In ginseng, several ginsenosides have been demonstrated to alleviate dextran sulfate sodium (DSS)-induced colitis, especially the six ginsenosides in this study. However, which ginsenoside has the most potent anti-inflammatory effect and may be selected as a promising candidate for the treatment of colitis remains unclear. A cell inflammation model was induced by lipopolysaccharide (LPS) for 12 h and mouse colitis was induced by sterile water containing DSS lasting seven days. Cytokines associated with inflammation, pyroptosis, and ferroptosis were assessed by quantitative real-time PCR (qPCR), the level of reactive oxygen species (ROS) and changes in macrophage polarization were tested by flow cytometry, and analysis of intestinal metabolites by LC-MS/MS was performed. The results in this study displayed that among the six ginsenosides, Rf, Rg1, and Rg3 were the most effective in reducing LPS-induced inflammation in cells. Compared with Rg3 and Rf, Rg1 was superior in restoring body weight and the length of colon, decreasing the disease activity index (DAI), and reducing splenomegaly and colon inflammation. Meanwhile, Rg1 significantly decreased the expression of M1-related pro-inflammation cytokines and increased the expression of M2-related anti-inflammation cytokines. Rg1 also decreased CD86+M1 macrophages and polarized them towards CD206+M2 macrophages. The 700 targeted gut metabolite assays revealed that Rg1 treatment brought the metabolite composition closer to that of DSS-naive mice, while six key metabolites, including dodecanoylcarnitine, isobutyric acid, and decanoylcarnitine, and so on, all were significantly reversed. Our results demonstrated that among the six ginsenosides, Rg1 had the most extraordinary anti-inflammatory effect in LPS-induced cells and DSS-induced mice, and, more importantly, it blunted colitis through regulating macrophage polarization and intestinal metabolites.
