Multi-omics approaches to explore the therapeutic mechanism for ginsenoside Rg1 against MASLD.

Ginsenoside Rg1 (G-Rg1), a traditional Chinese medicine, alleviates metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanism by which G-Rg1 improves metabolic disorders in MASLD by regulating the gut microbiota remains ambiguous‌. We constructed a diet-induced murine MASLD model and employed 16S rRNA sequencing and non-targeted metabolomic analysis to ‌investigate the mechanism of G-Rg1 in treating MASLD, focusing on its regulatory effect on the gut microbiota. Our results revealed that G-Rg1 significantly increased the 5-hydroxyindoleacetic acid levels and activated the aryl hydrocarbon receptor (AHR) by enhancing intestinal permeability, modulating the gut microbiota composition, and influencing tryptophan metabolism. Therefore, G-Rg1 improved immune function and reduced liver inflammation and lipid deposition in the MASLD mouse model. In contrast, the effect of G-Rg1 was impaired upon removal of the gut microbiota. Furthermore, fecal microbiota transplantation in G-Rg1-treated mice improved MASLD. These finding s suggest that regulating the gut microbiota may play an important role in G-Rg1's ability to protect against MASLD. G-Rg1 may exert its anti-MASLD effects through the gut microbiota, tryptophan metabolism, AHR activation, and interleukin-22 signaling, offering a novel approach for G-Rg1-mediated MASLD treatment.