Gut microbial-derived indole-3-propionate improves cognitive function in Alzheimer’s disease
Intermittent fasting (IF) offers a potential strategy to counteract Alzheimer's disease (AD) progression. In our 16-week study on AD transgenic mice, IF positively affected cognitive function and reduced amyloid-β (Aβ) accumulation, verifying the IF's role in modulating neuroinflammation. Multiomics integration revealed strong links between IF-induced hippocampal gene expression, gut microbiota, and serum metabolites beneficial for cognition. Indole-3-propionic acid (IPA) emerged as a pivotal microbial metabolite. Blocking its neuronal receptor, pregnane X receptor (PXR), abolished IF's effects. Human data paralleled these findings, showing lower IPA levels in patients with mild cognitive impairment and AD than in controls. IPA supplementation and IPA-producing <i>Clostridium sporogenes</i> reproduced IF's cognitive benefits, whereas PXR blockade in neurons or disruption of IPA synthesis abrogated them. IPA crossed the blood-brain barrier, exhibited potent anti-inflammatory activity, and suppressed Aβ accumulation, essential for neuroprotection. These results underscore microbial metabolites regulated by IF, particularly IPA, as therapeutic candidates for AD, highlighting the critical role of the gut-brain axis in neurodegeneration.
Authors
- Xiaowei Jia (ORCID: https://orcid.org/0000-0002-1093-9615)
- Lu Deng (ORCID: https://orcid.org/0000-0002-3744-4102)
- Jun Gong (ORCID: https://orcid.org/0000-0002-4402-1263)
- Lin Shi (ORCID: https://orcid.org/0000-0001-9709-3394)
- Mengzhen Jia (ORCID: https://orcid.org/0000-0002-2458-3023)
- Qingyuan Li (ORCID: https://orcid.org/0000-0001-9318-7772)
- Jun Hu (ORCID: https://orcid.org/0000-0002-3017-8147)
- Xuebo Liu (ORCID: https://orcid.org/0009-0000-0381-6353)
- Kun Xu (ORCID: https://orcid.org/0000-0001-5714-9090)
- Shuang Zhou (ORCID: https://orcid.org/0009-0005-6374-4837)
- Yuhao Wang (ORCID: https://orcid.org/0000-0002-4539-3720)
- Zhigang Liu (ORCID: https://orcid.org/0000-0002-6863-6561)
- Yu Zhao (ORCID: https://orcid.org/0000-0002-2844-993X)
- Xuhui Chen (ORCID: https://orcid.org/0009-0003-3444-1226)
- Yihang Zhao (ORCID: https://orcid.org/0000-0002-4040-2691)
- Xinyu Hu (ORCID: https://orcid.org/0000-0002-8825-3664)
- Chen Ding (ORCID: https://orcid.org/0000-0002-3228-8585)
- Fangjie Ning
- Ling Li (ORCID: https://orcid.org/0009-0005-1925-091X)
- Cong Yang (ORCID: https://orcid.org/0009-0003-6652-0527)
Institutions
- City University of Hong Kong, Shenzhen Research Institute (CN)
- Peking University Shenzhen Hospital (CN)
- Shaanxi Normal University (CN)
- Northwest A&F University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1126/sciadv.adw8410
- Citations
- 5
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 4.03