Bile acids metabolism involved in the beneficial effects of Danggui Shaoyao San via gut microbiota in the treatment of CCl4 induced hepatic fibrosis

Danggui Shaoyao San (DSS) is a traditional Chinese medicine (TCM) first recorded in the Synopsis of the Golden Chamber. DSS has proven efficacy in treating hepatic fibrosis (HF). However, the effects and mechanisms of DSS on HF are not clear. To investigate the effect of DSS on HF via gut microbiota and its metabolites (SCFAs, BAs). HF rats were induced with CCl4 and treated with DSS. Firstly, the therapeutic efficacy of DSS in HF rats and the protection of gut barrier were assessed. Then, 16S rRNA gene sequencing and untargeted fecal metabolomics preliminarily explored the mechanism of DSS in treating HF, and identified different microbiota and metabolic pathways. Finally, targeted metabolomics and RT-qPCR were used to further validate the mechanism of DSS for HF based on the metabolism of SCFAs and BAs. After 8 weeks of administration, DSS significantly reduced the degree of HF. In addition, DSS alleviated inflammation in the ileum and reduced the levels of LPS and D-lactate. Furthermore, DSS altered the structure of gut microbiota, especially Veillonella, Romboutsia, Monoglobus, Parabacteroides, norank_f_Coriobacteriales_Incertae_Sedis. These bacteria have been linked to the production of SCFAs and the metabolism of BAs. Untargeted metabolomics suggested that DSS may play a role via BAs metabolism. Subsequently, targeted metabolomics and RT-qPCR further confirmed the key role of DSS in increasing SCFAs levels and regulating BAs metabolism. DSS can alleviate CCl4-induced HF and protect the gut barrier. DSS may exert its beneficial effects on HF by affecting the gut microbiota and its metabolites (SCFAs, BAs).