Time‐restricted feeding mitigates Alzheimer's disease‐associated cognitive impairments via a <i>B. pseudolongum</i>‐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 <i>Bifidobacterium pseudolongum</i> (<i>B. pseudolongum</i>) and propionic acid (PA) with key genes in AD pathogenesis. Oral supplementation of <i>B. pseudolongum</i> 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 <i>B. pseudolongum</i> or PA as potential AD therapies.
Authors
- Rui Gao (ORCID: https://orcid.org/0000-0003-4841-5929)
- Hangqi Li (ORCID: https://orcid.org/0000-0001-8071-7471)
- Xuebo Liu (ORCID: https://orcid.org/0000-0001-6370-2868)
- Yuanqiang Zou (ORCID: https://orcid.org/0000-0003-2380-264X)
- Lin Shi (ORCID: https://orcid.org/0000-0001-9709-3394)
- Weixuan Dong (ORCID: https://orcid.org/0000-0002-7303-4143)
- Jiabin Ma
- Mengzhen Jia (ORCID: https://orcid.org/0000-0002-2458-3023)
- Jun Hu (ORCID: https://orcid.org/0000-0002-3017-8147)
- Xiaoshuang Dai (ORCID: https://orcid.org/0000-0001-6563-7756)
- Zhigang Liu (ORCID: https://orcid.org/0000-0002-6863-6561)
- Jiao Chen (ORCID: https://orcid.org/0000-0003-2367-4369)
- Chen Ding (ORCID: https://orcid.org/0000-0001-8673-3464)
- Xuhui Chen (ORCID: https://orcid.org/0000-0002-9791-2051)
- Bin Bao (ORCID: https://orcid.org/0000-0001-9312-5096)
- Yihang Zhao (ORCID: https://orcid.org/0000-0002-4040-2691)
Institutions
- BGI Group (China) (CN)
- City University of Hong Kong, Shenzhen Research Institute (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Peking University Shenzhen Hospital (CN)
- BGI Research (CN)
- Shaanxi Normal University (CN)
- Northwest A&F University (CN)
Publication Details
- Journal
- iMeta
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1002/imt2.70006
- Citations
- 35
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 28.21
Funders
- Foundation for Food and Agriculture Research
- Natural Science Foundation of Shenzhen City
- National Natural Science Foundation of China
- National Plan for Science, Technology and Innovation
- Shenzhen Science and Technology Innovation Program