Abstract
Liver fibrosis is a chronic pathological process that various pathogenic factors lead to abnormal hyperplasia of hepatic connective tissue, and its main feature is the excessive deposition of extracellular matrix. However, there are currently no drugs approved for the treatment of liver fibrosis. Phillygenin (PHI), a lignan isolated from Forsythiae Fructus, showed potential anti-inflammatory and anti-fibrosis effects but the mechanisms remain unknown. In view of the vital role of gut microbiota in the development of liver fibrosis, this study aimed to explore whether PHI could protect intestinal epithelial barrier and attenuate liver fibrosis by maintaining the homeostasis of intestinal microbiota. Therefore, the liver fibrosis model was induced by intraperitoneal injection of olive oil containing 10% carbon tetrachloride (CCl4) for 4 weeks in C57BL/6J mice. Histological analysis including Hematoxylin-Eosin, Masson, Sirius red, and immunohistochemistry staining were carried out to detect the histopathology and collagen deposition of mice liver tissues. The biochemical indexes related to liver function (ALT, AST, AKP, γ-GT), fibrosis (HYP, HAase, LN, PC III, IV-C) and inflammation (TNF-α, MIP-1, LPS) were determined by specific commercial assay kits. In vivo experimental results showed that PHI could improve liver histopathological injury, abnormal liver function, collagen deposition, inflammation and fibrosis caused by CCl4. Moreover, PHI restored the intestinal epithelial barrier by promoting the expression of intestinal barrier markers, including ZO-1, Occludin and Claudin-1. More importantly, the corrective effect of PHI on the imbalance of gut microbiota was confirmed by sequencing of the 16 S rRNA gene. In particular, PHI treatment enriches the relative abundance of Lactobacillus, which is reported to alleviate inflammation and fibrosis of damaged liver. Collectively, PHI attenuates CCl4-induced liver fibrosis partly via modulating inflammation and gut microbiota.
Highlights
Liver fibrosis is a dynamic pathophysiological process which intrahepatic connective tissue undergoes dysplasia during chronic liver injury caused by various pathogenic agents (Aydın and Akçalı, 2018)
Data was expressed as the mean ± SD (n 6). #p < 0.05, ###p < 0.001 represent compared with solvent control group. *p < 0.05, **p < 0.01, ***p < 0.001 represent compared with carbon tetrachloride (CCl4) group. n. s indicates no significant
The results showed that there was almost no collagen fiber production in the normal control group and solvent control group, while CCl4 could induce the production of a large amount of collagen fibers
Summary
Liver fibrosis is a dynamic pathophysiological process which intrahepatic connective tissue undergoes dysplasia during chronic liver injury caused by various pathogenic agents (Aydın and Akçalı, 2018). If the pathogeny of chronic liver injury is not promptly removed, inflammation and liver fibrosis will be continuously activated, which may further develop into liver cirrhosis or even hepatocellular carcinoma (Parola and Pinzani, 2019). The effective treatment for patients with advanced liver fibrosis or liver cirrhosis is only liver transplantation (Koyama et al, 2016). Some studies have shown that liver fibrosis is a reversible pathological feature in the early stage of chronic liver disease (Sun and Kisseleva, 2015). It is urgent to develop effective, safe and economical anti-hepatic fibrosis drugs
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