Abstract: This study systematically investigated the alleviating effect and underlying mechanism of Boletus edulis extract on dextran sodium sulfate-induced enterocolitis in mice. An integrated approach combining ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), multi-omics analysis, molecular docking, and network pharmacology was employed. The results showed that the active components of B. edulis extract and their potential targets were identified by UPLC-MS/MS and comprehensive analysis of multi-omics database. The targets of these active ingredients were predicted by network pharmacology and screened for potential targets of B. edulis against inflammatory bowel disease. By constructing compound-target interaction networks and protein-protein interaction networks, key target genes such as AKT1 and TNF were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that the active components of B. edulis exerted anti-inflammatory effects by affecting several inflammation-related signaling pathways including the nuclear factor-kappa B (NF-κB) signaling pathway. Molecular docking studies further confirmed the interaction of the active ingredients in B. edulis with inflammation-related molecules and revealed that the anti-inflammatory effect of emeheterone (3,6-dibenzyl-5-methoxy-4-oxido-1H-pyrazin-4-ium-2-one) in B. edulis was particularly significant in inflammatory bowel disease. In addition, histological analysis with periodic acid-Schiff staining confirmed that B. edulis significantly restored intestinal mucin expression in dextran sodium sulfate-induced mice, and blood metabolomics analysis revealed that B. edulis ameliorated systemic metabolic disorders induced by dextran sodium sulfate by improving tryptophan and tyrosine metabolism. In summary, B. edulis may repair the intestinal mucosal barrier by inhibiting the nuclear factor-κB signaling pathway, effectively ameliorate dextran sodium sulfate-induced metabolic disorders in mice and restore metabolic homeostasis by regulating tryptophan and tyrosine metabolism. Overall, B. edulis can be used as a natural multi-targeted intervention strategy for intestinal inflammation with potential applications in the prevention and treatment of inflammatory bowel disease, providing a theoretical basis for the development of novel intestinal health intervention programs.

Key words: Boletus edulis extract; inflammatory bowel disease; nuclear factor-κB signaling pathway; metabolomics