Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and systemic inflammation, with increasing evidence implicating the gut-brain axis in its pathogenesis. Altered gut microbiota composition and reduced levels of neuroprotective microbial metabolites, such as short-chain fatty acids (SCFAs), have been reported in patients with PD. Branched-chain amino acids (BCAAs), essential nutrients influenced by microbial metabolism, may contribute to neuroimmune regulation through SCFA production, particularly propionate, and modulation of PI3K/Akt/mTORC1 signaling. In this study, we investigated whether dietary BCAA supplementation influences neurodegenerative processes in PD through gut microbiota remodeling and microbial propionate production, and examined the potential involvement of the PI3K/Akt/mTORC1 signaling pathway. We combined human clinical observations with mechanistic studies in MPTP-induced PD mouse models and MPP⁺-treated SH-SY5Y neuronal cells. Gut microbiota composition was profiled using 16S rRNA sequencing, and fecal and serum metabolites were analyzed by GC-MS. Neurobehavioral performance, dopaminergic neuron integrity, apoptosis-related markers, and PI3K/Akt/mTORC1 pathway activation were evaluated using immunohistochemistry, Western blotting, and cellular assays with or without pharmacological inhibition. PD patients exhibited gut dysbiosis, reduced BCAA levels, and depletion of SCFA-producing taxa. In mice, BCAA supplementation partially restored microbial composition and enhanced predicted propionate biosynthesis pathways. Propionate administration improved motor performance, preserved dopaminergic neurons, mitigated neuroinflammatory responses, and reduced apoptosis in vivo and in vitro. Mechanistically, propionate restored PI3K, Akt, and mTORC1 phosphorylation, upregulated Bcl-2, and suppressed cleaved caspase-3, effects that were abolished by PI3K inhibition. Collectively, these findings identify a gut microbiota-BCAA-propionate axis that may influence neurodegenerative processes through modulation of PI3K/Akt/mTORC1 signaling, highlighting microbial metabolites as potential modulators of gut-brain communication in PD.
