The gut-brain axis is increasingly recognized as a critical pathway in Parkinson's disease (PD), but the gut-targeted mechanisms underlying the therapeutic effects of herbal formulas remain poorly understood. In this study, an enterogenic PD-like mouse model was established by long-term rotenone gavage and treated with Duzhong Fang (DZF) to investigate whether DZF acts through intestinally retained components to influence gut-brain α-synuclein pathology. DZF markedly improved motor dysfunction, increased nigral tyrosine hydroxylase (TH)-positive cell density, alleviated colonic inflammation, and reduced α-Syn accumulation in the vagus nerve and brain, while colonic α-Syn showed a decreasing trend. Mechanistically, DZF downregulated colonic TPH1 and 5-HT3A expression, reshaped gut microbiota composition, and modulated fecal metabolites related to tryptophan metabolism and the 5-HT biosynthetic pathway. Molecular docking predicted potential interactions between TPH1 and gut-retained gingerol-related compounds, including 6-shogaol, 10-gingerdione, 10-gingerol, and 4-gingerol. These findings suggest that DZF ameliorates rotenone-induced PD-like phenotypes and may act by modulating the intestinal TPH1/5-HT-related pathway and α-Syn pathology along the gut-brain axis. This study supports a gut-targeted, neural-regulated therapeutic paradigm for traditional Chinese medicine and provides potential lead compounds for gut-directed anti-PD intervention.
