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

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.