6-Shogaol Complements Levodopa Therapy by Modulating Brain-Gut Metabolomes in a Parkinson's Disease Model.

Levodopa remains the primary therapy for Parkinson's disease (PD); however, its benefits are largely confined to motor symptom relief, without altering disease progression. Growing evidence implicates the gut-brain axis in PD, linking gastrointestinal dysfunction and microbial shifts to neuronal cell death. Gut-brain metabolomics is critical for clarifying these interactions and guiding adjunct strategies to enhance intestinal motility and neuroprotection beyond levodopa. Therefore, this study aimed to characterize gut and brain metabolomic alterations induced by levodopa and to evaluate whether co-administration with 6-shogaol, previously identified as a gut-brain axis modulator, modifies these changes in relation to motor and gastrointestinal functions. Male C57BL/6 mice were assigned to normal, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid, levodopa, or 6-shogaol+levodopa groups. PD was induced by repeated MPTP/probenecid injections, and 6-shogaol was administered orally with levodopa. Motor performance, gut motility, dopamine levels in the brain, and metabolomic profiles were subsequently assessed. Levodopa improved motor deficits in the MPTP/probenecid model, while 6-shogaol co-administration preserved these benefits and additionally restored gastrointestinal motility, a non-motor feature unresponsive to levodopa alone. The combination further increased striatal dopamine and levodopa levels, suggesting enhanced dopaminergic availability. Metabolomic profiling revealed distinct brain-gut signatures, including alterations in energy, lipid, and amino acid pathways, with specific metabolites linked to motor function, dopamine regulation, and gut activity. These findings suggest that 6-shogaol complements levodopa by modulating brain-gut metabolomic networks to improve motor and non-motor features of PD.