Triclosan exposure causes abnormal bile acid metabolism through IL-1β-NF-κB-Fxr signaling pathway.

Triclosan (TCS) is an eminent antibacterial agent. However, extensive usage causes potential health risks like hepatotoxicity, intestinal damage, kidney injury, etc. Existing studies suggested that TCS would disrupt bile acid (BA) enterohepatic circulation, but its toxic mechanism remains unclear. Hence, the current study established an 8-week TCS exposure model to explore its potential toxic mechanism. The results discovered 8 weeks consecutive administration of TCS induced distinct programmed cell death, inflammatory cell activation and recruitment, and excessive BA accumulation in liver. Furthermore, the expression of BA synthesis and transport associated genes were significantly dysregulated upon TCS treatment. Additional mechanism exploration revealed that Fxr inhibition induced by TCS would be the leading cause for unusual BA biosynthesis and transport. Subsequent Fxr up-stream investigation uncovered TCS exposure caused pyroptosis and its associated IL-1β would be the reason for Fxr reduction mediated by NF-κB. NF-κB blocking by dimethylaminoparthenolide ameliorated TCS induced BA disorder which confirmed the contribution of NF-κB in Fxr repression. To sum up, our findings conclud TCS-caused BA disorder is attributed to Fxr inhibition, which is regulated by the IL-1β-NF-κB signaling pathway. Hence, we suggest Fxr would be a potential target for abnormal BA stimulated by TCS and its analogs.