Synergistic Hepatotoxicity of Voriconazole and Mild Inflammation: Involvement of Bile Acid Dysregulation, Intestinal Dysbiosis, and TLR4 Pathway Activation

Voriconazole (VCZ) is the first-line drug for invasive fungal infections. However, the growing concern regarding its hepatotoxicity necessitates a comprehensive understanding of the underlying mechanisms responsible for VCZ-induced liver injury. In this study, we found that rats treated with a nontoxic dose of lipopolysaccharides (LPS) and VCZ triggered liver injury, as demonstrated by increased serum biochemical indicators and swollen lesions of liver cells. Accordingly, the bile acid metabolism was disordered in the LPS+VCZ group, manifested as remarkable increases in primary bile acids (CDCA, GCDCA), secondary bile acids (DCA, TDCA), and total secondary bile acids in the liver. The species richness and diversity of the gut microbiota were reduced, with Bacteroides and Sutterella emerging as the dominant bacteria in the LPS+VCZ group. The increases in Bacteroides and Isoprevotella might be associated with VCZ-induced cholestatic liver injury. Furthermore, VCZ down-regulated the expression of BSEP, MRP2, and nuclear receptors and up-regulated the expression of bile acid synthetase CYP7A1. Meanwhile, it stimulated the TLR4-Myd88-NF-κB pathway, which promoted the release of inflammatory factors. In addition, the expression of ZO-1 and Occludin in the ileum was decreased in the LPS+VCZ group. These findings suggest that VCZ may induce liver injury by regulating bile acid metabolism and gut microbiota in the context of mild inflammation.