Parkinson's disease (PD) is a neurodegenerative disorder characterized by gut microbiota dysbiosis and excessive inflammatory responses. Intermittent fasting (IF) exerts neuroprotective effects on neurodegenerative diseases. However, the impact of IF on PD and its mechanisms still need to be elucidated. In the present study, we found that 13-week IF regimen (designed as alternate-day fasting) mitigated motor impairment, α-synuclein aggregation, and loss of dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Meanwhile, IF attenuated intestinal dysfunctions, intestinal pro-inflammatory cytokines (tumor necrosis factor-αlphα (TNF-α) and interleukin-1 beta (IL-1β)) levels, and gut barrier destruction. Furthermore, IF alleviated brain barrier impairment and suppressed the activation of astrocytes and microglia. Mechanistic studies revealed that IF suppressed the toll-like receptor 4 (TLR4)/NF-κB signaling pathway both in the colon and substantia nigra. 16S rRNA sequencing demonstrated that IF alleviated MPTP-induced microbiota dysbiosis, decreasing harmful bacteria abundances (Proteobacteria, Burkholderiales, Sutterellaceae, Parasutterella, Burkholderiales_bacterium, and Desulfovibrio_fairfieldensis) while increasing probiotic bacteria abundances (Oscillospirales, Rikenellaceae, and Lactobacillus_murinus), which were significantly correlated with the anti-inflammatory effects of IF. Gas chromatography-mass spectrometry (GC-MS) revealed that IF induced the levels of fecal short chain fatty acids (SCFAs). Antibiotics intervention abolished the beneficial effects of IF, suggesting that gut microbiota contributed to the neuroprotection of IF for PD. These findings suggest that IF regimen may serve as a novel therapeutic strategy for PD, likely linked to its regulation of gut microbiota to inhibit gut-brain axis inflammation.
