Early-life gut microbiota and the pediatric gut-lung axis: systematic review of clinical, preclinical, and mechanistic evidence
This systematic review finds consistent associations between early gut dysbiosis and worse pediatric respiratory outcomes, but methodological heterogeneity prevents causal conclusions or definitive clinical recommendations.
| Population | Infants and children aged 0 to 16 years, including preterm neonates |
|---|---|
| Intervention | Early-life gut microbial colonization patterns; perinatal factors (delivery mode, breastfeeding, antibiotics, diet); probiotic, prebiotic, and synbiotic interventions |
| Comparator | Healthy controls, alternative microbial profiles, or no intervention |
| Outcome | Asthma and wheezing; Bronchiolitis; Bronchopulmonary dysplasia; Respiratory infections; Probiotic/prebiotic effect on respiratory outcomes; SCFA modulation of pulmonary regulatory T cells; Allergic sensitization and asthma phenotypes |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| Asthma and wheezing | No pooled estimate; consistent observational association between early dysbiosis and increased risk — in the RR/OR/IC available | — | Low | — | |
| Bronchiolitis | No pooled estimate; observational association between reduced Lactobacillus/Bifidobacterium and increased bronchiolitis risk — in the RR/OR/IC available | — | Low | — | |
| Bronchopulmonary dysplasia | No pooled estimate; aberrant colonization associated with BPD in preterm infants — in the RR/OR/IC available | — | Low | — | |
| Respiratory infections | No pooled estimate; early microbial signatures associated with susceptibility — in the RR/OR/IC available | — | Low | — | |
| Probiotic/prebiotic effect on respiratory outcomes | Mixed results across included RCTs; in the uniform effect direction — in the pooled RR/OR/IC available | — | Low | — | |
| SCFA modulation of pulmonary regulatory T cells | Preclinical animal models only; in the human quantitative estimate available | — | Very low | — | |
| Allergic sensitization and asthma phenotypes | Observational association between specific microbial signatures and allergic sensitization in older children — in the pooled RR/OR/IC available | — | Low | — |
Context
The pediatric gut-lung axis is biologically plausible: gut-derived metabolites, especially SCFAs, modulate pulmonary mucosal immunity during a critical immune developmental window. Early microbiota alterations have been associated with asthma, bronchiolitis, recurrent wheezing, respiratory infections, and bronchopulmonary dysplasia. Methodological fragmentation across clinical, preclinical, and mechanistic studies prevents quantitative synthesis.
What the study showed
The review synthesized primary evidence from clinical (RCTs, cohorts, case-control) and preclinical studies. Early dysbiosis — including reduced Lactobacillus, Bifidobacterium, and fecal butyrate — was consistently associated with increased risk of asthma, wheezing, and bronchiolitis in observational studies, but no pooled effect estimates were available due to heterogeneity in methods, biological samples, and outcomes. Probiotic interventions showed mixed results across included RCTs, with no uniform effect on clinically relevant respiratory outcomes. Mechanistic evidence from animal models supports the role of SCFAs in modulating pulmonary regulatory T cells, but clinical translation remains undemonstrated.
How it was done
Systematic review conducted per PRISMA 2020, registered in PROSPERO (CRD420251062905). Search covered PubMed, Web of Science, and Scopus, January 2014 to March 2025. Included primary clinical studies (RCTs, cohorts, case-control, longitudinal) and preclinical studies with translational relevance; secondary reviews were used only for mechanistic context, not for evidence synthesis. The exact number of included primary studies and aggregate sample size were not specified in the provided text.
Effect magnitude
No meta-analysis was performed; individual effect sizes were not reported in aggregate. The review provides no consolidated 95% CIs or pooled effect estimates for any outcome.
Risk of bias
Substantial heterogeneity in sequencing methodologies, biological samples, outcome definitions, and populations prevents quantitative synthesis. Risk of bias was not assessed with an explicitly stated standardized tool (RoB 2, ROBINS-I, or equivalent) for individual studies in the available text. Restriction to English-language publications after 2014 introduces publication and language bias. Preclinical studies dominate mechanistic evidence, limiting direct causal inference in humans.
What this study does NOT prove
This review does not prove causality between early-life gut microbiota and pediatric respiratory disease. It does not support the efficacy of any specific microbiota-targeted intervention for respiratory outcomes in children.
In clinical practice
Current evidence does NOT support routine recommendation of probiotics, prebiotics, or synbiotics for prevention of pediatric respiratory disease based on this review. Clinicians should interpret associations between early microbiota and respiratory outcomes as hypothesis-generating, not as established causal relationships. Breastfeeding and judicious antibiotic use remain recommended by other guidelines, but their mechanisms via the gut-lung axis are not causally proven.
Limitations
Substantial heterogeneity in sequencing methodologies, biological samples, outcome definitions, and populations prevents quantitative synthesis. Risk of bias was not assessed with an explicitly stated standardized tool (RoB 2, ROBINS-I, or equivalent) for individual studies in the available text. Restriction to English-language publications after 2014 introduces publication and language bias. Preclinical studies dominate mechanistic evidence, limiting direct causal inference in humans.
What is still missing
Well-designed RCTs with clinically relevant respiratory endpoints, standardized microbiome methodologies, and long-term longitudinal studies are required to establish causality and guide interventions.
Technical appendix
Version history
- 1.0 · 2026-10-18 — Auto-generated under Evidence Standard v1.0