People consume more salt than the recommended levels due to poor dietary practices. The effects of long-term consumption of high-salt diets (HSD) on liver fibrosis are unclear. This study aimed to explore the impact of HSD on liver fibrosis. In this study, a carbon tetrachloride (CCL4)-induced liver fibrosis mouse model was used to evaluate fibrotic changes in the livers of mice fed a normal diet (ND) and an HSD. The HSD exacerbated liver injury and fibrosis. Moreover, the protein expression levels of transforming growth factor β (TGF-β), tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein 1 (MCP-1) were significantly higher in the HSD group than in the normal group. The proportion of macrophages and activation significantly increased in the livers of HSD-fed mice. Meanwhile, the number of macrophages significantly increased in the small intestinal lamina propria of HSD-fed mice. The levels of profibrotic factors also increased in the small intestine of HSD-fed mice. Additionally, HSD increased the profibrotic chemokines and monocyte chemoattractant levels in the portal vein blood. Further characterization suggested that the HSD decreased the expression of tight junction proteins (ZO-1 and CLDN1), enhancing the translocation of bacteria. Enterococcus promoted liver injury and inflammation. In vitro experiments demonstrated that Enterococcus induced macrophage activation through the NF-κB pathway, thus promoting the expression of fibrosis-related genes, leading to liver fibrogenesis. Similarly, Enterococcus disrupted the gut microbiome in vivo and significantly increased the fibrotic markers, TGF-β, and alpha smooth muscle actin (α-SMA) expression in the liver. IMPORTANCE This study further confirms that Enterococcus induce liver fibrosis in mice. These results indicate that an HSD can exacerbate liver fibrosis by altering the gut microbiota composition, thus impairing intestinal barrier function. Therefore, this may serve as a new target for liver fibrosis therapy and gut microbiota management.
Keywords: Enterococcus; high-salt diet; liver fibrosis; macrophage.