Gut Microbiota-Driven Metabolic Alterations Reveal the Gut-Brain Communication of Ergothioneine in Ameliorating Cognitive Impairment in APP/PS1 Mice

The pathogenesis of Alzheimer’s disease (AD) is complex, and there are currently no effective therapeutic drugs available. Growing evidence suggested that dietary factors may play a vital role in the prevention and mitigation of AD. In this study, we investigated the effects of ergothioneine (ET), administered through drinking water for 6 months, on cognitive impairment in APPswe/PS 1dE9 (APP/PS1) mice. Treatment with ET (40 mg/kg) significantly enhanced cognitive function, reduced neuronal damage, decreased Aβ accumulation, suppressed microglial overactivation, and lowered TNF-α expression in the mouse brain. Moreover, ET treatment partially restored neurotransmitter and chemokine homeostasis in the brain. Notably, ET administration reshaped the gut microbiota of APP/PS1 mice, including increased abundance of Alistipes, Clostridiales_unclassified, and Peptococcaceae_unclassified . ET also enhanced the formation of butyric acid, isobutyric acid, and valeric acid. Serum metabolomic analysis revealed distinct metabolic profiles of APP/PS1 from wild-type (WT) mice, with sphingolipids and glycerophospholipids identified as the most enriched pathways influenced by ET treatment. Correlation analysis elucidated the alterations in gut microbiota networks, contributions of the gut microbiota to short-chain fatty acids and serum metabolic profiles, and mediatory roles of metabolites between the gut microbiota and AD. Altogether, this study elucidated the protective effects of ET on the gut-brain axis in AD, underscoring its potential as an early dietary intervention to improve memory function and alleviate AD symptoms. These findings provide a foundational and theoretical basis for the development of ET-based dietary strategies for AD prevention.