Role of the microbiota-gut-lung axis in the pathogenesis of pulmonary disease in children and novel therapeutic strategies

Abstract

Emerging evidence highlights the microbiota-gut-lung axis (MGLA) as a pivotal regulator of pediatric respiratory health, yet mechanistic insights are lacking and therapeutic applications remain unclear. This review synthesizes cutting-edge findings to delineate how gut microbiota-derived metabolites, particularly short-chain fatty acids (SCFAs), orchestrate pulmonary immunity and disease pathogenesis in children. Leveraging multi-omics integration (metagenomics, metabolomics, transcriptomics), emerging studies have uncovered novel microbe-host interactions driving immune dysregulation in asthma, pneumonia, and cystic fibrosis. A comprehensive map of gut-lung crosstalk has been established across these conditions. Current studies suggest that early-life gut dysbiosis, shaped by delivery mode, antibiotics, and diet, disrupts SCFA-mediated immune homeostasis, amplifying T-helper 2 cell inflammation and impairing alveolar macrophage function. Crucially, we identified disease-specific microbial signatures (e.g., depletion of Lachnospira and Faecalibacterium in asthma) and demonstrated that fecal microbiota transplantation and probiotic interventions restore microbial balance, attenuating airway inflammation in preclinical models. This work pioneers the translation of MGLA insights into precision medicine strategies, highlighting dietary modulation and microbial therapeutics as viable alternatives to conventional treatments. By bridging microbial ecology and immune dynamics, our findings provide actionable biomarkers for early diagnosis and personalized interventions, addressing critical gaps in pediatric respiratory disease management. The integration of multi-omics frameworks not only advances mechanistic understanding but also positions the MGLA as a transformative target in reducing global childhood morbidity. Future research must prioritize longitudinal studies and clinical trials to validate these innovations, ultimately redefining therapeutic paradigms for GLA-driven pathologies.

Keywords: gut–lung axis; microbial metabolites; multi-omics; pediatric respiratory diseases; precision medicine.

Figure 1

Gut microbiota modulates pathophysiological processes in pediatric pulmonary diseases via immune regulatory mechanisms. The gut microbiota orchestrates immune regulatory mechanisms that influence the pathogenesis of childhood pulmonary diseases via microbial metabolites (e.g., SCFAs and LPS) and immune signaling networks, which critically regulate immune system development and disease progression. DCs recognize LPS, leading to upregulated CD80/CD86/HLA-DR expression, enhanced antigen-presenting capacity, and IL-12p70 secretion, thereby driving Th1 polarization to reinforce anti-infective immunity. Gut-derived LPS activates the TLR4/NF-κB pathway, triggering pulmonary inflammation. SCFAs inhibit histone deacetylase activity to promote Treg differentiation and anti-inflammatory IL-10 secretion, while simultaneously activating alveolar macrophages via GPCRs to suppress pro-inflammatory cytokine (TNF-α, IL-6) release. Additionally, trans-tissue migration of CCR2⁺ ILC2s further modulates pediatric pulmonary disease pathogenesis. CCR2+CCR4+ILC2s, C-C chemokine receptor type 2-positive and C-C chemokine receptor type 4-positive type 2 innate lymphoid cells; CCR2+ILC2s, C-C chemokine receptor type 2-positive type 2 innate lymphoid cells; CD80/CD86, cluster of differentiation 80/86; DC, dendritic cell; GPCRs (GPR41/GPR43), G protein-coupled receptors (G protein-coupled receptor 41/G protein-coupled receptor 43); HLA-DR, human leukocyte antigen – DR isotype; IL, interleukin; LPS, lipopolysaccharide; SCFAs, short-chain fatty acids; Th1, T helper 1 cells; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cells.

Figure 2

Distinct features of gut and respiratory microbiota dysbiosis in pediatric pulmonary diseases. The GLA exhibits dynamic microbiota alterations in childhood asthma, pneumonia, CF, and OSAS. Children with asthma have reduced gut abundance of immunomodulatory taxa (e.g., Lachnospira, Faecalibacterium, Rothia) alongside expansion of pro-inflammatory genera (e.g., Enterococcus). Patients with pneumonia display diminished intestinal Bifidobacterium and Lactobacillus abundance with concurrent enrichment of Escherichia coli. In CF, the gut microbiota is characterized by substantial enrichment of opportunistic pathogens (e.g., Burkholderia cepacia complex, Pseudomonas aeruginosa) and depletion of beneficial species (e.g., Bacteroides, Faecalibacterium prausnitzii). OSAS is associated with reduced levels of SCFA-producing bacteria (e.g., Clostridia, Ruminococcus), which exacerbates systemic inflammation via the metabolic–immune axis. GLA, gut–lung axis; CF, cystic fibrosis; OSAS, obstructive sleep apnea syndrome; SCFAs, short-chain fatty acids.

Figure 3

Gut dysbiosis drives disease-specific mechanisms in pediatric pulmonary disorders via metabolic and signaling pathways. The GLA orchestrates disease-specific mechanisms underlying childhood asthma, pneumonia, bronchitis, CF, and OSAS. In children with asthma, perinatal microbiota alterations with reduced alpha diversity are modulated by maternal breastfeeding-associated metabolites. In pneumonia, gut dysbiosis reduces acetate levels, impairing the GPR43-mediated phagocytic function of alveolar macrophages, and deaminotyrosine deficiency compromises IFN-I-dependent anti-influenza immunity. Bronchitis is linked to diminished gut-derived acetate, leading to pulmonary IFN-β reduction whereas prenatal supplementation with Lactobacillus jensenii lowers disease incidence. In CF, Bacteroides-derived propionate deficiency disrupts GPR41 signaling, causing neutrophil phagocytic dysfunction, and Clostridioides difficile depletion exacerbates inflammation via dysregulated bile acid metabolism (FXR/TGR5 axis). Reduced SCFA-producing bacteria contribute to OSAS pathogenesis, which is alleviated by C. butyricum and prebiotics. GLA, gut–lung axis; DAT, desaminotyrosine; GM, gestational mother; GPR43, G protein-coupled receptor 43; IFN-I, type I interferon; Mφ, macrophage; NPF, neutrophil phagocytic function; OSAS, obstructive sleep apnea syndrome; SCFAs, short-chain fatty acids.

Figure 4

Therapeutic strategies targeting the GLA for pediatric pulmonary diseases: mechanisms and clinical interventions. Targeting the GLA offers a novel approach to managing childhood pulmonary diseases through gut microbiota modulation. FMT restores microbial homeostasis by administering healthy donor fecal suspensions via oral capsules, duodenal tubes, or colonoscopy/enema delivery. Probiotics alleviate respiratory symptoms via immunomodulation; prebiotics promote the growth of beneficial bacteria and provide metabolic substrates, thereby reducing pulmonary disease risk. Dietary interventions reshape gut microbiota composition, enhance SCFA production, and mitigate disease progression (e.g., pneumonia). Current evidence indicates that probiotics are more effective against eczema and allergic rhinitis than against asthma, highlighting the need to optimize strain selection, dosage, and treatment duration to improve GLA-targeted therapeutic precision. FMT, fecal microbiota transplantation; GLA, gut–lung axis; SCFAs, short-chain fatty acids.