[Effects of evodiamine on carbon tetrachloride-induced liver fibrosis mice based on modulating gut microbiota]

Objective: To access the effects of evodiamine on carbon tetrachloride (CCl(4)) -induced liver fibrosis mice and study the mechanism based on modulating gut microbiota. Methods: From August 2019, 30 SPF male C57BL/6 mice were randomly divided into normal, model and evodiamine groups. Mice in control group received intraperitoneal injection of olive oil (2 ml/kg, twice per week) for 6 weeks. Mice in model and evodiamine groups received intraperitoneal injection of 20% CCl(4) (2 ml/kg, twice per week) for 6 weeks to induce liver fibrosis mice. Then, mice in evodiamine group received orally of evodiamine (18 mg/kg) for 4 weeks. The levels of serum alanine aminotransferase (ALT) , aspartate aminotransferase (AST) , albumin (ALB) and total protein (TP) were detected. The pathological changes of liver tissue were observed. The effects of evodiamine on the abundance and diversity of intestinal microflora in liver fibrosis mice were determined. The mRNA and protein expression levels of inflammatory factors[interleukin-6 (IL-6) , interleukin-1β (IL-1β) , and tumor necrosis factor α (TNF-α) ] in liver tissue were measured. Results: Compared with the normal group, the body weight, serum ALB and TP levels of the model group were decreased, the liver index, ALT and AST levels were increased, and the intestinal flora Shannon and Simpson indexes were decreased (P<0.01) . Compared with the normal group, the abundance of Lactobacillus, Akkermansia and Bacteroides in the feces of the model group decreased, while the abundance of Enterococcus and Lachnoclostridium increased (P<0.01) . Compared with the normal group, the mRNA and protein expressions levels of IL-6, IL-1β, and TNF-α in the liver tissue of the model group were significantly increased (P<0.01) . Compared with the model group, evodiamine could reduce liver index and serum ALT and AST levels, increase ALB and TP levels (P<0.05) , improve inflammatory cell infiltration and fibrosis degree in liver tissue, and up regulate intestinal flora Shannon and Simpson indexes in liver fibrosis mice (P<0.05) . Compared with the model group, evodiamine could increase the abundance of Lactobacillus, Akkermansia, Bacteroides, and reduce the abundance of Enterococcus and Lachnoclostridiun (P<0.05) . Compared with the model group, evodiamine could reduce the mRNA and protein levels of IL-6, IL-1β and TNF-α in liver tissue of liver fibrosis mice (P<0.05) . Conclusion: Evodiamine can ameliorate CCl(4)-induced liver fibrosis through modulating gut microbiota and inhibiting the inflammatory response in liver.