EVO disrupted bile acid metabolism by interfering with BSEP/MRP2/CYP7A1/CYP27A1 pathways, while simultaneously triggering inflammation and apoptosis through PPAR/NF-κB/ZO-1/caspase-3 pathway, ultimately leading to hepatotoxic effects in normal animals. However, UC can mitigate the impact of EVO on protein expression levels in the hepatic, thereby reducing EVO-induced hepatotoxicity. Meanwhile, under UC conditions, EVO can restore the expression levels of relevant proteins in the intestinal tract, thereby maintaining its therapeutic efficacy against UC. Conclusion The hepatotoxicity observed under healthy conditions and the therapeutic effectiveness of EVO against UC are both associated with EVO's regulation of the PPAR/NF-κB/ZO-1/caspase-3 pathway. The influence of EVO on the expression of these key proteins within the gut-liver axis may either counteract or synergistically amplify by different physiological states, potentially leading to varied biological responses across multiple organs. These findings offer valuable insights for the safety assessment and development of traditional Chinese medicines that may pose hepatotoxic risks.