Low-Medium Polarity Ginsenosides from Wild Ginseng Improves Immunity by Activating the AhR/MAPK Pathway through Tryptophan Metabolism Driven by Gut Microbiota

The gut microbiota contribute significantly to the immune system. Low-medium polarity ginsenosides from wild ginseng (LWG) have potential immunomodulatory effects. However, how the LWG regulates gut microbiota to enhance immunity remains unclear. To explore the interaction between gut microbes and metabolites mediating LWG's immunomodulatory effects, this study examined LWG's impact on splenocytes and CTX-induced immunosuppressed mice. Metabolomic and metagenomic analyses were conducted in vivo to explore the mechanism by which LWG regulates gut microbiota to enhance immunity. <i>In vitro</i> data suggest that LWG at 4 μg/mL enhances the splenocyte activity. Furthermore, LWG effectively reduces symptoms in immunocompromised mice, including weight loss and intestinal mucosal damage. LWG alleviated gut microbiota disturbance, restored tryptophan metabolites (IA, IAA, and IPA), and significantly increased JNK, ERK, and p38MAPK protein levels, which were downstream of AhR. Our study demonstrated that LWG improves the immunity by reshaping gut microbiota, restoring intestinal mucosa, and boosting the gut microbiota-related metabolism of tryptophan to activate the AhR/MAPK pathway. This research offers new insights into the mechanism by which LWG regulates immune function.