2026, 42(8): 1866-1877.
DOI: 10.12449/JCH260819
Abstract:
Objective To investigate the therapeutic effect of Biejiajian Pills on rats with carbon tetrachloride （CCl4）-induced hepatic fibrosis and its mechanism based on the bile acid （BA）-short-chain fatty acid （SCFA） metabolic axis. Methods The method of CCl4 induction was used to establish a rat model of hepatic fibrosis， and 32 male Sprague-Dawley rats were randomly divided into control group， model group， Biejiajian Pills group （2.2 g/kg）， and silymarin group （43.19 mg/kg）， with 8 rats in each group. All rats except those in the control group were given intraperitoneal injection of CCl4 （diluted with corn oil at a ratio of 4∶6， 2 mL/kg） to induce a model of hepatic fibrosis for 8 consecutive weeks， and the rats in the drug administration groups were given the corresponding drug by gavage. An automatic biochemical analyzer was used to measure the serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， total bilirubin （TBil）， and albumin （Alb）； chloramine-T colorimetry was used to measure the content of hydroxyproline （HYP） in liver tissue； HE staining and Masson staining were used to observe liver histopathological changes； UPLC-MS/MS and GC-MS were used to measure the levels of BAs and SCFAs. The Shapiro-Wilk test and the Levene test were performed for all data to determine normality and homogeneity of variance； a one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups； the Kruskal-Wallis H test was used for comparison of Ishak score between groups， and the Dunn’s test was used for further comparison between two groups. The Benjamini-Hochberg method was used for multiple comparison correction in the screening of differentially expressed metabolites in metabolomics data. The variable importance in projection （VIP） values were obtained in combination with the orthogonal partial least squares-discriminant analysis （OPLS-DA） model， and metabolites with VIP>1 and P<0.05 were selected as significantly differentially expressed metabolites between groups. The robustness of the OPLS-DA model was evaluated through 200 permutation tests， and the main parameters of the model were reported， including the interpretation rate of the model for categorical variables （R2Y） and the predictive ability of the model （Q2）. A Spearman’s rank correlation analysis was performed. Results The results of staining showed ordered arrangement of hepatocytes in the Biejiajian Pills group， with significant alleviation of inflammatory cell infiltration and collagen fiber deposition. Compared with the control group， the model group had significant increases in the serum levels of TBil and HYP and a significant reduction in the serum level of Alb （all P<0.05）. Compared with the control group， the Biejiajian Pills group had significant increases in the serum levels of AST， ALT， TBil， and HYP and a significant reduction in the serum level of Alb （all P<0.05）， and the silymarin group had significant increases in the serum levels of ALT， TBil， and HYP and a significant reduction in the serum level of Alb （all P<0.05）. Compared with the model group， the Biejiajian Pills group had significant reductions in the serum levels of ALT， AST， TBil， and HYP （all P<0.05）， and the silymarin group had significant reductions in the serum levels of ALT， TBil， HYP， and AST and a significant increase in the serum level of Alb （all P<0.05）. Mechanism studies showed that compared with the control group， the model group had significant reductions in the levels of taurolithocholic acid， tauro-α-muricholic acid， taurocholic acid， glycodeoxycholic acid， taurohyocholic acid， chenodeoxycholic acid， glycohyodeoxycholic acid， 7，12-diketolithocholic acid， taurochenodeoxycholic acid， and glycochenodeoxycholic acid and significant increases in the levels of hyodeoxycholic acid， norcholic acid， β-muricholic acid， and cholic acid （all P<0.05）. Compared with the model group， the Biejiajian Pills group had significant increases in the levels of the protective BAs taurolithocholic acid， chenodeoxycholic acid， taurocholic acid， taurohyocholic acid， and taurodeoxycholic acid and significant reductions in the levels of tauro-α-muricholic acid， tauro-β-muricholic acid， taurohyodeoxycholic acid+tauroursodeoxycholic acid， α-muricholic acid， glycoursodeoxycholic acid， and norcholic acid （alll P<0.05）. As for SCFAs， compared with the model group， the Biejiajian Pills group had significant increases in the levels of acetic acid， propionic acid， isobutyric acid， butyric acid， isopentanoic acid， pentanoic acid， and hexanoic acid （all P<0.05）. Compared with the model group， the silymarin group had significant reductions in the levels of taurolithocholic acid， tauro-α-muricholic acid， norcholic acid， glycocholic acid， deoxycholic acid， tauro-β-muricholic acid， taurodeoxycholic acid， taurohyodeoxycholic acid+tauroursodeoxycholic acid， and α-muricholic acid and significant increases in the levels of taurocholic acid and chenodeoxycholic acid， as well as significant increases in the levels of the SCFAs acetic acid， propionic acid， pentanoic acid， and hexanoic acid （all P<0.05）. The correlation analysis showed that the metabolism of BAs and SCFAs was correlated with the changes in serum indicators. Conclusion Biejiajian Pills can alleviate CCl4-induced hepatic fibrosis in rats by regulating the BA/SCFA metabolic axis.
Wu Longda, Du Yuanqin, Wei Yanfei, et al. Effect and mechanism of action of Biejiajian Pills on a rat model of hepatic fibrosis induced by carbon tetrachloride[J]. J Clin Hepatol, 2026, 42(8): 1866-1877.. doi: 10.12449/JCH260819.
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