Zhang Fushen, Xu Weiye, Tang Qian, Huang Jufang
Department of Anatomy and Neurobiology, Xiangya School of Basic Medical Sciences, Central South University, Changsha, China.
Key Laboratory of Oral Health Research, Xiangya School of Stomatology, Central South University, Changsha, China.
Sci Rep. 2025 Aug 28;15(1):31765. doi: 10.1038/s41598-025-15921-w.
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.
自闭症谱系障碍（ASD）是一种影响全球1%人口的神经发育障碍，越来越多地与微生物群-肠道-脑轴的失调相关。虽然遗传和环境因素已得到充分研究，但肠道微生物代谢产物在ASD发病机制中的作用仍未得到充分探索。在本研究中，我们整合了网络药理学、分子对接和多数据库分析，以阐明肠道微生物衍生代谢产物调节ASD的分子机制。利用gutMGene、GeneCards和OMIM数据库，我们确定了51个与ASD相关基因和肠道代谢产物靶点相交的核心靶点。四种拓扑算法（度、EPC、MCC、MNC）的验证确定AKT1和IL6为关键枢纽基因，蛋白质-蛋白质相互作用（PPI）网络分析表明了这一点。功能富集突出了与PI3K/Akt和IL-17信号通路的重要关联。微生物群-代谢产物-靶点-信号（MMTS）网络将八种关键代谢产物（如短链脂肪酸、吲哚衍生物）与AKT1/IL6调节联系起来。药物相似性和毒性评估证实了所选代谢产物的短链脂肪酸（乙酸盐、丁酸盐、丙酸盐）和吲哚衍生物的安全性。分子对接显示甘油胆酸（AKT1：-10.2 kcal/mol）和3-吲哚丙酸（IL6：-4.9 kcal/mol）之间具有很强的结合亲和力，表明它们与ASD密切相关。本研究为微生物代谢产物与ASD之间的关系提供了新的研究方向，并为未来的研究人员提供了更好的帮助。
