The identification of metabolites from gut microbiota in autism spectrum disorder via network pharmacology.

Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting 1% of the global population, is increasingly associated with dysregulation of the microbiota-gut-brain axis. While genetic and environmental factors have been well-studied, the role of gut microbial metabolites in the pathogenesis of ASD remains underexplored. In this study, we integrated network pharmacology, molecular docking, and multi-database analysis to elucidate the molecular mechanisms by which gut microbiota-derived metabolites regulate ASD. Utilizing the gutMGene, GeneCards, and OMIM databases, we identified 51 core targets that intersect with ASD-related genes and gut metabolite targets. Validation of four topological algorithms (Degree, EPC, MCC, MNC) identified AKT1 and IL6 as key pivotal genes, as revealed by protein-protein interaction (PPI) network analysis. Functional enrichment highlighted important associations with the PI3K/Akt and IL-17 signaling pathways. The Microbiome-Metabolite-Target-Signaling (MMTS) network linked eight key metabolites (e.g., short-chain fatty acids, indole derivatives) to AKT1/IL6 regulation. Drug similarity and toxicity assessments confirmed the safety of short-chain fatty acids (acetate, butyrate, propionate) and indole derivatives of the selected metabolites. Molecular docking revealed a strong binding affinity between glycerylcholic acid (AKT1: - 10.2 kcal/mol) and 3-indolepropionic acid (IL6: - 4.9 kcal/mol), suggesting that they are closely related to ASD. This study provides a new research direction on the relationship between microbial metabolites and ASD and gives better help to future researchers.