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

• We identified three probiotic strains that significantly reduce amyloid-beta (Aβ) and prevent cognitive impairment in 5xFAD mice. • Lactobacillus reuteri is more abundant in healty human stool samples compared to those with mild cognitive impairment, suggesting its potential role in AD prevention. • Indole-3-lactic acid (ILA), a common major metabolite, and its precursor tryptophan improve cognitive function in 5xFAD mice. • ILA activates the AhR signaling pathway in microglia and astrocytes, promoting Aβ clearance. • AhR agonists or gut microbiome modulation to enhance AhR agonist production may offer new strategies for AD prevention and therapy. Alzheimer's disease (AD) pathogenesis has been associated with the gut microbiome and its metabolites, though the specific mechanisms have remained unclear. In our study, we used a multi-omics approach to identify specific microbial strains and metabolites that could potentially mitigate amyloidopathy in 5xFAD mice, a widely used model for AD research. Among the microbial strains tested, three showed promising results in reducing soluble amyloid-beta (Aβ) levels. Plasma metabolomics analysis revealed an enrichment of tryptophan (Trp) and indole-3-lactic acid (ILA) in mice with reduced soluble Aβ levels, suggesting a potential preventative role. The administration of a combined treatment of Trp and ILA prevented both Aβ accumulation and cognitive impairment in the 5xFAD mice. Our investigation into the mechanism revealed that ILA's effect on reducing Aβ levels was mediated through the activation of microglia and astrocytes, facilitated by the aryl hydrocarbon receptor (AhR) signaling pathway. These mechanisms were verified through experiments in 5xFAD mice that included an additional group with the administration of ILA alone, as well as in vitro experiments using an AhR inhibitor. Clinical data analysis revealed a greater abundance of Lactobacillus reuteri in the gut of healthy individuals compared to those at early stages of Aβ accumulation or with mild cognitive impairment. Additionally, human post-mortem brain analyses showed an increased expression of genes associated with the AhR signaling pathway in individuals without AD, suggesting a protective effect against AD progression. Our results indicate that ILA from gut microbes could inhibit the progression of amyloidopathy in 5xFAD mice through activation of AhR signaling in the brain. [ABSTRACT FROM AUTHOR]