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

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

Supplement	Dose	Health Outcome	Effect Type	Effect Size	Source
Lactobacillus sporogenes	—	Improved Cognitive Function	Beneficial	Large	View source 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