Beneficial Effects of Apple Polyphenol Extract and Time-Restricted Feeding on Ulcerative Colitis and Accompanying Depression-like Behaviors Are Correlated with Gut–Brain Axis Modulation

Time-restricted feeding (TRF) and apple polyphenol extract (APE) emerged as promising adjuvant strategies for managing inflammation and gut microbiota imbalances. Ulcerative colitis (UC), characterized by recurrent episodes, is difficult to cure and often accompanied by anxiety- and depression-like behaviors. To investigate whether TRF, APE, or their combined intervention could prevent UC and associated behavioral disorders, a dextran sulfate sodium (DSS)-induced UC model in C57BL/6 male mice was employed, and APE (500 mg/kg·body weight·day) was administered via gavage. Through a 36-day treatment, ameliorated UC was observed, along with reduced DAI scores, improved colonic pathological damage, intestinal barrier, and brain barriers by activating intestinal mitophagy with upregulated Parkin/Pink1, and suppressed NLRP3/ASC/Caspase-1 pathway-mediated inflammation. Furthermore, APE and TRF ameliorated UC accompanying behavioral disorders by suppressing astrocytes and microglia activation, preventing synaptic damages through upregulating BDNF and PSD-95 expression and enhancing neurotransmission by increasing the serum levels of 5-Hydroxytryptamine and norepinephrine. Notably, APE and TRF restored gut microbiota composition with increased Firmicutes/Bacterodetes ratio and boosted Akkermansia abundance while reducing the relative abundances of Citrobacter, Bacteroides, and Escherichia-Shigella . In conclusion, APE and TRF, both individually or in combination, significantly prevented DSS-induced UC and associated behavioral disorders, which were strongly associated with coordinated changes of gut–brain axis modulation.