Syringic Acid Improves Cholestatic Liver Disease by Regulating Bile Acid Metabolism and Intestinal Barrier

  OBJECTIVE  To explore the regulatory effect of syringic acid in cholestatic mice based on bile acid metabolism and intestinal barrier.

  METHODS  Twenty mice were randomly divided into control group, model group and low and high dose of syringic acid (70, 140 mg·kg^-1) groups. Intrahepatic cholestasis was induced by intraperitoneal injection of α-naphthalene isothiocyanate after 2 h of administration on the fifth day. After the last dose, the changes of body weight and liver mass of mice were recorded. Liver function indexes in serum and histopathology were detected, qPCR verified the expression of tight junction proteins Zonula Occludens Protein 1 (ZO-1), Occludin and Claudin-5 in mouse colon tissues, the changes of metabolites in serum were analyzed by using nontargeted metabolomics, and the changes of total bile acids in liver and feces were detected.

  RESULTS  Syringic acid could significantly reduce the serum alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) activity, total bilirubin (TBIL) and direct bilirubin (DBIL) levels (P < 0.05, P < 0.01) in the model group mice, and reduce liver damage and necrosis. Syringic acid reduced lymphocyte infiltration in the colon of mice in the model group and restored crypt morphology, while the high-dose syringic acid group significantly increased the mRNA expression levels of ZO-1, Occludin, and Claudin-5 in the colon (P < 0.05). The high-dose intervention of syringic acid significantly upregulated 11 metabolites and 29 metabolites, and the metabolites mainly involved the biosynthesis of secondary metabolites, secondary bile acid biosynthesis and bile secretion pathways. Syringic acid reduced the content of total bile acids in the liver and increased the excretion of total bile acids in feces (P < 0.05, P < 0.01).

  CONCLUSION  Syringic acid can significantly improve the phenotype of cholestasis in cholestatic mice, improve the damage of intestinal barrier, and promote the metabolism of bile acids in cholestatic mice, which may be the key pathway for syringic acid to improve cholestasis.