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

Area of Science:

• Neuroscience
• Microbiology
• Metabolomics

Background:

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder.
• Intermittent fasting (IF) shows promise in mitigating AD pathology.
• The gut-brain axis and microbial metabolites are implicated in neurodegeneration.

Purpose of the Study:

• To investigate the mechanisms by which IF impacts AD progression.
• To identify key microbial metabolites involved in IF's neuroprotective effects.
• To explore the therapeutic potential of these metabolites for AD.

Main Methods:

• 16-week study using AD transgenic mice.
• Multiomics integration (genomics, metabolomics, microbiota analysis).
• Pharmacological blockade of neuronal pregnane X receptor (PXR) and microbial metabolite manipulation.
• Assessment of cognitive function, amyloid-beta (Aβ) accumulation, and neuroinflammation.
• Analysis of human patient data (mild cognitive impairment and AD).

Main Results:

• IF improved cognitive function and reduced Aβ accumulation in mice.
• IF modulated hippocampal gene expression, gut microbiota, and serum metabolites.
• Indole-3-propionic acid (IPA) was identified as a crucial metabolite mediating IF's effects.
• Blocking neuronal PXR or IPA synthesis abolished IF's benefits.
• Lower IPA levels were observed in human patients with mild cognitive impairment and AD.
• IPA supplementation and administration of IPA-producing bacteria replicated IF's cognitive benefits.
• IPA demonstrated anti-inflammatory activity and reduced Aβ accumulation in the brain.

Conclusions:

• Intermittent fasting exerts neuroprotective effects against Alzheimer's disease.
• The gut microbial metabolite indole-3-propionic acid (IPA) is a key mediator of IF's benefits.
• Targeting IPA and the gut-brain axis presents a promising therapeutic strategy for AD.