Wu Qiong, Zhu Fangsi, Yao Yu, Chen Luyun, Ding Yijie, Su Yong, Ge Chaoliang
School of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China.
Department of Pharmacy, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China.
Front Pharmacol. 2024 Aug 30;15:1408459. doi: 10.3389/fphar.2024.1408459. eCollection 2024.
Si-Ni-San (SNS), a traditional Chinese medicine, is effective in treating liver fibrosis with an unclear mechanism. Although 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 (CCl)-treated mice were dosed with SNS to examine the anti-fibrotic effects and the involved mechanism. Biochemical parameters, histological staining, and analyses of fibrotic gene expression were used to evaluate the anti-fibrotic effect of SNS, while intestinal flora and SCFA content were determined by 16S rRNA and LC-MS to evaluate the mechanism.
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. 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 the disturbance in intestinal flora results in elevated SCFA levels, which further exacerbates hepatocyte apoptosis in liver fibrosis, while SNS suppresses CCl-induced liver fibrosis at least partially by reinstating intestinal flora homeostasis and reducing SCFA levels.
四逆散（SNS）是一种中药，在治疗肝纤维化方面有效，但其作用机制尚不清楚。尽管肠道菌群紊乱及随后短链脂肪酸（SCFAs）的分泌被认为与肝纤维化的进展有关，但SNS是否通过调节肠道菌群和SCFAs产生抗纤维化作用仍不清楚。
在本研究中，用四氯化碳（CCl）处理的小鼠给予SNS，以检查其抗纤维化作用及相关机制。使用生化参数、组织学染色和纤维化基因表达分析来评估SNS的抗纤维化作用，同时通过16S rRNA和液相色谱-质谱联用仪测定肠道菌群和SCFA含量以评估其机制。
结果表明，SNS改善了肝功能，减少了肝细胞凋亡和游离脂肪酸受体2/3（FFAR2/3）表达，恢复了肠道菌群失调，并降低了丙酸（PA）、丁酸（BA）和异丁酸（IsA）水平。实验表明，PA、BA和IsA加剧了肿瘤坏死因子-α（TNF-α）诱导的HepG2细胞凋亡。值得注意的是，在无菌小鼠中，SNS的保护作用受到损害。
总之，我们的实验结果表明，肠道菌群紊乱导致SCFA水平升高，这进一步加剧了肝纤维化中的肝细胞凋亡，而SNS至少部分地通过恢复肠道菌群稳态和降低SCFA水平来抑制CCl诱导的肝纤维化。
