AUTHOR=Wu Qiong , Zhu Fangsi , Yao Yu , Chen Luyun , Ding Yijie , Su Yong , Ge Chaoliang 

TITLE=Sini san regulates intestinal flora and short-chain fatty acids to ameliorate hepatocyte apoptosis and relieve CCl4-induced liver fibrosis in mice

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1408459

DOI=10.3389/fphar.2024.1408459

ISSN=1663-9812

ABSTRACT=Sini-san (SNS), a traditional Chinese medicine, is effective in treating liver fibrosis with an unclear mechanism. While disturbance of intestinal flora and the subsequent secretion of short-chain fatty acids (SCFAs) is suggested to be involved in the progression of liver fibrosis, whether SNS produces the anti-fibrosis effect through the regulation of intestinal flora and SCFAs remains unclear. In the current study, carbon tetrachloride (CCl4) treated mice were dosed with SNS to examine the anti-fibrosis effect and the involved mechanism. Biochemical parameters, histological staining and analyses of fibrotic gene expression were used to evaluate the anti-fibrosis effect of SNS, while intestinal flora and SCFAs content were determined by 16S rRNA and LC-MS to evaluate the mechanism. In vivo results showed that SNS improved liver function, reduced hepatocyte apoptosis and FFAR2/3 expression, and restored intestinal dysbiosis and reduced PA, BA and IsA levels. In vitro experiments showed that PA, BA and IsA exacerbated TNF-α-induced HepG2 apoptosis. Notably, the protective effects of SNS were compromised in pseudo-sterile mice. In conclusion, our experimental results suggest that disturbance in intestinal flora results in elevated SCFAs, which further exacerbates hepatocyte apoptosis in liver fibrosis, while SNS suppresses CCl4-induced liver fibrosis at least partially by reinstating intestinal flora homeostasis and reducing SCFAs levels.