INTRODUCTION: Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration, neuroinflammation, and emerging evidence of gut microbiota dysbiosis. Although nicotine has been implicated in neuroprotection, whether its enantiomers exert stereoselective effects on the gut-brain axis remains unknown. METHODS: We systematically compared the effects of S-nicotine and R-nicotine in an MPTP-induced mouse model of PD. Motor function, nigrostriatal dopaminergic neuronal loss, neuroinflammatory responses, intestinal barrier integrity, and gut microbiota composition were assessed. RESULTS: Both enantiomers ameliorated motor deficits, attenuated nigrostriatal dopaminergic neuronal loss, and suppressed neuroinflammatory responses, yet exhibited markedly different efficacy profiles. S-nicotine produced robust neuroprotection at a lower effective dose (1 mg/kg), associated with improved motor performance, reduced central and peripheral inflammation, preservation of intestinal barrier integrity, and coordinated remodeling of the gut microbiota characterized by enrichment of Akkermansiaceae (notably Akkermansia). In contrast, R-nicotine required a higher dose (3 mg/kg) to achieve comparable neuroprotection and induced weaker and more heterogeneous microbiota alterations. Correlation analyses further revealed that S-nicotine-associated enrichment of Akkermansia was closely linked to improvements in motor function, reduced inflammatory status, and enhanced intestinal integrity. DISCUSSION: These findings demonstrate pronounced stereoselective and dose-dependent effects of nicotine enantiomers on neuroimmune modulation and identify gut microbiota remodeling as a functionally relevant correlate of nicotine-mediated neuroprotection in PD. Our results highlight the therapeutic potential of targeting the microbiota-gut-brain axis through chiral interventions and support S-nicotine as a promising candidate for neuroprotective strategies in aging-related neurodegenerative disorders.