The pediatric gut microbiome represents a dynamic ecosystem of bacteria, fungi, viruses, and archaea. Indeed, the human gut is inhabited by between 100 thousand and 100 billion bacteria per milliliter of luminal content depending on the region and is therefore the most densely colonized organ (14). Crucially, this microbial consortium not only supports nutrient metabolism but also calibrates systemic immunity via endocrine and metabolic crosstalk (15, 16). This symbiotic relationship is established from birth with the infant gut microbiota and continues to evolve during the critical early years of life. During this period, infants experience rapid growth, with substantial increases in height, weight, and head circumference. Concurrently, their metabolic organs, immune system, digestive system, and neurocognitive functions undergo substantial development and maturation. This phase is also pivotal for formation of the gut microbiota, which is essential for maintaining overall health (17).

In contrast to the gut, the respiratory microbiome exhibits spatiotemporal stratification—nasal cavities favor Staphylococcus and Corynebacterium, whereas lower airways are dominated by Prevotella and Streptococcus—with bacterial loads (10^3–10⁵ CFU/mg) that are orders of magnitude lower than intestinal levels (18, 19). Our understanding of bacterial component development in the airways is more limited than our knowledge of the gut microbiota. Some evidence (primarily from mouse models) suggests that the respiratory microbiota matures during childhood, a process that is crucial for promoting tolerance to airborne allergens (20). Despite shared dominant phyla (Bacteroidetes/Firmicutes), the lung microbiome displays unique assembly rules; microbial immigration (inhalation/microaspiration), elimination (mucociliary clearance), and local replication dynamically sculpt the community structure (21).

Deciphering the co-evolution of gut and respiratory microbiomes is fundamental to understanding pediatric immune ontogeny. During early life, these microbial communities transcend passive colonization; they actively direct immune cell differentiation via metabolite signaling (e.g., SCFAs), epigenetic modulation, and pathogen exclusion (22). Integrated analysis of human cohort data has revealed that synchronized gut–lung microbiota maturation establishes a systemic immune “set-point,” dysregulation of which underlies susceptibility to pneumonia and asthma. This paradigm shifts the focus from cataloging microbial taxa to decoding their functional networks, a cornerstone of our therapeutic discovery platform.

Upon birth, infants start to develop their initial microbiome, with its composition being shaped by the delivery method, whether through natural, vaginal, or cesarean birth (23). The initial bacterial colonization and various other factors following childbirth strongly influence an infant’s early-life microbiome, which subsequently regulates immune system development of the newborn (24). Whereas vaginal birth establishes a maternally derived microbiome enriched in Lactobacillus and Bifidobacterium, cesarean delivery favors skin-associated Staphylococcus and environmental taxa (25). Crucially, this immunomodulatory process exhibits developmental stage-specific sensitivity, as evidenced by murine and human studies demonstrating irreversible immune programming defects when microbial exposure is disrupted during early postnatal windows (26, 27). This foundational microbial assembly orchestrates lymphoid tissue development and immune cell education—processes that are vulnerable to disruption by antibiotics or formula feeding. Such dysbiosis propagates systemic immune misprogramming, elevating the risks for asthma and obesity via GLA signaling (28).

The gut microbiome operates as a microbial tutor during infancy, instructing immune cell differentiation through metabolite- and antigen-driven dialogues. Key taxa (e.g., Clostridia clusters) promote expansion of regulatory T cells (Tregs) via SCFA production, and segmented filamentous bacteria drive T-helper 17 cell (Th17) polarization via interleukin 23 (IL-23)/IL-17 axis activation (29). This trans-organ immunity, mediated by circulating microbial metabolites and trained immune cells, forms the mechanistic bedrock of the GLA (30).

In the intestinal environment, pattern recognition receptors (PRRs), including toll-like receptors (TLRs), C-type lectin receptors, NOD-like receptors, and RIG-I-like receptors, can identify specific molecular patterns in the microbiota, thereby initiating immune responses. The activation of PRRs not only promotes the maturation and activation of immune cells but also modulates their migration and function through the production of cytokines and chemokines (31). Specifically activated PRRs can induce dendritic cells (DCs) to produce IL-12p70, a crucial Th1-polarizing cytokine for anti-infection and anti-tumor immune responses. Moreover, PRR activation enhances the expression of surface molecules such as CD80, CD86, and human leukocyte antigen-DR (HLA-DR) on DCs, thereby improving their antigen-presenting capacity and T-cell activation ability (32).

A previous study redefined the gut microbiome as a systemic immune rheostat, with microbial metabolites (e.g., SCFAs, indoles) serving as endocrine-like messengers that synchronize lung immunity (33). Via integrated metagenomic–metabolomic analysis, spatial gradients of these molecules have been mapped from gut to bronchoalveolar lavage, correlating their depletion with neutrophilic inflammation in severe asthma (34) ( Figure 1 ). This paradigm-shifting discovery positions fecal metabolite profiling as a noninvasive biomarker for predicting corticosteroid responsiveness—a cornerstone of our precision pulmonology framework. By decoding the gut–lung dialogue, we can pioneer microbiota-centric strategies to reset immune homeostasis in pediatric respiratory diseases.

The GLA operates as a bidirectional immunoregulatory circuit wherein microbial components and metabolites systemically modulate pulmonary immunity via three primary mechanisms: 1) molecular mimicry: bacterial LPS primes alveolar macrophages via TLR4 (35); 2) metabolite trafficking: gut-derived SCFAs, particularly propionate and butyrate, suppress IL-13-driven eosinophilia by enhancing airway epithelial barrier integrity (36); 3) immune-cell migration: intestinal Th17 cells recruited to the lungs exacerbate neutrophilic inflammation in asthma, a process amplified by dysbiosis-induced IL-23 signaling (37). Disruption of gut barrier integrity promotes microbial translocation (e.g., circulating LPS), which triggers nuclear factor-kappa B (NF-κB)-mediated pulmonary hyperinflammation (38). A murine study demonstrated that elevated circulating propionate levels promote hematopoiesis of DC precursors in bone marrow, subsequently affecting DCs in the lungs and draining lymph nodes, thereby resulting in an impaired ability of these DCs to activate Th2 cells within the lung tissue (39). These pathways collectively enhance intestinal mucosal immunity while systemically modulating immune cell differentiation and function. Notably, animal studies substantiate that SCFAs can attenuate pulmonary inflammation by activating Tregs and conditioning DCs to suppress Th2-polarized responses in murine models, thereby recalibrating Th1/Th2 equilibrium (40) ( Figure 1 , Table 1 ).

SCFAs—primarily acetate, propionate, and butyrate—serve as keystone metabolites linking the gut microbiota to pulmonary immune homeostasis (11, 41). Emerging evidence suggests that elevated levels of SCFAs in infants are associated with a reduced incidence of asthma, potentially mediated through dual anti-inflammatory mechanisms (42). First, SCFAs activate G protein-coupled receptors (GPR41/GPR43) on alveolar macrophages via receptor-dependent signaling, enhancing pathogen clearance while suppressing pro-inflammatory cytokine release (e.g., tumor necrosis factor alpha [TNF-α], IL-6) (22, 43). Second, SCFAs modulate immune cell function through epigenetic regulation: by inhibiting histone deacetylase (HDAC) activity; these promote anti-inflammatory factor expression (including IL-10) and Treg differentiation while simultaneously restraining Th17 cell overactivation. These coordinated actions maintain pulmonary immune homeostasis and mitigate inflammation (42, 44) ( Table 1 ). Although SCFA concentrations are low in the lungs, gut-derived propionate can induce bone marrow precursors to generate macrophages. These macrophages then migrate to the lungs and attenuate allergic inflammation by promoting IL-10 production (11). These findings establish SCFAs as systemic immunomodulators that exert hormone-like signaling functions (45). Collectively, the above findings underscore SCFAs as pivotal gut-derived mediators that orchestrate pulmonary immune homeostasis via receptor-dependent signaling and epigenetic mechanisms. The ability of SCFAs to prime anti-inflammatory responses both locally and systemically highlights their therapeutic potential in asthma and other inflammatory lung diseases ( Figure 1 ).

Emerging evidence highlights the pivotal role of immune cell trafficking in gut–lung communication wherein innate lymphoid cells (ILCs) and gut-primed Tregs migrate to pulmonary tissues via mesenteric lymphatics under chemokine guidance (46). Extending these observations, one study provided mechanistic insights into the cytokine-regulated bidirectional trafficking of ILC2s using integrated pseudotemporal analysis, lineage tracing, and ectopic transplantation assays. That study delineated a unidirectional maturation trajectory wherein lung-derived C-C chemokine receptor type 2-positive (CCR2⁺) ILC2s migrate to the intestine via IL-33-dependent pathways, undergoing phenotypic transition characterized by a transient CCR2⁺CCR4⁺ double-positive population and terminal differentiation into CCR4⁺ gut-resident ILC2s. This migratory axis demonstrates strict tissue tropism under homeostasis, with no detectable reverse migration from intestinal ILC2s to pulmonary niches. Strikingly, IL-25 stimulation subverts this physiological unidirectionality, potentiating intestinal ILC2s to acquire trans-tissue migratory competence toward pulmonary compartments (47). This cellular crosstalk establishes a “mobile immune network” that integrates microbial signals and tissue-specific immunity ( Figure 1 ).

The GLA, which is crucial for immune balance and respiratory health, strongly influences pediatric pulmonary diseases. Understanding its role in diseases such as asthma and bronchopulmonary dysplasia could offer new therapeutic strategies. Future research priorities include standardizing methodologies for gut microbiota and metabolite profiling in pediatric cohorts, elucidating age-dependent variations in GLA functionality, and developing targeted interventions (e.g., SCFA prodrugs, microbiota transplantation) to restore immune homeostasis.

Asthma remains a leading chronic pediatric condition, accounting for approximately 400,000 annual deaths globally (48, 49). The current global prevalence of asthma exceeds 300 million individuals, with a projected increase to 400 million by 2025 (50). Emerging evidence implicates GLA dysbiosis in asthma pathogenesis, with microbial alterations influenced by perinatal factors including cesarean delivery, neonatal antibiotic exposure, maternal nutritional patterns, formula supplementation, and microbial environmental exposures (51, 52). Longitudinal cohort studies demonstrate that diminished gut microbial diversity during early infancy correlates with subsequent asthma development. Infants who develop asthma exhibit significantly reduced α-diversity metrics as early as 1 month postpartum (52), with temporal microbiota dynamics showing critical developmental windows for asthma predisposition. Specifically, transient depletion of immunomodulatory taxa (Lachnospira, Veillonella, Faecalibacterium, and Rothia) at 3 months postnatally distinguishes high-risk infants (53) ( Table 1 ). Phylum-level analysis reveals Firmicutes dysregulation in pediatric patients with asthma, characterized by decreased anti-inflammatory species (e.g., Roseburia) and expansion of pro-inflammatory genera (Enterococcus, Clostridium) (54) ( Figure 2 ).

This ecological imbalance coincides with impaired mucosal immune programming during critical developmental windows, as evidenced by multi-omics integration of microbial community dynamics, host metabolomic signatures, and nutritional patterns (49, 55, 56). Notably, gut dysbiosis, particularly the depletion of Akkermansia, Bifidobacterium, and Faecalibacterium species during critical developmental windows, is strongly associated with heightened susceptibility to asthma and allergic disorders (26, 27) ( Figure 2 ). Mechanistically, microbial metabolic output—particularly SCFA biosynthesis—mediates dietary microbiota–immune crosstalk, with reduced SCFA production correlating with asthma risk in low-diversity microbiomes (1, 11).

Breastfeeding exerts important modulatory effects on asthma-related microbial metabolites (49). Contrary to historical sterility assumptions, human milk contains dynamic microbial communities and prebiotic compounds that shape the infant gut ecology (57, 58). Multivariate analysis has revealed that exclusive breastfeeding ≥4 months is an independent protective factor against asthma development (49), highlighting nutritional–microbial interactions in early-life asthma prevention ( Figure 3 ).

Pneumonia is an infection that inflames the air sacs and other parts of the lungs and is often caused by bacteria, viruses, or other pathogens (59, 60). Pneumonia remains a leading cause of childhood morbidity and mortality, accounting for 14% of deaths in children under 5 years globally, with an estimated 120 million cases annually (61). Research has shown that viral infections, such as influenza, can substantially alter the gut microbiome, even without detectable viral particles in the gastrointestinal tract (62). Compelling evidence links the gut microbiota composition to pneumonia susceptibility and severity (63). Mice with a depleted gut microbiome exhibit increased bacterial spread, heightened inflammation, organ dysfunction, and elevated mortality following Streptococcus pneumoniae infection, compared to those with a normal microbiome. Fetal microbiota transplantation (FMT) can restore pulmonary bacterial levels and normalize immune responses in these mice. The gut microbiome modulates metabolic pathways in alveolar macrophages, affecting cellular responsiveness, with macrophages from mice that have a depleted microbiome showing reduced phagocytic activity against S. pneumoniae (64) ( Table 1 ). Mechanistic studies reveal two key pathways: 1) macrophage priming: gut-derived acetate enhances alveolar macrophage phagocytic capacity against S. pneumoniae via GPR43-dependent metabolic reprogramming (65) ( Table 1 ); antiviral defense: microbiota-derived desaminotyrosine protects the host from influenza by modulating the type I interferon (IFN-I) response (66) ( Figure 3 ).

Pneumonia poses a serious health risk to children worldwide, with high case numbers and mortality rates, emphasizing the need for prevention and better treatment (67). Preterm infants with pneumonia exhibit reduced gut microbiota diversity and disturbances of the gut (68). Children’s underdeveloped immune systems make them vulnerable to severe illness and death due to pneumonia. The gut microbiota, particularly early in life, influences lung immunity and the pneumonia risk, highlighting the importance for health of a balanced gut microbiome (23). Pneumonia can affect the composition of the gut microbiota, primarily leading to a decrease in Bifidobacterium (10), Lactobacillus (69), and Clostridium (70), and causing an increase in Escherichia coli (59). Infant gut microbiota diversity and functionality increase during the first years of life, influenced by the delivery mode and feeding type (71). In pneumonia, Pseudomonas, Escherichia/Shigella, Streptococcus, and Akkermansia are decreased Bacillota are increased, at the phylum level, with specific genera being more or less abundant in cases of pneumonia. Preterm infants with pneumonia exhibit reduced gut microbiota diversity and gut disturbances (68) ( Figure 2 ).

The prevalence of pediatric COVID-19 cases ranges from 1% to 13.3% of total reported infections (72). A recent study revealed significantly reduced α-diversity in young patients with COVID-19 (aged <6 months), aligning with prior studies attributing such disparities to the unique infant microbiota, which is shaped by feeding patterns (73). Beyond gut microbiota alterations, intestinal inflammation, microbial translocation, and intestinal barrier dysfunction have also been identified as factors associated with COVID-19 infection and that are potentially attributable to microbiota-driven perturbations (74). The critical role of microbiota has prompted experts to question whether the host microbiota status should be considered prior to vaccine development. Furthermore, the development of oral vaccines and maintenance of microbial homeostasis may facilitate early containment of COVID-19 outbreaks or future pandemics (74).

Respiratory syncytial virus (RSV)-associated bronchiolitis affects 33 million children under age 5 years annually, with 3.2 million requiring hospitalization (75). Emerging data implicate gut microbiota dynamics in disease progression. Cohort studies reveal that infants hospitalized with severe RSV bronchiolitis exhibit gut dysbiosis characterized by Enterobacteriaceae overgrowth and Bifidobacterium depletion (76). RSV infections are particularly dangerous for infants under age 2 years, leading to high rates of morbidity and mortality. Early infancy is a key period in gut microbiota development that may play a role in bronchiolitis through various mechanisms beyond the Th1/Th2 imbalance theory. Research indicates that acetic acid produced by gut microbes can stimulate lung IFN-β production, enhancing type 1 IFN responses by activating GPR43 and NF-κB (77) ( Table 1 ). This activation can modulate the protective effects of acetic acid against RSV, potentially reducing pneumonia symptoms ( Figure 3 ).

Current research is investigating intervention strategies for respiratory illnesses, with clinical trials demonstrating that Bifidobacterium species stimulated by human milk oligosaccharides contribute to the prevention of subsequent respiratory infections (e.g., bronchitis). This protective mechanism is mediated via Bifidobacterium-driven enhancement of acetate production, with elevated acetate levels being mechanistically linked to improved intestinal barrier function (78). Emerging clinical evidence has revealed that maternal supplementation with Lactobacillus johnsonii confers transgenerational protection against RSV infection, with offspring exhibiting attenuated airway mucus production and Th2-mediated immune responses. In a murine study, this intervention maintained congruent gut microbiota profiles in both dams and progeny, accompanied by a synchronized reduction in pro-inflammatory metabolites in the maternal plasma, breast milk, and offspring circulation (79). Mechanistically, Lactobacillus-driven modulation of maternal microbial ecosystems and associated metabolic reprogramming are positively correlated with enhanced neonatal airway defense mechanisms against RSV pathogenesis (79).

CF is an inherited disorder transmitted through an autosomal recessive pattern, resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This defect induces the accumulation of abnormally viscous mucus secretions, which primarily compromise pulmonary and gastrointestinal functions (80). CF affects approximately 70,000 people worldwide (81). Lung infections caused by bacteria such as Pseudomonas aeruginosa, S. aureus, Burkholderia cepacia complex, and Stenotrophomonas maltophilia worsen respiratory function and contribute to disease morbidity (19). Research supports the existence of a “GLA” in chronic respiratory diseases such as CF, affecting mucosal immunity across these systems (82, 83). Cross-sectional studies have revealed that pediatric patients with CF exhibit marked gut dysbiosis, characterized by a marked depletion of beneficial taxa including Bacteroides, Bifidobacterium adolescentis, Faecalibacterium prausnitzii, Actinomyces, Eubacterium, Ruminococcus, Dorea, Akkermansia, Peroxisome-associated Firmicutes and Pantoea (84, 85), alongside concurrent enrichment of opportunistic pathogens such as Staphylococci, Streptococci, Veillonella dispar, Propionibacterium, and Clostridium difficile (84) ( Figure 2 ).

Mechanistic studies identify two critical pathways linking gut dysbiosis to pulmonary decline. Reduced levels of Bacteroides-derived propionate in SCFA deficiency impair neutrophil phagocytic function via compromised GPR41 signaling (81, 86). Concurrently, diminished Clostridium scindens activity disrupts bile acid metabolism by reducing deoxycholic acid production, which exacerbates airway inflammation through dysregulation of the FXR/TGR5 signaling axis (87) ( Figure 3 , Table 1 ).

A prospective cross-sectional study elucidated that children with CF exhibit a dietary pattern characterized by high fat and low fiber, which is associated with intestinal dysbiosis, elevated fecal calprotectin, and respiratory microbial disturbance, collectively leading to impaired lung function and increased lung exacerbation (82). Another study highlighted the therapeutic potential of microbiota-targeted interventions (e.g., probiotics, CFTR modulators) in mitigating systemic and respiratory morbidity in children with CF by restoring the gut microbial balance, enhancing immunomodulation, reversing SCFA deficits, and disrupting pathogenic gut–lung crosstalk, thereby attenuating chronic inflammation and improving pulmonary outcomes (88). These findings highlight the gut microbiome as a modifiable determinant of CF progression, paving the way for microbiota-centric adjuvant therapies.

OSAS affects 2%–4% of children, with increasing prevalence linked to pediatric obesity and adenotonsillar hypertrophy (89). OSAS is a prevalent chronic respiratory disorder marked by repeated pharyngeal collapse and ventilation disruption during sleep, leading to apnea and sleep disturbances (90). Emerging evidence implicates gut microbiota dysbiosis as both a contributor and consequence of OSAS pathophysiology (91, 92). Cross-sectional studies demonstrate that children with moderate-to-severe OSAS exhibit gut microbiome alterations characterized by an increase in Clostridia and Ruminococcus species, coupled with depletion of SCFA-producing bacteria such as Faecalibacterium and other taxa associated with SCFA synthesis (93, 94) ( Figure 2 ).

In one study, researchers hypothesized that diminished intestinal SCFAs underlie hypertension pathogenesis in OSA. OSA significantly elevated systolic blood pressure after 7 and 14 days, an effect abolished by administration of the probiotic Clostridium butyricum or the prebiotic Hylon VII. 16S rRNA sequencing revealed significant enrichment of SCFA-producing bacterial taxa following C. butyricum or Hylon VII treatment. OSA exposure reduced cecal acetate concentrations by 48%, which was prevented by both interventions. Furthermore, C. butyricum and Hylon VII attenuated OSA-induced gut dysbiosis, goblet cell depletion, mucus layer thinning, and cerebral microglial activation (95) ( Figure 3 , Table 1 ). A systematic review and meta-analysis indicated that OSA is associated with intestinal barrier dysfunction. Furthermore, the severity of OSA appears to be associated with elevated levels of biomarkers of intestinal barrier dysfunction (96). These preclinical findings suggest that microbiota modulation may serve as a potential adjuvant strategy for OSAS management, although clinical validation in pediatric populations is warranted.

The gut microbiota and its metabolites are increasingly recognized as potential biomarkers for pediatric pulmonary diseases. Omics approaches have been used to identify microbial signatures associated with disease states, including an elevated Firmicutes/Bacteroidetes ratio indicative of dysbiosis in respiratory conditions (15, 97). In COVID-19, the gut microbiota composition correlates with disease severity and immune dysregulation, characterized by depleted SCFA-producing taxa and impaired L-isoleucine biosynthesis (98, 99) ( Table 1 ). Experimental models have further demonstrated metabolic disturbances, such as increased serum lactate and reduced acetate levels in pulmonary hypertension (97). Although these findings underscore the diagnostic potential of microbiota profiling, current evidence remains fragmented, necessitating large-scale longitudinal studies to validate microbial and metabolic biomarkers across diverse pediatric populations (15).

Therapeutic strategies targeting the GLA show promise in modulating immune responses and improving clinical outcomes. Probiotics, such as Lactobacillus plantarum, enhance IFN-I production and reduce viral loads in influenza models whereas Clostridium orbiscindens-derived desaminotyrosine strengthens antiviral defenses (62, 69). SCFAs exert systemic anti-inflammatory effects by promoting Treg differentiation (via HDAC inhibition) and suppressing Th2/Th17 polarization (through GPR41/43 signaling), with fecal propionate levels inversely correlated with asthma risk in infants (39, 40). Omega-3 polyunsaturated fatty acids (PUFAs) such as DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) can regulate immune cell functions, reduce inflammatory responses, and enhance antiviral immune reactions, thereby playing a protective role in pediatric pulmonary diseases. Research has found that prenatal supplementation with omega-3 PUFAs can influence the airway microbiota of infants, reducing the risk of respiratory infections (100). Despite these advances, standardized protocols for strain selection, dosing, and long-term safety monitoring remain critical challenges in clinical translation.

Despite growing interest in the GLA and its role in pediatric respiratory disorders, critical methodological and translational gaps hinder progress. A predominant reliance on cross-sectional studies limits causal inference because observed associations—such as the reduced gut microbiota diversity in asthma—cannot be used to distinguish whether dysbiosis drives disease or vice versa. Large-scale longitudinal cohorts tracking microbiota dynamics from early life to disease onset are essential to resolve such ambiguity. Furthermore, small sample sizes (<100 participants) and geographical biases (e.g., overrepresentation of European populations) reduce generalizability, and inconsistent sample handling protocols introduce technical variability that obscures biological signals.

The complexity of gut microbiota data presents another layer of difficulty. Integrating taxonomic, metabolic, and functional profiles requires advanced bioinformatics capabilities that are often unavailable to smaller research teams. Compounding this issue, key confounders such as diet are insufficiently addressed. Most studies focus narrowly on the short-term effects of isolated nutrients, overlooking the cumulative impact of dietary patterns and individualized eating behaviors. Genetic predispositions and environmental exposures (e.g., air pollution, antibiotic use) further interact with microbiota in ways that remain poorly characterized, highlighting the need for multifactorial models.

Translating preclinical findings to clinical applications involves additional hurdles. Although animal studies have elucidated mechanisms such as SCFA-mediated immune modulation, they fail to replicate the complexity of human pediatric immune development and environmental exposures. Clinical trials must navigate inherent challenges including stringent participant matching for age, feeding practices, and comorbidities; prolonged follow-up (≥5 years) to assess outcomes in slowly progressing diseases; and unresolved safety concerns regarding probiotics or microbiota-targeted therapies in children.

Finally, the dynamic nature of the gut microbiota during childhood complicates research and intervention design. Most studies capture static snapshots, ignoring developmental trajectories and cumulative microbial effects on disease. Pronounced inter-individual variability, shaped by gene–environment–diet interactions, further complicates the development of personalized approaches. Addressing these limitations requires multinational longitudinal cohorts, multi-omics integration driven by artificial intelligence, and pediatric-specific therapeutic frameworks to advance GLA research from correlation to causation and clinical utility.

The role of the gut microbiome in pediatric respiratory diseases is an emerging field with implications for new therapeutic strategies. Future research should focus on the GLA, particularly the impact of microbial metabolites on immune modulation. Multi-omics approaches will help deepen understanding regarding the complex interactions between the gut microbiota and children’s respiratory health. A key objective is to identify microbial signatures and metabolites that serve as biomarkers for early diagnosis and prognosis of diseases such as asthma and pneumonia, enabling personalized medicine based on individual microbiome profiles. It is also crucial to explore the role of the gut microbiome in responses to treatments such as FMT and probiotics/prebiotics, as well as to design clinical trials assessing their efficacy and safety. Research should also investigate the microbiome’s influence on vaccine responses and immunotherapies for respiratory diseases, potentially leading to microbe-based adjuvants that boost vaccine efficacy. The impact of diet on the gut microbiome and lung health in children merits further study, with a focus on dietary interventions to improve respiratory outcomes. Finally, translating preclinical findings into clinical practice is essential. Future research should connect laboratory discoveries with clinical applications, implementing evidence-based interventions that leverage the GLA to prevent and treat pediatric respiratory diseases, with the aim to reduce the impact of these diseases on children’s health and quality of life globally.