Abstract
The role of gut microbiota and their metabolites in respiratory diseases via the "gut-lung axis" has garnered increasing attention, yet their specific mechanisms in bronchiectasis (BIS) remain unclear. This study integrates network pharmacology with bioinformatics approaches, including Mendelian randomization (MR) and molecular dynamics (MD), to systematically investigate the mechanisms of gut microbiota metabolites in BIS pathogenesis and explore potential therapeutic interventions. Intersection targets between gut microbiota metabolites and BIS were screened using network pharmacology. A protein-protein interaction (PPI) network was constructed, and MR combined with MD simulations were employed to validate interactions between core targets and metabolites. A total of 40 metabolite-disease intersection targets were identified, with 17 core genes prioritized. MR analysis revealed a significant protective effect of the peroxisome proliferator-activated receptor gamma (PPARG) gene against BIS (IVW method: β = -0.141, OR = 0.868, P = .030). Molecular docking confirmed strong binding affinity of butyrate and 10-keto-12Z-octadecenoic acid to PPARG (affinity: -3.731 and -5.666 kcal/mol, respectively). Drug-likeness and toxicological analyses indicated both compounds possess therapeutic potential, with 10-keto-12Z-octadecenoic acid demonstrating superior properties. MD simulations further validated the stability of metabolite-PPARG complexes. Gut microbiota metabolites mediate protective mechanisms in BIS pathogenesis through PPARG, and 10-keto-12Z-octadecenoic acid emerges as a novel lead compound for treatment. This study provides a theoretical foundation for precision therapy targeting the gut-lung axis.