Study of gut microbiota metabolites on combating pediatric solid tumor via bioinformatics, network pharmacology, molecular docking and survival analysis

Abstract Background This study aims to investigate the role of gut microbiota metabolites in treatment of pediatric solid tumors (PSTs) treatment. Methods PST expression data were obtained from the TARGET database, with normal reference samples from GTEx. Gut microbiota metabolite-associated targets and cyclophosphamide-associated targets were retrieved from gutMGene and CTD, respectively. Differential expression, functional enrichment, protein-protein interaction, and network analyses were used to prioritize candidate genes and pathways. Tumor-type-stratified differential expression analyses were performed to assess the consistency of IL6 and TNF expression patterns across individual PST types, and molecular docking was used to estimate metabolite-target binding affinity. Kaplan-Meier analysis was used to examine associations between gene expression and survival. Results Interleukin-6 (IL6) and tumor necrosis factor (TNF) were identified as the core targets. Lipid and atherosclerosis, pathogenic Escherichia coli infection, rheumatoid arthritis, Chagas disease, and the Toll-like receptor signaling pathway were identified as key pathways involved in the progression of PST. Butyrate, 3-indolepropionic acid, acetate, trimethylamine oxide, succinate, and propionate were determined as critical metabolites in combating PST. 3‑indolepropionic acid showed computationally‑predicted favorable binding affinity with IL6 and TNF. PST patients with high expression of IL6 and TNF showed associations with poorer survival outcomes within this retrospective cohort. Stratified analyses showed a consistent direction of IL6 down-regulation across the three tumor types, whereas TNF expression varied by tumor type. Conclusion Our computational analyses suggest that the gut microbiota‑derived metabolite 3‑indolepropionic acid may interact with IL6 and TNF with favorable predicted binding affinity, generating a testable hypothesis for its potential role in PSTs that requires further experimental validation.