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Gut microbial-derived indole-3-propionate improves cognitive function in Alzheimer's disease.

  • 2025-11-28
  • Science advances 11(48)
    • Ling Li
    • Mengzhen Jia
    • Cong Yang
    • Yihang Zhao
    • Jun Hu
    • Yu Zhao
    • Xinyu Hu
    • Fangjie Ning
    • Chen Ding
    • Qingyuan Li
    • Jun Gong
    • Xiaoran Jia
    • Kun Xu
    • Yuhao Wang
    • Shuang Zhou
    • Lu Deng
    • Lin Shi
    • Xuhui Chen
    • Xuebo Liu
    • Zhigang Liu

Study Design

Population
AD transgenic mice; Human data in patients with mild cognitive impairment and AD compared with controls
Methods
In our 16-week study on AD transgenic mice, intermittent fasting (IF); Human data paralleled these findings
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 Clostridium sporogenes 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.

Research Insights

  • Lactobacillus sporogenes→Improved Cognitive Function

    IF positively affected cognitive function and reduced amyloid-β (Aβ) accumulation... IPA supplementation and IPA-producing <i>Clostridium sporogenes</i> reproduced IF's cognitive benefits

    Effect
    Beneficial
    Effect size
    Large
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