Peer-reviewed article
The Gut-Lung-Joint Axis: A Conceptual Framework for Microbiome-Mediated Crosstalk Between Respiratory and Rheumatic Diseases in Childhood.
Lisa Gazzolari, Laura Di Domenico, Natalie Leone, Saverio La Bella, Paola Di Filippo et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a narrative review of scientific literature on how gut microbiome composition may influence the development of respiratory and rheumatic diseases in children through interconnected biological pathways. The authors examine evidence from 37 studies published between 2020 and 2026, focusing on the gut-lung axis and gut-joint axis separately, and propose a new integrated conceptual model called the gut-lung-joint axis. The review discusses how early-life factors such as delivery method, breastfeeding, infections, and antibiotic exposure shape the developing microbiome and immune system. While the review notes an epidemiological association between asthma and juvenile idiopathic arthritis in children, it acknowledges that current evidence shows non-specific findings and does not establish causal mechanisms.
Key points
- Early alterations in gut microbial composition may influence susceptibility to respiratory and rheumatic diseases in childhood
- Common findings across studies include dysbiosis, impaired epithelial barrier integrity, altered microbial metabolite production, and immune dysregulation
- Epidemiological evidence shows children with asthma have approximately twofold higher odds of juvenile idiopathic arthritis (OR 2.10, 95% CI 1.56-2.81)
- Early-life factors including delivery mode, breastfeeding, infections, antibiotic exposure, and environment influence immune development and microbiome composition
- Current evidence does not establish microbiome-mediated causality; the gut-lung-joint axis is proposed as a hypothesis-generating conceptual model requiring further research
Limitations
This is a narrative literature review that synthesises existing evidence without conducting new research or testing mechanisms. The review does not establish causal links between microbiome changes and disease outcomes, and the proposed gut-lung-joint axis model remains largely untested with no clinical validation provided.
Abstract
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.