Microbiome-derived indole-3-lactic acid reduces amyloidopathy through aryl-hydrocarbon receptor activation

Area of Science:

• Neuroscience
• Microbiology
• Metabolomics

Background:

• Alzheimer's disease (AD) pathogenesis is linked to the gut microbiome, but mechanisms remain unclear.
• Amyloid-beta (Aβ) accumulation is a hallmark of AD.
• Identifying microbial metabolites that mitigate AD pathology is crucial.

Purpose of the Study:

• To identify specific gut microbial strains and metabolites that reduce amyloidopathy in a mouse model of AD.
• To elucidate the mechanisms by which these metabolites exert their effects.
• To explore the clinical relevance of these findings in human subjects.

Main Methods:

• Multi-omics approach (microbiome and metabolomics) in 5xFAD mice.
• Administration of microbial metabolites (tryptophan and indole-3-lactic acid - ILA).
• In vivo (mouse models) and in vitro experiments, including AhR inhibitor studies.
• Analysis of human clinical and post-mortem brain data.

Main Results:

• Three microbial strains reduced soluble Aβ levels in 5xFAD mice.
• Tryptophan (Trp) and ILA were enriched in mice with reduced Aβ.
• Combined Trp and ILA treatment prevented Aβ accumulation and cognitive decline.
• ILA reduced Aβ by activating microglia/astrocytes via the aryl hydrocarbon receptor (AhR) pathway.
• Lactobacillus reuteri was more abundant in healthy individuals.
• AhR pathway gene expression was higher in non-AD brains.

Conclusions:

• Indole-3-lactic acid (ILA), derived from gut microbes, can inhibit amyloidopathy progression in AD models.
• ILA acts through the aryl hydrocarbon receptor (AhR) signaling pathway in the brain.
• Gut microbiome metabolites represent a potential therapeutic strategy for Alzheimer's disease.