Fermented red ginseng enhances cognitive function via gut-brain axis: Role in microbiota modulation and insulin sensitivity

Background Fermentation of red ginseng ( Panax ginseng Meyer; RG) by Lactiplantibacillus plantarum may enhance its neuroprotective properties through ginsenoside biotransformation and generation of bioactive metabolites. This study compared the protective effects of L. plantarum -fermented red ginseng (FRG) and non-fermented RG against scopolamine-induced memory impairment through the gut–brain axis. Methods Chemical profiling (UHPLC-QTOF-MS/MS) and network pharmacology were used to predict molecular targets and pathways. Male Sprague-Dawley rats received daily oral RG (200 mg/kg), FRG-low (50 mg/kg), FRG-high (FRG-H, 200 mg/kg), or donepezil (10 mg/kg, positive control) for 6 weeks, with daily intraperitoneal scopolamine (2 mg/kg) co-administered during the final 3 weeks. Cognitive function, hippocampal neuroprotection, neuroinflammation, metabolic parameters, and gut microbiota were assessed. Results Fermentation increased ginsenosides s-Rg3 and Rg5 and phenyllactic acid. Network pharmacology identified FRG targets including GSK3B, PPARG, CXCL8, and PTGS2, enriched in neuroinflammation and insulin sensitivity pathways. FRG-H improved all cognitive parameters and reduced hippocampal neuronal death, oxidative stress, and acetylcholinesterase activity, while suppressing neuroinflammatory cytokines (TNF-α, IL-17A, IL-1β) and upregulating mRNA expression of neurotrophic factors ( BDNF 3.6-fold; CNTF 1.4-fold), alongside restored CREB/Akt/GSK-3β signaling. Systemically, FRG improved insulin sensitivity (HOMA-IR reduced by 58.7%), enriched beneficial gut bacteria ( Akkermansia muciniphila , Blautia faecis ), and increased serum butyrate concentration. Conclusion Fermentation enhanced the neuroprotective effects of RG in a scopolamine-induced memory impairment model, accompanied by coordinated changes in hippocampal signaling, metabolic pathways, and gut microbiota. These findings suggest that L. plantarum fermentation may enhance the functional potential of RG through gut–brain axis–related mechanisms and support further investigation in chronic disease models.