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.

Asthma is a heterogeneous syndrome featuring variable pathophysiology, clinical presentation and treatment response. This review examines a comprehensive endotype-phenotype framework for asthma assessment with an emphasis on characteristics beyond T2 inflammatory status alone. Endo-phenotype assessment can be performed across three domains: clinical (symptoms, exacerbations, co-morbidities), structural and physiological, and inflammatory endotype. The clinical domain includes mucus hypersecretion, perception of airway narrowing, and obesity-related asthma. Airway remodelling is the central, structural endo-phenotype that defines asthma, given its relationship with fixed airflow limitation, airway hyperresponsiveness, small airway dysfunction, lung function decline, and asthma severity. However, it is the most difficult parameter to measure, and it is increasingly recognised that there is a critical need to be able to measure it longitudinally, beyond bronchial biopsy. Finally, T2-high asthma is relatively well characterised with several effective anti-inflammatory therapies available, including a range of biologics. In contrast, T2-low asthma remains a heterogenous and potentially difficult to characterise endo-phenotype, although some treatment studies have demonstrated benefit when subjects have been appropriately characterised and selected. Emerging multi-omic approaches may enhance the detailed characterisation of patients in future. Adopting an endo-phenotype framework allows clinicians and researchers to confront the complexity of asthma, better manage patients with a precision medicine approach and enhance mechanistic understanding, which is critical for new therapeutics to be developed for asthma.