Neuroprotective Effects of Time‐Restricted Feeding Combined With Different Protein Sources in MPTP‐Induced Parkinson's Disease Mice Model and Its Modulatory Impact on Gut Microbiota Metabolism

ABSTRACT Dietary interventions alleviate Parkinson's disease (PD) progression by modulating the gut microbiota. However, the interaction between time‐restricted feeding (TRF) and dietary protein composition remains unclear. This study examines the effects of casein (animal‐derived) and soy protein (plant‐derived) on PD pathology in an MPTP‐induced mouse model and their influence on TRF efficacy. MPTP induces dopaminergic neuron loss and neuroinflammation regardless of protein source, but casein‐fed mice show partial motor dysfunction and gut barrier disruption, whereas soy protein‐fed mice maintain motor function and barrier integrity. TRF differentially modulates PD outcomes: in casein‐fed mice, it alleviates partial motor deficits by suppressing monoamine oxidase B (MAO‐B) and reducing dopamine (DA) metabolism, without rescuing DA levels or neuron survival. In soy protein‐fed mice, TRF suppresses MAO‐B, preserves dopaminergic neurons, restores DA levels, and reduces neuroinflammation. Analysis of gut microbiota and metabolomics suggests that TRF may reduce Allobaculum and branched‐chain amino acids (BCAAs) in casein‐fed mice, while increasing Akkermansia and short‐chain fatty acids (SCFAs) in soy protein‐fed mice. Mechanistic assays suggest that Allobaculum and BCAAs impair gut barrier function and aggravate inflammation. In conclusion, TRF exerts protein‐dependent neuroprotective effects, with soy protein combined with TRF offering a promising dietary strategy for PD management.