The Microbiome-Gut-Lung axis in Respiratory Diseases: From Biological Mechanisms to Clinical Translation.

Respiratory diseases exhibit substantial heterogeneity in clinical phenotypes and underlying pathobiology that cannot be fully captured by conventional lung-centred frameworks. Accumulating evidence implicates a role for the microbiome-gut-lung axis in respiratory disease pathogenesis. Within this bidirectional axis, gut-derived microbial metabolites and structural components can modulate pulmonary immunity, whereas respiratory infection and exposures can reciprocally influence the gut microbiota. Dysregulation of the microbiome-gut-lung axis may influence respiratory disease susceptibility, progression, and clinical presentation. In this Review, we outline core mechanisms of gut-lung crosstalk, including metabolite-driven immunomodulation, pattern recognition receptor signalling and reciprocal immune-ecological remodelling. We synthesize phenotype-specific evidence linking the axis to major chronic inflammatory airway diseases (asthma, chronic obstructive pulmonary disease, cystic fibrosis and bronchiectasis) and acute respiratory disorders (pneumonia and sepsis-associated acute respiratory distress syndrome), emphasizing mechanistic and clinical evidence. We discuss the translational promise of gut-lung signatures as biomarkers and treatable traits and review current therapies with microbiome effects and emerging microbiome-targeted interventions. Finally, we address key challenges and propose future research priorities to advance clinical management leveraging the gut-lung axis.