The Gut-Lung-Joint Axis: A Conceptual Framework for Microbiome-Mediated Crosstalk Between Respiratory and Rheumatic...

There is growing interest in the role of the gut microbiome in immune development and homeostasis during childhood. Increasing evidence suggests that early alterations in microbial composition might influence susceptibility to both respiratory and rheumatic diseases through interconnected pathways. While the gut-lung and gut-joint axes have been investigated separately, their integration into a biologically specific and testable model remains largely unexplored. In this narrative review, the literature was searched in PubMed/MEDLINE and Scopus for evidence syntheses published from 2020 to 2026; 37 eligible evidence syntheses were included, comprising 26 addressing the gut-lung/respiratory domain and 11 addressing the gut-joint/rheumatic domain. We examine current knowledge of microbiome-mediated interactions linking the gut, lungs, and joints in childhood. We discuss the development of the paediatric microbiome and the influence of early-life factors, including mode of delivery, breastfeeding, infections, antibiotic exposure, and environmental determinants, on immune programming. We then summarise evidence supporting the gut-lung axis in paediatric respiratory diseases and the gut-joint axis in juvenile idiopathic arthritis (JIA), highlighting recurrent but non-specific findings such as dysbiosis, impaired epithelial barrier integrity, altered microbial metabolite production, and immune dysregulation. Recent paediatric epidemiological evidence also showed that JIA was more prevalent among children with asthma than among those without asthma (0.81% vs. 0.23%), with asthma associated with approximately twofold higher odds of JIA after propensity-score weighting (OR 2.10, 95% CI 1.56-2.81), although this association does not establish microbiome-mediated causality. We finally critically examine whether more specific mechanisms, including gut-primed immune-cell trafficking, antigen-specific amplification, and metabolite-receptor convergence, could provide testable links between pulmonary and articular inflammation. On this basis, we propose the gut-lung-joint axis as a conceptual, hypothesis-generating model. Future research integrating microbiome profiling, immune-cell clonality, immunophenotyping, and metabolomics will be required to test its predictions and clarify its clinical relevance.