Integrative Network Pharmacology Analysis of Gut Microbial Metabolite-Mediated Gut-Eye Axis Regulation in Major Blinding Retinal Diseases.

Objective: To systematically investigate the shared and disease-specific mechanisms by which gut microbial metabolites may regulate age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion (RVO) through a network pharmacology framework. Design: Bioinformatics-based network pharmacology study. Subjects: Publicly available gut microbial metabolite, metabolite-target, and disease-associated gene data sets related to AMD, DR, and RVO were analyzed. Methods: Gut microbial metabolites were retrieved from gutMGene, and potential human targets were predicted using the Similarity Ensemble Approach and SwissTargetPrediction. Disease-associated genes were collected from GeneCards, Online Mendelian Inheritance in Man, and the Comparative Toxicogenomics Database. Intersection genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Protein-protein interaction networks were constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and candidate hub targets were prioritized in Cytoscape. Drug-likeness and toxicity profiles of key metabolites were evaluated using SwissADME and ADMETlab 3.0. An integrated microbiota-substrate-metabolite-target (M-S-M-T) network was constructed to characterize gut-eye axis regulation. Main Outcome Measures: Intersection genes, enriched biological functions and pathways, high-centrality candidate hub targets, predicted drug-likeness and toxicity profiles of metabolites, and M-S-M-T regulatory relationships. Results: A total of 226 gut microbial metabolites and 1518 predicted host targets were identified. Intersection analysis revealed 47, 44, and 40 metabolite-related genes associated with AMD, DR, and RVO, respectively, including 38 genes shared across all 3 diseases. Enrichment analyses showed convergent involvement of microbial signal sensing, inflammatory regulation, oxidative stress, apoptosis, and vascular homeostasis. Nuclear factor kappa B, mitogen-activated protein kinase, phosphatidylinositol 3-kinase-protein kinase B, tumor necrosis factor, VEGF, Toll-like receptor, and nucleotide-binding oligomerization domain-like receptor pathways formed a shared inflammatory-oxidative-vascular signaling module. Protein-protein interaction analysis identified interleukin 6, tumor necrosis factor, protein kinase B alpha, and tumor protein p53 as recurrent high-centrality candidate hub targets. Key metabolites, including indole-3-propionic acid, tryptamine, phenylalanine, and indole-3-lactic acid, showed favorable predicted drug-likeness and safety profiles. Conclusions: Gut microbial metabolites may contribute to AMD, DR, and RVO through shared inflammatory, oxidative stress, and vascular signaling networks. These findings provide a systems-level framework for gut-eye axis regulation and support further experimental validation of microbiota-based systemic intervention strategies. Financial Disclosures: The author has no/the authors have no proprietary or commercial interest in any materials discussed in this article.