Swainsonine Induces Liver Inflammation in Mice via Disturbance of Gut Microbiota and Bile Acid Metabolism

Abstract

Swainsonine induced liver inflammation in livestock; however, the underlying mechanisms, especially the role of bile acids (BAs), in the pathogenesis remained elusive. Here, our results showed that swainsonine induced hepatic inflammation via changing BA metabolism and gut microbiota in mice. Swainsonine significantly upregulated the levels of deoxycholic acid (DCA) and taurine-β-muricholic acid (T-β-MCA) in the serum and liver of mice due to the markedly increased genus Clostridium and the decreased genus Lactobacillus in the gut. As antagonists of the farnesoid X receptor (FXR), elevated DCA and T-β-MCA inhibited hepatic Fxr gene expression and thus suppressed FXR-SHP signaling and activated hepatic Cyp7a1 gene expression, which induced a significant upregulation of the total BA level in serum, contributing to liver inflammation. These findings offer new insights into the underlying mechanisms in which swainsonine induced liver inflammation in mice via the gut−liver axis and suggest that gut microbiota and its metabolite BAs may be underlying triggering factors.

Impaired Indole Acetic Acid and Reduced Indole-Producing Bacteria Contribute to Swainsonine-Induced Liver Inflammation

“…According to our previous findings, swainsonine induced hepatic inflammation by modulating intestinal microbes and their bile acid metabolites . In the present study, swainsonine treatment regulated the gut microbial composition as well as the levels of microbially derived indole metabolites.…”

“…Targeted 500 metabolomics were used to obtain a comprehensive profile of liver and serum metabolites in different groups. The results of liver pathology and biochemical indexes that swainsonine induced hepatic inflammation in mice have been described in the previous study . We visualized the differences in the metabolites of the liver and serum using the OPLS-DA model score plots (Figure ).…”

“…Swainsonine markedly increased the concentrations of taurine-beta-muricholic acid (T-β-MCA) and deoxycholic acid (DCA), inhibited FXR-SHP signaling pathway, and increased total BA concentrations, leading to hepatic inflammation. 18 However, the underlying mechanisms, especially the role of a comprehensive profile of liver and serum metabolites and microbial-derived indole metabolites, were still unknown. In this study, we hypothesized that swainsonine-induced hepatic inflammation had a close relationship with indole-producing bacteria and indole metabolites.…”

Metabolomic analysis of swainsonine poisoning in renal tubular epithelial cells

“…Previous results genomic study showed consistent enrichment in bile metabolism and drug metabolism-cytochrome P450 when rat renal tubular epithelial cells were exposed to the same conditions as in this study. Additionally, Fu et al ( 25 ) demonstrated that SW induced liver inflammation by altering bile acid metabolism and intestinal microbiota in mice. Thus, these results suggest that exposure to SW may significantly alter the bile acid metabolism whether these changes is associated with the SW-induced cellular damage remain to be investigated.…”

“…Unfortunately, research papers exploring the intoxication mechanisms of SW are highly limited, with only a solitary study identified. In this study, the author cleverly harnessed targeted metabolomics and high-throughput sequencing techniques to reveal that SW has the capacity to profoundly alter bile acid metabolism and disrupt the delicate balance of intestinal microbiota in mice, ultimately triggering inflammatory reactions in the liver ( 25 ). Nevertheless, our understanding of the kidney toxicity and associated metabolites triggered by SW remains tenuous, necessitating further investigation in this vital area.…”