Abstract
The classic carbon tetrachloride (CCl4)-induced liver injury model is widely used to study the pathogenesis of fibrosis and evaluate anti-fibrosis drugs. Here, we investigated the dynamic changes in the gut microbiota, bile acids (BAs) and the gut barrier over different fibrosis severities in a CCl4-based model. 16S rDNA sequencing demonstrated that the beneficial taxon Lactobacillus was always underrepresented, and pathogens including Escherichia_Shigella, Clostridium_sensu_stricto_1, Colidextribacter, and Lachnospiraceae_UCG_010 were significantly overrepresented across liver fibrosis severities. Gut dysbiosis was more severe at the early stage of liver injury and advanced stage of fibrosis. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis revealed that with the progress of fibrosis, unconjugated BAs in faeces were significantly decreased and conjugated BAs in serum were significantly increased. The FXR-SHP signalling pathway in the liver and ileum was statistically repressed in the fibrosis groups. Determination of lipopolysaccharide (LPS) and fluorescein isothiocyanate (FITC)-dextran levels in plasma showed that the intestinal barrier remained relatively intact in the advanced fibrosis stage. The advances in knowledge of the gut-liver axis provided by this study yield new insights for application in research and drug evaluation.