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

Abstract 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.