The Gut Microbiota/Gut Brain/BDNF Axis: A Mechanistically Defined Pathway Mediating the Neuroprotective Effects of Ginsenoside Re in Parkinson’s Disease

Ginseng, as a traditional natural food and edible resource, has shown potential in the treatment of neurodegenerative diseases, particularly Parkinson’s disease (PD), through its active components, ginsenosides (GS) and ginsenoside Re (GsRe). This study aimed to systematically investigate the neuroprotective effects and molecular underpinnings of total GS and GsRe in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model, with a focus on gut brain axis modulation. The results showed that, GS and GsRe ameliorated motor deficits, reduced substantia nigra pars compacta (SNpc) dopaminergic neuron loss, restored intestinal barrier integrity, and reversed gut dysbiosis. Mechanistically, GsRe crossed the BBB, upregulated brain derived neurotrophic factor (BDNF), and inhibited the TLR4 adaptor WDFY1, blocking excessive NF-κB activation, M1 microglial polarization, and neuronal apoptosis. BDNF deficiency exacerbated TLR4 pathway hyperactivation, confirming BDNF’s upstream regulatory role. GS and GsRe target the gut brain axis as an integrated hub: normalizing gut microecology to limit peripheral inflammatory signal translocation, while suppressing central neuroinflammation via the BDNF/TLR4 axis. These findings provide a mechanistic basis for GS and GsRe based PD interventions, bridging gut dysbiosis and central neuroinflammation through a dual targeting strategy.