Anti-Alzheimers molecular mechanism of icariin: Insights from gut microbiota and metabolome combined network pharmacology

Abstract Background Icariin (ICA), an active ingredient extracted from a natural plant called Epimedii, has shown a broad application prospect in the treatment of Alzheimer's disease (AD). Nevertheless, its potential therapeutic mechanism remains largely unknown.The present study aims to investigate the therapeutic effect and the underlying mechanism of ICA on AD by an integrated analysis of gut microbiota and metabolomics. Methods The cognitive impairment of mice was measured using the Morris Water Maze. Hematoxylin and eosin staining was used to identify the AD-induced pathologic change. 16S rRNA sequencing and multi-metabolomics were performed to analyze the alterations in microbiota and serum/fecal metabolism. Results Our results demonstrated that ICA intervention could markedly improve cognitive dysfunction in APP/PS1 mice and typical AD pathologies in the hippocampus of APP/PS1 mice. Gut microbiota analysis showed that ICA administration could reverse the imbalance of gut microbes in APP/PS1 mice by elevating the proportion of Akkermansia and reducing the proportion of Alistipe . Metabolomic analysis revealed AD-induced metabolic disorder was improved by ICA via glycerophospholipid metabolism and sphingolipid metabolism. Correlation analysis suggested that these were closely related to the abundance of Alistipe and Akkermansia . Conclusion These findings indicated that ICA may serve as a promising therapeutic approach for AD, and that the ICA-mediated protective effects were associated with the amelioration of microbiota disturbance and metabolic disorder.