Integrated analysis of metabolomic and gut microbiota reveals idiosyncratic drug-induced liver injury resulting from the combined administration of bavachin and icariside II

Abstract

Background: Xianlinggubao (XLGB), a widely used Chinese patent medicine for osteoporosis, has garnered significant attention due to its potential to cause liver injury. The constituents Psoraleae Fructus (PF) and Epimedii Folium (EF) present in XLGB have been implicated in causing idiosyncratic drug-induced liver injury (IDILI). However, the specific components and mechanisms underlying liver injury related to these tonics remain elusive. This study aimed to establish that the combination of bavachin, the primary active compound in PF, and icariside II, the main active compound in EF, induces IDILI in a TNF-α-mediated mouse model. Methods: To assess the impact of bavachin and icariside II on the liver in the presence of TNF-α immune stress, an animal model was developed. LC-MS/MS metabolomics technology was employed to identify biomarkers associated with TNF-α-induced IDILI and the combination of bavachin and icariside II. Additionally, 16S rRNA high-throughput sequencing technology was utilized to explore changes in the species composition and relative abundance of gut microbiota at the genus level. Spearman correlation analysis was conducted to unveil the relationship between gut microbiota and in vivo metabolites. Results: The study observed that the combined administration of bavachin and icariside II induced hepatic injury in the TNF-α-mediated susceptibility mouse model of IDILI. Under TNF-α stimulation, there was an elevation in methylcarbamyl PAF, LPE (22:5/0:0), and PC (O-1:0/O-16:0) levels in mouse livers following bavachin and icariside II administration, while Gly-Tyr, Leu-Gly, and Trp-Ser levels decreased. These differentially expressed metabolites associated with liver injury were predominantly enriched in metabolic pathways such as sphingolipid metabolism, sphingolipid signaling pathway, and necroptosis. Noteworthy, the gut of mice with liver injury induced by the bavachin and icariside II combination exhibited a significant increase in Bacteroides and Desulfovibrionaceae abundance. Correlation analysis revealed a positive association between Bacteroidaceae and Desulfovibrionaceae with methylcarbamoyl PAF and indole-3-acetate, while a negative correlation was observed with Gly-Tyr, Leu-Gly, and Trp-Ser. Conclusions: These findings demonstrated that the combination of bavachin and icariside II increased the risk of IDILI in vivo, providing a promising scientific basis for understanding the component basis of IDILI resulting from the compatibility of EF and PF. http://links.lww.com/AHM/A97