Ginsenoside Rk3 Alleviates Neuroinflammation and Gastrointestinal Dysfunction in Parkinson’s Disease via Modulation of Gut Microbiota-Mediated Butyric Acid Metabolism

Accumulating evidence links gut microbiota dysbiosis and metabolic disorders to the pathogenesis of Parkinson’s disease (PD). Ginsenoside Rk3 (Rk3), a rare ginseng saponin, possesses anti-inflammatory and microbiota-modulating properties. However, its role in the regulation of the gut-brain axis remains unclear. In this study, the key gut microbial species and microbial metabolites associated with the PD-protective effects of Rk3 was explored using rotenone-induced PD mouse model through behavioral experiments, multiomics analysis and targeted bacteria/metabolites supplementation. Rk3 could restore the intestinal microbial homeostasis by enriching Lactobacillus murinus and Clostridium, and delay PD progression by lightening neuroinflammation in a gut microbiota-dependent manner. Crucially, Rk3 significantly increased levels of microbial metabolite butyrate, which could protect dopaminergic neurons and mitigate neuroinflammation by inhibiting histone deacetylase (HDAC) activity and activating the JAK/STAT3 signaling pathway. Overall, Rk3 delays PD progression via intestinal microbial homeostasis remodeling, highlighting its therapeutic potential for neurodegenerative disorders mediated by the gut-brain axis.