Revealing the impact of gut microbiota-derived metabolites on depression through network pharmacology

A total of 208 metabolites and 223 targets were initially extracted from the gutMGene v1.0 database. In addition, 1,630 and 1,321 targets were identified using the Similarity Ensemble Approach and Swiss Target Prediction databases, respectively, resulting in 921 overlapping targets. By integrating data from gutMGenev1.0, 13 core targets were finally identified. A microbiota-metabolite-target-signal pathway-disease network was constructed using Cytoscape 3.9.1, revealing 15 metabolites associated with the IL-17, TLR, and PI3K-Akt signalling pathways. Among these, five metabolites exhibited favourable drug similarity and acceptable toxicological profiles. Molecular docking confirmed the stable binding of two key metabolites-succinate and phenylacetylglutamine-to their respective targets. The results showed that succinate and phenylacetylglutamine demonstrated strong binding affinities to IL-1β and GSK3B, both involved in the IL-17, TLR, and PI3K-Akt signalling pathways. IL-17 and TLR4, as important pro-inflammatory cytokines, are closely associated with the development of depression, while the PI3K/AKT signalling pathway plays a key role in its pathogenesis. The present study reveals the potential mechanisms by which gut microbiota influence MDD and provides a scientific basis and a comprehensive research framework for future investigations.