During development, the formation of the respiratory and intestinal tracts is orchestrated by analogous signaling pathways and transcription factors. The Wnt, Bmp and Fgf signaling pathways are essential for modulating cell proliferation, differentiation and migration, thereby ensuring the normal development of the respiratory and intestinal tracts (15–17). In addition, various transcription factors, such as Nkx2.1 and Sox9, are pivotal in driving the development of both systems (18–20). These factors regulate the expression of key genes involved in organ morphogenesis, underscoring their critical role in the coordinated development of the respiratory and intestinal tracts. Collectively, these signaling pathways and transcription factors highlight the shared regulatory mechanisms between these two systems, providing insights into their interrelated functions and potential shared pathologies.

The respiratory and intestinal tracts exhibit notable structural and functional parallels. Structurally, the mucosa of both tracts belongs to the mucosal immune system and comprises epithelium and lamina propria. They both feature a luminal structure consisting of endoderm-derived epithelial cells, which undergo comparable morphogenetic processes during development, such as the establishment of epithelial cell polarity and the formation of intercellular junctions (13). Functionally, both tracts are essential for maintaining ventilation and material exchange to support the normal physiological functions of the body, whilst also being capable of producing secretory immunoglobulin A. These structural and functional similarities underscore their homology in embryonic histogenesis (21).

The extensive similarities between the respiratory and intestinal tracts not only enhance the comprehension of their interplay during physiological development, but also establish the biological foundation for bidirectional communication within the gut-lung axis. While acknowledging that structural homology alone does not guarantee communication, we contend that the anatomical and developmental parallels between respiratory and intestinal tracts create a permissive biological framework for bidirectional crosstalk. These parallels further offer insights into the mechanisms underlying related diseases, providing a framework for exploring pathophysiological connections between these systems (22).

The gut-lung axis displays dynamic bidirectional crosstalk between the intestinal and pulmonary systems (21). Lung diseases have been previously shown to impact intestinal function and vice versa (21,23–28). Amongst the key elements facilitating this interaction is the bacterial flora, which serves as a critical link between these two systems (29). Accumulating evidence has indicated that commensal bacteria residing in the gut and lungs are indispensable for the development and maintenance of immune homeostasis (30,31). These microbiota begin to colonize newborns not only at birth but also during fetal development. A previous study identified overlapping gut and lung microbiota in human fetuses as early as 10–18 weeks of gestation (32). It has also been reported that gut and lung microbiota can translocate between these organs through fluid circulation, where metabolites derived from gut microbiota can influence lung physiology through various immune-mediated pathways (such as immune cell migration, mucosal immune disruption and alterations in gut-lung microenvironmental cytokines) (33). The gut-lung axis therefore provides a framework for understanding the interplay between local microbiota and distal immune mechanisms, offering novel perspectives on disease pathogenesis and progression. This conceptual model not only improves the comprehension of the physiological connections between the gut and lungs, but also highlights potential therapeutic targets for disorders affecting these interconnected systems.

In preterm neonates, gut microbiota development is predominantly determined by gestational age. A previous study has indicated that the gut microbiota of premature infants residing in a tightly controlled microbial environment progresses through a choreographed succession of bacterial classes from Bacilli to Gammaproteobacteria to Clostridia (41). Antibiotics, vaginal vs. caesarian birth, diet and age of the infants when sampled influence the pace, but not the sequence of progression (41). Korpela et al (42) delineated four phases of gut microbiota maturation in preterm infants, where the first three phases are dominated by Staphylococcus, Enterococcus and Enterobacter, then the fourth phase is characterized by the prevalence of Bifidobacterium. This progression is closely associated with postmenstrual age. Compared with term infants, preterm neonates exhibit reduced gut microbiota diversity, increase in conditionally pathogenic bacteria and delayed colonization by beneficial species, such as Bifidobacteriaceae and Bacteroidetes (43).

The intestinal microbiota of preterm infants delivered vaginally is primarily sourced from the vaginal microbiota of the mother, including Lactobacillus, Prevotella and Sneathiella spp (44). By contrast, the gut microbiota of preterm infants born through cesarean section (C-section) more closely resembles the skin of the mother and the environmental microbiota, which is predominantly comprised of Staphylococcus, Corynebacterium and Propionibacterium spp. Notably, the colonization of beneficial bacteria, such as Lactobacillus, Bifidobacterium and Bacteroides spp., is delayed in infants delivered by C-section (44,45). This disparity in gut microbiota composition between infants delivered vaginally and by C-section diminishes at 4 and 12 months after birth (45).

Feeding practices notably influence the gut microbiota composition of preterm infants, with breastfed infants exhibiting greater microbial diversity. Breast milk is rich in diverse microbiota and human milk oligosaccharides (HMOs), which promote the growth of Bifidobacterium (46). Consequently, the gut of breastfed preterm infants is predominantly colonized by Bifidobacterium and Lactobacillus, whereas Bacteroides spp. and Clostridium sporogenes are more prevalent in formula-fed infants (46). In particular, pasteurized donor breastmilk has been shown to assist preterm infants in developing a gut microbiota profile resembling that of breastfed healthy neonates, accelerating the acquisition of microbial diversity (47).

Antibiotics can exert a profound impact on the gut microbiota. Preterm infants frequently receive antibiotics for extended durations during the perinatal period, longer than their term counterparts. This prolonged exposure can markedly reduce the quantity and diversity of gut microbiota, leading to a depletion of beneficial bacteria (48). In addition, extended antibiotic use is associated with increased colonization by potentially pathogenic bacteria, such as Escherichia coli, Shigella, Enterobacteriaceae and Enterococcus, which may contribute to the emergence of antibiotic-resistant bacteria (49).

Gut microbiota is integral to the health of preterm infants, where it serves a key role in maintaining intestinal immune homeostasis. A balanced symbiotic relationship between commensal microbiota and the host is essential for establishing effective immune defense and immune tolerance. Conversely, dysbiosis of the gut microbiota can disrupt this delicate balance, leading to immune system dysfunction and increasing the risk of various morbidities in preterm infants (50).

BPD is a multifactorial and heterogeneous disease, the pathogenesis of which is rooted in repeated injury to immature lungs and aberrant repair processes triggered by a number of factors, such as infection, mechanical ventilation and hyperoxia (1,4). Maintaining a healthy gut microbiota is crucial for immune homeostasis in preterm infants. Furthermore, emerging evidence has indicated that both pulmonary and gut microbiota are altered in infants with BPD (10,51). Clinical studies have demonstrated that in preterm infants, the progression of BPD is associated with dynamic changes in the Proteobacteria and Firmicutes phyla and the Lactobacillus genus within the lung microbiota, where that pulmonary dysbiosis may exacerbate BPD severity (52,53). Specifically, preterm infants with severe BPD exhibit more pronounced changes in the respiratory microbiota, characterized by reduced Staphylococcus and increased Ureaplasma during early postnatal colonization (54,55).

The interaction between lung and gut microbiota is bidirectional, with alterations in one able to influence the other. This interplay is mediated through shared immune signaling pathways, including cytokine signaling and Toll-like receptor (TLR) activation, in addition to neuroendocrine pathways, such as the hypothalamic-pituitary-adrenal axis and vagus nerve-mediated communication, which collectively impact respiratory and gastrointestinal health. Previous studies have shown associations between gut dysbiosis and changes in lung microbiota composition, with reciprocal effects of lung microbiota perturbations on gut health (56,57). Chen et al (11) divided preterm infants with a gestational age of 26–32 weeks into a BPD and non-BPD group and demonstrated that gut microbiota diversity was significantly reduced in the BPD group compared with non-BPD group at postnatal day 28. Furthermore, other clinical studies reported lower Shannon diversity of the gut microbiota indices in infants with BPD, which documented that the relative abundance of Proteobacteria was elevated in the gut microbiota of the BPD group whereas the abundance of the Firmicutes phylum was decreased, between postnatal days 14 and 28 (54,58). To address confounding factors, such as preterm birth and delivery mode, Lal et al (59) investigated the gut microbiota of vaginally delivered preterm infants and revealed that BPD was associated with increased relative abundance of Escherichia coli and Shigella, with decreased levels of Klebsiella and Salmonella in the gut microbiota (10). These findings collectively support the existence of intestinal dysbiosis in BPD, highlighting the gut-lung axis as a potential therapeutic target for mitigating disease progression.

Infants with BPD exhibit disruptions in both the respiratory and gut microbiota. This can influence BPD progression by both regulating immune-related gene expression and inducing systemic and intrapulmonary inflammatory responses (60). In a BPD mouse model, antibiotic-induced intestinal commensal disruption during the perinatal period promotes a more severe BPD phenotype, characterized by increased lung fibrosis, vascular remodeling, alveolar inflammation and higher rates of morbidity and mortality. This was attributed to the disruption of intestinal commensal bacterial colonization, highlighting the gut-pulmonary axis as a key factor in BPD development (61).

Intestinal microecology disorders can promote BPD progression through the gut-lung axis and the mechanisms may include the following: i) Intestinal barrier disruption, where gut dysbiosis can compromise the intestinal barrier, increasing intestinal permeability to allow bacterial translocation to the lungs. Additionally, dysbiosis-generated metabolites may trigger immune cell activation, leading to local or systemic inflammation and metabolic disturbances (62). ii) Amplification of pulmonary inflammation, where gut dysbiosis can exacerbate lung injury by promoting pulmonary inflammation. A previous study indicated that TLRs can recognize lipopolysaccharides (LPS) from gut bacteria, upregulating IL-1β expression to activate NF-κB in a rodent model. This initiates an inflammatory cascade to exacerbates lung injury (63). iii) Metabolic dysregulation, where gut dysbiosis influences BPD development through various metabolic pathways. Li et al (64) determined that 129 differentiated metabolites were changed in patients with BPD via metabolomics analysis, and a correlation analysis revealed a remarkable relationship between gut microbiota and metabolites. Other studies have shown that oral administration of Lactobacillus plantarum L168 may play a protective role in BPD by regulating the systemic metabolome, such as glutathione metabolism and arachidonic acid metabolism (65). iv) Association with growth restriction. Gut dysbiosis is strongly associated with growth restriction and BPD in preterm infants. Given the critical role of the gut microbiota in the extrauterine growth of VLBW infants and the protective effects of nutritional support against BPD (66), modulating gut microbiota to improve nutritional status may reduce BPD risk in preterm infants.

Compared with term infants, preterm infants have a reduced diversity of gut microbial communities, where factors such as exposure to hyperoxia, antibiotic exposure and nosocomial infections, further disrupt microbial homeostasis. These disruptions compromise the gut barrier, trigger inflammatory responses, metabolic disorders and malnutrition, all of which further impair lung tissue repair through the gut-lung axis, ultimately accelerating the progression of BPD (53).

The core pathological feature of BPD in preterm infants is the developmental arrest of immature lungs due to injuries, such as hyperoxia and mechanical ventilation (1). The gut-lung axis may contribute to BPD through the following mechanisms: i) Early disruption of gut microbiota diversity, where both the gut and lungs of preterm infants are immature. Prolonged hyperoxia inhibits the growth of beneficial bacteria, such as Lactobacillus, increasing pathogen abundance and causing dysbiosis. This dysbiosis can intensify pulmonary inflammation and alveolar developmental disorders by altering metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), volatile organic compounds (VOCs) and butyrate, as soon as impairing immune regulation (67,68). BPD-related dysbiosis is characterized by reduced biodiversity and the absence of specific bacteria (such as Lactobacillus) (11,58). By contrast, necrotizing enterocolitis (NEC)-associated lung injury involves a complete gut microbiota collapse, with endotoxins (including LPS) entering the circulation and triggering systemic inflammation (69). ii) Hyperoxia-induced microbiota-inflammation interactions. Hyperoxia exposure induces alveolar epithelial cells damage in BPD, simultaneously alters gut microbiota composition and promotes bacterial translocation to the lungs. This process activates immune and inflammatory pathways, releasing cytokines (such as IL22, IL6 and IL17) that inhibit alveolar development (60,61). NEC-related lung injury, however, results from systemic inflammation and sepsis caused by acute intestinal necrosis, rather than the direct effects of hyperoxia (69,70).

The neonatal immune response consists of both innate and adaptive components. In preterm infants with an immature immune system, airway and gut microbiota serve a crucial role in immune development. The ‘intestinal microbiota translocation’ theory posits that gut microbiota or bacterial products can directly transfer to the lungs through the gut-lung axis, disrupting pulmonary microecological balance. Additionally, gut microbial metabolites entering the pulmonary circulation through systemic circulation can stimulate lung immune cells, activating inflammatory responses and inducing lung injury (71). Furthermore, these metabolites, including SCFAs, can enter the bone marrow through the bloodstream, promoting hematopoiesis and stimulating hematopoietic stem cell differentiation (31). These cells then migrate to the respiratory tract, modulating lung inflammation in conjunction with the aforementioned mechanisms.

The gut barrier is a critical defensive system within the gastrointestinal tract, preventing pathogen and endotoxin invasion to avert inflammation and bacterial translocation. Numerous factors, such as gestational age, feeding practices and antibiotic use, can all disrupt the intestinal microecological balance, affecting gut barrier maturation in preterm infants (10). In neonates with NEC, intestinal mucosal macrophages and immune cells clear the majority of bacteria. However, surviving bacteria or their inflammatory fragments can reach the lungs, activating alveolar macrophages and causing lung injury (72). Gut-derived bacterial products, including bacterial fragments and metabolites, can enter the pulmonary circulation through the systemic circulation to stimulate lung immune cells (such as macrophages, T cells and neutrophils) to trigger inflammation (29). Dickson et al (73) previously detected live gut bacteria in the lungs of septic mouse models and in the bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome, suggesting that local or systemic inflammation can mediate gut microbiota translocation, disrupting lung microecological homeostasis. Intestinal microecological imbalances can also increase gut permeability, potentially allowing bacterial products to directly transfer to the lungs and exacerbate pulmonary inflammation. Notably, recent studies have drawn attention to the impact of strain-specific microbiota (65,74). Shen et al (65) observed reduced lung injury and improved lung development in BPD rats exposed to Lactiplantibacillus plantarum L168. These results suggested that L168 may improve BPD through downregulation of the TLR4/NF-κB/Chemokine (C-C motif) ligand 4 pathway (65). By contrast, although supplementing Lactobacillus reuteri DSM17938 has been shown to improve intestinal health, it has no notable therapeutic effects on BPD (75). The differences between the two suggest strain-specific microbiota effects.

Alterations in gut flora composition can impact pulmonary immune function, with bacterial metabolites serving a key role in gut-lung immune communication and potentially contributing to BPD progression. SCFAs are essential gut microbiota metabolites that exhibit anti-inflammatory properties by reducing immune cell migration and adhesion and increasing anti-inflammatory cytokine release. SCFAs can traverse the gut-lung axis to modulate pulmonary immunity, with two primary immunomodulatory mechanisms suggested: i) Driving anti-inflammatory responses through downstream effector molecules; and ii) inhibiting histone deacetylase (HDAC) activity to regulate immune responses. SCFAs can also promote anti-inflammatory responses in extraintestinal organs, mitigating airway inflammation. Low fecal acetic acid levels in preterm infants have been associated with higher BPD incidence, whereas acetic acid supplementation could reduce inflammation in mice with hyperoxia-exposed BPD, decrease the proportion of Escherichia-Shigella, increase the abundance of Ruminococcus and attenuate lung injury, potentially preventing neonatal BPD (76).

Other gut microbiota metabolites, such as TMAO and VOCs, can also influence BPD pathology by reducing airway inflammation and restoring epithelial function. Altered urinary metabolites, including lactate, taurine, TMAO, inositol and gluconate, have all been observed in infants with BPD (77). Specifically, alanine and betaine levels are elevated whereas TMAO, lactate and glycine levels are reduced in patients with BPD compared with those in non-BPD controls (78). Notably, gut microbiota can alter TMAO levels, and TMAO can activate inflammation and induce oxidative stress, thereby modulating BPD susceptibility (79). Fecal VOCs, produced by intestinal flora during polysaccharide fermentation, can influence lung function by altering the air-liquid interface properties of pulmonary surfactants, stimulating pro-inflammatory factor production and exacerbating oxidative stress. These effects suggest a potential link between VOCs and BPD development (80). Previous studies have shown associations between fecal VOC changes and BPD severity, where VOCs have demonstrated potential for early BPD diagnosis and prediction within the first 2 weeks of birth (81,82). Furthermore, it has been shown that butyrate can enhance gene expression (such as p16INK4a, p14ARF, and p15INK4b) by inhibiting HDACs, thereby promoting histone acetylation and a more relaxed chromatin structure (83,84). SCFAs can also influence DNA methylation patterns by modulating DNA methyltransferases, chromatin remodeling complexes, microRNAs and transcription factors (85,86). However, the exact role of these epigenetic mechanisms in BPD pathogenesis remains to be fully clarified.

It has been previously demonstrated that the gut microenvironment serves a crucial role in modulating pulmonary immunity through the gut-lung axis. Gut microenvironment disruption can lead to increased cytokines and inflammatory mediators, which then spill over into the systemic circulation, driving lung inflammation, disrupting the lung microenvironment and worsening BPD. This process involves alterations in key inflammatory pathways, including changes in IL-17, IL-22, IL-6 and TNF-α signaling (87). Metabolites from gut microbiota, such as polysaccharide A, α-galactosylceramide and tryptophan metabolites, can activate proinflammatory factors, including IL-17 and IL-22, triggering local or systemic inflammation and immune dysfunction. Aberrant signaling from these metabolites can alter the developing lungs, contributing to lung disease (88). In neonatal mice with BPD, T helper (Th)17 inflammatory responses are heightened in the lung tissue, where neutralizing IL-17 with specific antibodies can alleviate BPD-associated lung injury (89). Additionally, Lactobacillus species degrade tryptophan to produce IL-22, which suppresses immune responses and promotes regulatory T-cell development, in turn protecting both gut and lung tissues (81). FMT has also shown promise in mitigating acute lung injury in rats by reducing inflammatory cell infiltration and lung interstitial exudation through downregulating TNF-α, IL-1β, IL-6 and TGF-β expression (90). These findings underscore the influence of the gut microbiota on inflammatory mediator levels and its subsequent impact on pulmonary pathology.

A primary communication pathway within the gut-lung axis involves the migration of immune cells between the gut and lungs, activating mucosal immunoregulatory mechanisms and influencing BPD progression (91). Certain intestinal mucosal immune cells, such as CD4⁺ and CD8⁺ cells, can reside in both the gut and lungs, suggesting that mucosal immunity may constitute the immune network between the lungs and the intestines (29). In BPD, lung inflammation involves immune cell infiltration, some of which originate from the gut and are activated by intestinal immune responses before migrating to the lungs (91). Innate lymphoid cells (ILCs) and dendritic cells (DCs) migrating along the gut-lung axis may serve a notable role in BPD pathogenesis (92,93).

ILCs are widely distributed in the mucosa of the intestine and respiratory tract, where they regulate immunity and mucosal barrier homeostasis through cytokine secretion (92,94). Gut ILCs can enter the bloodstream through the mesenteric lymphatic system and migrate to the lungs, contributing to epithelial repair (71). In neonatal mice with BPD, type 2 ILCs (ILC2) numbers are elevated in the lung tissue and are associated with alveolar differentiation arrest (92,94). ILC2 depletion by anti-CD90.2 antibodies has been reported to alleviate BPD-related lung injury (94). ILC2 can migrate from the intestine to the lungs under the induction of IL-25 and participate in the immune inflammatory response of the lungs (90). This was demonstrated in a previous study where connecting the circulatory systems of two mice and injecting IL-25 into one led to ILC2 migration from the gut of the treated mouse to the lungs of both, exacerbating lung inflammation (63). This suggests that inflammatory stimulus may drive ILC2 recruitment to the lungs through the gut-lung axis, impacting BPD pathogenesis, but the exact molecular mechanisms require further investigation.

Type 3 ILCs (ILC3), a critical component of mucosal immunity, serve an essential role in defending against lung infections in preterm infants. A previous study showed that the level of ILC3 expression is notably elevated in the lung tissue of mice with BPD, promoting Th17 inflammatory responses and exacerbating lung injury (89). In preterm infants with NEC, gut mucosal DCs can recognize intestinal dysbiosis, triggering ILC3 migration to the lungs of neonatal mice. This disrupts pulmonary innate immunity and impairs type II alveolar epithelial cell secretion of surfactants, leading to lung injury (88). Gray et al (93) previously demonstrated that intestinal DCs can drive ILC3 migration to the lungs. Disrupting postnatal bacterial colonization or selectively deleting DCs blocks IL-22 and ILC3 migration, increasing susceptibility to Streptococcus pneumoniae in neonatal mice (93). This highlights the role of commensal gut bacteria in orchestrating pulmonary mucosal immunity, crucial for lung defense system maturation. Disrupting ILC3 homeostasis in neonatal lungs may impair the pulmonary mucosal defense system, raising the risk of respiratory infections and inflammatory diseases, worsening BPD incidence and severity. Novel insights into mucosal immunoregulation may offer promising avenues for understanding BPD development, emphasizing the complex gut-lung axis interactions. In conclusion, the present review discussed the immunological modulation of the lung-gut axis in BPD (Fig. 2).