Background. Alzheimer’s disease places a heavy economic burden to healthcare systems around the world. However, the effective treatments are still lacking. Traditional Chinese medicines (TCM) of Schisandra chinensis and Acorus tatarinowii Schott have the pharmacological effects of sedation and neuroprotection and have been clinically proven to be effective in the treatment of AD. However, their main anti‐Alzheimer’s compounds and functional mechanisms remain unclear. Purpose. To elucidate the main therapeutic components and possible mechanisms of Sc‐At in AD using a comprehensive strategy combining metabolomics and network pharmacology. Methods. First, the UPLC‐QTOF/MS method was used to identify the main chemical constituents of Schisandra chinensis and Acorus tatarinowii Schott alcohol extracts in vitro and in vivo. Secondly, the theoretical active ingredients, targets, and pathways of Sc‐At for AD treatment were predicted by network pharmacology methods. Finally, plasma metabolomics were detected by UPLC‐QTOF/MS to analyze the differential metabolites and metabolic pathways related to Sc‐At. Based on the analyses above, the anti‐AD mechanism of Sc‐At was explored. Results. A total of 95 chemical components were identified in Sc‐At extracts in vitro, and 34 prototype drug components were detected in rat plasma; network pharmacology screening identified 14 drug components in line with the principle of Lipinski, of which 10 were present for in vitro drug composition analysis. For these 10 components, 58 AD disease targets were predicted, and 85 AD‐related KEGG signaling pathways were enriched. Six core biomarkers of Sc‐At (cis‐8,11,14,17‐eicosatetraenoic acid, prostaglandin H2, sphingosine 1‐phosphate, enol‐phenylpyruvate, 3‐methoxytyrosine, and pristanoyl‐CoA) were regulated to a normal state during the treatment of AD. Conclusion. The mechanism of Sc‐At for the treatment of AD can be achieved by the effect of the 10 compounds of Sc‐At on TNF, MAPK8, MAPK14, PTGS1, and other targets, thereby affecting arachidonic acid metabolism, neurotransmitters, and sphingolipid metabolism.

Schisandrin is one of the main active compounds isolated from the fruit of Schisandrae chinensis Fructus, which is scientifically proven to have beneficial effects on Alzheimer’s disease (AD) treatment at the cellular and whole organism level. However, the oral availability of schisandrin is very low, thus implying that the underlying mechanism of therapeutic effect on AD treatment is yet to be clarified fully. Therefore, we speculated that the therapeutic effect of schisandrin on AD is mainly by regulating the imbalance of the gut microbiota (GM). In this study, behavioral experiments and H&E staining were used to confirm the pharmacological effects of schisandrin on rats with AD. 16S rDNA gene sequencing and feces, plasma, and brain metabolomics techniques were utilized to investigate the therapeutic effects and the underlying mechanisms of schisandrin on cognitive impairment in rats with AD. The results indicated that schisandrin improved cognitive impairment and hippocampal cell loss in rats. The UPLC-QTOF/MS-based metabolomics studies of the feces, plasma, and brain revealed that 44, 96, and 40 potential biomarkers, respectively, were involved in the treatment mechanism of schisandrin. Schisandrin improved the metabolic imbalance in rats with AD, and the metabolic changes mainly affected the primary bile acid biosynthesis, sphingolipid metabolism, glycerophospholipid metabolism, and unsaturated fatty acid biosynthesis. Schisandrin can improve the GM structure disorder and increase the abundance of beneficial bacteria in the gut of rats with AD. The predictive metagenomics analysis indicated that the altered GM was mainly involved in lipid metabolism, steroid hormone biosynthesis, arachidonic acid metabolism, biosynthesis of unsaturated fatty acids, and bacterial invasion of epithelial cells. Spearman’s correlation analysis showed a significant correlation between affected bacteria and metabolites in various metabolic pathways. Overall, the data underline that schisandrin improves the cognitive impairment in rats with AD by affecting the composition of the GM community, thus suggesting the potential therapeutic effect of schisandrin on the brain–gut axis in rats with AD at the metabolic level.