Neuroprotective Effects of Biosynthetic <scp>d</scp> ‐Calcium Pantothenate and Cyanocobalamin Against MPTP‐Induced Parkinsonism via Microbiota Modulation, Metabolic Homeostasis Restoration, and Endoplasmic Reticulum Stress Inhibition

ABSTRACT Vitamin B5 (VB5) and Vitamin B12 (VB12) are essential micronutrients widely distributed in functional foods, yet their neuroprotective potential against Parkinson's disease (PD) via gut microbiome and metabolic remains under‐investigated. This study aimed to explore the physiological and metabolic effects of VB5 and VB12 in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mice by performing biochemical, untargeted metabolomic, 16S microbiota, and Western blot analyses. The results demonstrated that the mice supplemented with VB5 and VB12 showed ameliorated motor deficits, reduced oxidative stress, restored neuronal damage, and inhibited endoplasmic reticulum stress (ERS) via the downregulating of the PERK‐eIF2α‐activating transcription factor 4 (ATF4)‐CHOP signaling pathway. Furthermore, 16S rRNA sequencing revealed that VB5 and VB12 interventions modulated the gut‐microbiota dysbiosis, specifically by decreasing Desulfovibrio and enriching Prevotella abundance. Untargeted metabolomics further demonstrated that the interventions modulated the metabolic landscape of the serum and striatum. Specifically, in the striatum, VB5 and VB12 mitigated energy failure by replenishing mitochondrial coenzymes and suppressing purine degradation. They also attenuated local neuroinflammation by reducing pro‐inflammatory lipid mediators. These central improvements were closely associated with the restoration of circulating neuroactive precursors, particularly l ‐tyrosine. Collectively, these findings provide a theoretical basis for developing VB5 and VB12‐fortified functional foods as a promising nutritional strategy to prevent PD‐associated neurodegeneration.