Time-restricted feeding mitigates Alzheimer's disease-associated cognitive impairments via a B. pseudolongum-propionic acid-FFAR3 axis

Time-restricted feeding (TRF) holds promise for alleviating cognitive decline in aging, albeit the precise mechanism via the gut-brain axis remains elusive. In a clinical trial, we observed, for the first time, that a 4-month TRF ameliorated cognitive impairments among Alzheimer's disease (AD) patients. Experiments in 5xFAD mice corroborated the gut microbiota-dependent effect of TRF on mitigating cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Multi-omics integration linked Bifidobacterium pseudolongum ( B. pseudolongum ) and propionic acid (PA) with key genes in AD pathogenesis. Oral supplementation of B. pseudolongum or PA mimicked TRF's protective effects. Positron emission tomography imaging confirmed PA's blood-brain barrier penetration, while knockdown of the free fatty acid receptor 3 (FFAR3) diminished TRF's cognitive benefits. Notably, we observed a positive correlation between fecal PA and improved cognitive function in an AD cohort, further indicating that TRF enhanced PA production. These findings highlight the microbiota-metabolites-brain axis as pivotal in TRF's cognitive benefits, proposing B. pseudolongum or PA as potential AD therapies. Graphical A 4-month of time-restricted feeding (TRF) intervention alleviated cognitive impairments in Alzheimer's disease (AD) patients, while a 3-month TRF regimen improved spatial memory, reduced amyloid-beta accumulation, and promoted microglial aggregation around plaques in AD mice. Antibiotic-induced gut microbiota depletion partly abolished TRF's benefits. Through creatively integrating gut microbiota, metabolites, and hippocampal genes, Bifidobacterium pseudolongum ( B. pseudolongum ) and propionic acid (PA) were identified as key contributors to TRF's cognitive effects, with supplementation of either mimicking TRF's protective benefits. Positron emission tomography imaging revealed that PA directly crossed the blood-brain barrier, and PA supplementation restored disrupted metabolism in AD mice. Knockdown of its receptor free fatty acid receptor 3 (FFAR3) diminished TRF's protective effects. A case-control study showed a negative association between PA and cognitive status, while the TRF clinical intervention linked fecal PA to cognitive status. These findings suggest PA as a potential biomarker and underscore precise TRF-based nutritional interventions as a promising strategy for managing neurodegenerative diseases. Highlights Time-restricted feeding (TRF) improved cognitive function in Alzheimer's disease (AD) patients, with notable enhancement in executive function. Multi-omics integrated analysis in AD mice identified Bifidobacterium pseudolongum ( B. pseudolongum ) and propionic acid (PA) as key mediators of TRF's cognitive benefits. The potential molecular mechanism by which TRF alleviates cognitive impairment induced by AD involves the B. pseudolongum –PA-free fatty acid receptor 3 (FFAR3) pathway. Case-control study and TRF clinical intervention demonstrated PA as a potential biomarker for AD.