Science advancesNov 30, 2025

Gut bacteria product indole-3-propionate may improve thinking skills in Alzheimer's disease

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Intermittent fasting appeared to improve Alzheimer's-like cognition through the gut-derived metabolite indole-3-propionic acid and neuronal PXR signaling.

Evidence

This mixed mouse and human-data study tested intermittent fasting, IPA supplementation, IPA-producing bacteria, and PXR blockade in AD transgenic mice, with parallel IPA measurements in people with mild cognitive impairment, AD, and controls.

Caveat

The mechanistic evidence is mainly preclinical, and the human data show lower IPA levels rather than testing IPA or fasting as a treatment.

Simplified

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-producingreproduced 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. Clostridium sporogenes