Objective To explore the role of intestinal microbiota metabolite butyric acid in regulating the gut-brain autophagy signaling pathway to reduce α-Syn levels in both the colon and substantia nigra (SN) of PD model rats. Methods The intestinal metabolites were analyzed by GC-MS/MS. Behavioral experiments were conducted to assess the impact of butyric acid on 6-hydroxydopamine (6-OHDA)-induced PD rats. The auto-phagosomes were visualized by transmission electron microscopy (TEM). Immunohistochemistry, immunofluorescence, and western blotting were performed to assess the levels of tyrosine hydroxylase (TH), α-Syn and the PI3K/AKT/mTOR pathway in both the SN and colon of the rats. The pathway-related agonist were used to verify the autophagy mechanism in the primary neurons overexpressing A53T mutant α-Syn (A53T-α-Syn).Results The pharmacological findings revealed that Madopar, clinical drug for PD treatment, regulated the gut microbiota-derived organic acids, resulting in a significant increase in the level of butyric acid. Butyric acid improved autonomic movement, reduced α-Syn aggregation and attenuated the loss of dopaminergic neurons in 6-OHDA-induced PD rats. After oral administration of butyric acid, the accumulation of autophagosomes increased and the phosphorylation levels of PI3K, AKT and mTOR decreased in the SN and colon of rats. The effect of butyric acid on reducing A53T-α-Syn through the activation of the PI3K/AKT/mTOR-mediated autophagy pathway was further confirmed in A53T-α-Syn transgenic primary neurons. This effect could be inhibited by the PI3K agonist 740 Y-P Conclusion Our findings suggestes that intestinal microbiota metabolite butyric acid could protect neurons by activating autophagy to degrade α-Syn in the SN and colon, which are relates to the suppression of butyric acid on the activation of PI3K/AKT/mTOR signaling pathway