The Gut-Lung-Joint Axis: A Conceptual Framework for Microbiome-Mediated Crosstalk Between Respiratory and Rheumatic Diseases in Childhood.
- 1Department of Paediatrics, University of Chieti-Pescara, 66100 Chieti, Italy.
- 2School of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy.
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.
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BibTeX
@article{gazzolari2026gutlungjoint,
title = {{The Gut-Lung-Joint Axis: A Conceptual Framework for Microbiome-Mediated Crosstalk Between Respiratory and Rheumatic Diseases in Childhood.}},
author = {Lisa Gazzolari and Laura Di Domenico and Natalie Leone and Saverio La Bella and Paola Di Filippo and Dorina Hoxha and Sabrina Di Pillo and Francesco Chiarelli and Luciana Breda and Daniele Russo and Marina Attanasi},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198692},
url = {https://europepmc.org/article/MED/42883935},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Gut-Lung-Joint Axis: A Conceptual Framework for Microbiome-Mediated Crosstalk Between Respiratory and Rheumatic Diseases in Childhood.
AU - Lisa Gazzolari
AU - Laura Di Domenico
AU - Natalie Leone
AU - Saverio La Bella
AU - Paola Di Filippo
AU - Dorina Hoxha
AU - Sabrina Di Pillo
AU - Francesco Chiarelli
AU - Luciana Breda
AU - Daniele Russo
AU - Marina Attanasi
PY - 2026
DA - 2026/09/29
JO - International journal of molecular sciences
DO - 10.3390/ijms27198692
UR - https://europepmc.org/article/MED/42883935
AB - 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.
SN - 1422-0067
ER -