Early-Life Gut Microbiota and the Pediatric Gut–Lung Axis: A Systematic Review of Clinical, Preclinical, and Mechanistic Evidence

Background/Objectives: The early-life gut microbiota plays a pivotal role in immune maturation and may influence respiratory health through the gut–lung axis. However, evidence linking microbial development, dysbiosis, microbial metabolites, and microbiota-targeted interventions to pediatric respiratory outcomes remains heterogeneous. This systematic review aimed to synthesize clinical and preclinical evidence on the pediatric gut–lung axis and its underlying mechanisms. Methods: This systematic review followed PRISMA 2020 guidelines and a prospectively registered PROSPERO protocol (CRD420251062905). PubMed, Scopus, and Web of Science were searched for studies published from January 2014 to March 2025. Eligible primary studies included randomized controlled trials, observational studies, and mechanistically relevant animal models. Risk of bias was assessed using RoB 2, the Newcastle–Ottawa Scale, and SYRCLE’s tool, respectively. Reviews were examined separately to provide mechanistic and translational context without contributing to the primary evidence synthesis. Results: Twenty-five primary studies (11 clinical and 14 preclinical) were included in the systematic evidence synthesis, while 54 reviews provided complementary contextual evidence. Early gut and airway microbial communities showed substantial overlap after birth followed by progressive niche-specific divergence. Early-life dysbiosis, including depletion of beneficial taxa and expansion of potentially pathogenic bacteria, was associated with asthma, recurrent wheezing, respiratory infections, and neonatal lung injury. Short-chain fatty acids emerged as key mediators of gut–lung immune signaling. Clinical trials suggested potential respiratory and immunological benefits of probiotic and synbiotic interventions, while preclinical models supported mechanistic links involving intestinal barrier dysfunction, microbial metabolites, and inflammatory pathways. Conclusions: Current evidence supports a biologically plausible and clinically relevant pediatric gut–lung axis. However, methodological heterogeneity and the limited availability of longitudinal clinical studies warrant cautious interpretation and further well-designed research before microbiota-targeted strategies can be routinely translated into pediatric respiratory care.