Respiratory tract diseases are a major health problem, associated with high incidence and mortality rates worldwide (1). Respiratory tract infections are caused by the invasion and reproduction of pathogenic microorganisms in the respiratory tract, and can be broadly divided into upper and lower respiratory tract infections. Upper respiratory tract infections mainly affect areas at and above the throat, and include acute and chronic rhinitis, laryngitis and pharyngitis, while lower respiratory tract infections affect areas below the throat, and include acute and chronic bronchitis and pneumonia. The World Health Organization estimates that respiratory tract diseases were the fourth leading cause of death worldwide in 2016, accounting for nearly 3 million deaths, which corresponds to ~40 deaths per 100,000 population (2).

Children are particularly vulnerable to respiratory tract diseases, with each child reported to experience up to 12 cases of respiratory tract infection per year (3). Due to their underdeveloped immune systems, children are also prone to complications from respiratory tract diseases, including bronchitis, pneumonia, sinusitis and otitis media (4). Therefore, respiratory tract infections in children pose a great threat to health. Mild cases present with local symptoms such as sneezing, nasal congestion and dry cough, while some children may also experience symptoms such as a sore throat or discomfort in the throat (5). However, severe illness can occur, particularly in infants and young children, with rapid onset, mild local symptoms and severe systemic symptoms, manifesting as irritability, high fever, anorexia and fatigue, with shock and death occurring in the most severe cases (6).

The human microbiota and its surrounding microenvironment are closely linked to metabolism and health, and dysbiosis of the microbiota is strongly associated with respiratory tract diseases. As one of the organs with the most complex microbiota, the intestines have a marked impact on human health. The gut microbiota has various effects on human physiology, which are mediated via a number of different axes, including the gut-lung (7), gut-brain (8), gut-skeletal muscle (9), gut-organ (10) and gut-cardiac axes (11). Research into the gut microbiota has explored its influence on a wide range of conditions, including cancer (12), hypertension (13), obesity (14) and respiratory diseases (15).

With the advancement of microbial research techniques, the field of human microbial ecosystems has been increasingly studied (16). Although most studies on the microbiome have focused on diseases in adults, researchers have now started to investigate the role of microbial ecosystems in pediatric respiratory diseases. Studies of adults suggest that the gut microbiota can indirectly regulate pulmonary immune function (17). The bacterial population in the gut is large and diverse compared with that in other parts of the body, making it a particularly valuable topic of research. The development of the gut microbiota begins at birth, undergoes highly dynamic changes during in the first years of life and typically stabilizes after 1–3 years (18).

In the present review, the development of the gut microbiota during early life and its roles in human health are described. In addition, the associations of the gut microbiota with pediatric respiratory tract diseases are reviewed, with a focus on syncytial viral infections, childhood asthma and cystic fibrosis. Finally, probiotic-related therapeutic approaches are discussed. The review aims to provide new insights into the relationship between gut flora and pediatric respiratory diseases.

The innate and adaptive immune systems are known to be influenced by the composition of the gut microbiota during the first year of life (19). After birth, the immune system is not yet mature, and the first few years of life are a critical period for both microbiota establishment and maturation of the immune system (20). The microbial community participates in various processes within the body, including metabolism and regulation of the immune system, thereby playing a vital role in the overall health of infants (Fig. 1) (21).

The composition of the gut microbiota varies from birth, and differs in infants born vaginally from those born by cesarean section (22). Vaginally delivered infants are exposed to maternal vaginal and fecal microbiota, resulting in the presence of Lactobacillus, Prevotella and/or Sneathia in the gut microbiota (21,23). By contrast, infants delivered by cesarean section acquire microbiota from maternal skin, hospital staff or the hospital environment, including Staphylococcus, Corynebacterium and Propionibacterium (24,25). Infants born by cesarean section generally exhibit decreased microbial diversity compared with that of vaginally delivered infants (26). However, the gut microbiology of infants delivered by emergency cesarean section more closely resembles that of vaginal deliveries, likely due to partial exposure to the birth canal during early labor (27,28). Although the intrauterine environment was originally assumed to be sterile, the presence of a unique microbial environment has been identified in the placenta, comprising non-pathogenic commensal microbiota. This indicates that even during embryonic development, certain microorganisms may be in contact with and influence the fetus (29).

The earliest microbiota colonizing the infant gut are aerobic or parthenogenetic anaerobic bacteria, such as Enterobacteriaceae, Enterococcus and Staphylococcus. As anerobic bacteria increase and oxygen is consumed, the first strict anaerobes begin to proliferate, including Bifidobacterium, Clostridium and Lactobacillus. Among these, Bifidobacterium is one of the most predominant bacterial genera in the gut microbiota of human infants (30). In addition, preterm infants born at less than 37 weeks' gestation typically exhibit a reduced gut microbial diversity and lower levels of Bifidobacterium and Lactobacillus acidophilus (L. acidophilus) (31). Their gut microbiota may be altered due to factors such as exposure to medication or artificial feeding (32). Preterm infants also exhibit delayed gut colonization by commensal anerobic microorganisms, such as Bifidobacterium or Lactobacillus, and significantly elevated fecal levels of pathogenic microorganisms, including Enterobacteriaceae and Enterococcus (33,34).

Research has consistently demonstrated that breastfeeding provides a wide range of health benefits for infants (35). Breast milk contains various bioactive components essential for infant growth and development, including immunomodulatory factors, growth hormones, antimicrobials and prebiotics (36). It has been hypothesized that the inability of human milk oligosaccharides, which are abundant in breast milk, to be digested by infants plays a crucial role in shaping of the infant gut microbiota and protecting against infection (37,38).

Breast milk has its own microbiota, containing 1×10²−1×10⁴ viable bacteria/ml. Dominant genera include Staphylococcus, Streptococcus, Lactobacillus and Bifidobacterium, which promotes the formation of the intestinal microbiota in the infant (39). In addition to promoting colonization of the intestinal tract, breast milk is rich in immunoglobulins, such as immunoglobulins A, G and M, and maternal immune cells, both of which play important roles in infant immune defense and health (37,38).

The gut microbiota of formula-fed infants consists primarily of parthenogenetic anaerobes, such as Lactobacillus and Clostridium. Differences between the microbial communities of breastfed and formula-fed infants have been associated with long-term health outcomes, including an increased risk of developing allergic disease in formula-fed infants, whereas breastfeeding is protective (40). To address this, prebiotics such as short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides are often added to formula milk. They selectively promote the growth of Bifidobacterium and reduce the abundance of Enterococcus and Escherichia coli, thereby improving the composition of the gut microbiota (41). Although current infant formulas are unable to fully replicate the beneficial effects of breast milk on the gut microbiota, advances in prebiotic formulations have been shown to have a positive effect on infants (such as establish the gut microbiota and promote the colonization of bifidobacteria) (42).

Antibiotic treatment and malnutrition are two major factors that affect the gut microbiota, leading to gut dysbiosis (43). Disturbances during early life can impair the composition, maturation and function of the gut microbiota, leading to adverse health consequences later in life. While antibiotics are commonly used to treat bacterial infections, they destroy commensal bacteria in addition to harmful bacteria, thereby triggering intestinal dysbiosis (44). Early use of antibiotics has been shown to reduce the number of bifidobacteria in the neonatal gut, and broad-spectrum antibiotics can significantly alter the composition and structure of the gut microbiota, reducing its diversity by >25% (45,46). In addition, maternal antibiotic use during pregnancy and breastfeeding has been linked with neonatal microflora dysbiosis (47,48). Antibiotics reduce the diversity of the breast milk microbiota, thereby decreasing the abundance of Bifidobacterium in the neonatal gut (49). Malnourished children also exhibit disturbed intestinal flora, characterized by a significant reduction in Bifidobacterium and an altered ratio of aerobic to anaerobic bacteria in fecal samples, resembling immature intestinal flora (50). Malnutrition may also promote inflammation, impair nutrient absorption and exacerbate gut microflora dysbiosis (51,52). Some of the factors influencing the gut microbiota in early life are summarized in Table I (23,53–58).

The close relationship between the gut and lungs can be partly attributed to their shared embryonic origin and the fact that both are exposed to the external environment via the oral cavity and pharynx, which share physiological and structural features (59,60). Although the mechanisms underlying the gut-lung axis are not fully understood, the gut microbiota and its metabolites play an important role in host defense. Metabolites produced by the commensal gut microbiota activate and regulate certain cellular responses required to maintain inflammatory tone, thereby promoting microbiota-host homeostasis (61). The anaerobic fermentation of dietary fiber by the gut microbiota produces short-chain fatty acids with immunomodulatory functions, including the inhibition of immune cell chemotaxis and adhesion, induction of anti-inflammatory cytokine expression, and stimulation of apoptosis in immune cells (62). These fatty acid metabolites also increase the number and function of T regulatory (Treg), T helper (Th) 1 and Th17 effector cells through the inhibition of histone deacetylases, thereby reducing excessive inflammation and immune responses in respiratory tract diseases (63).

There are significant differences in the overall gut microbiome composition between patients with chronic obstructive pulmonary disease (COPD) and healthy individuals (64). The fecal microbiome of patients with COPD shows increased abundances of Streptococcus, Rothia, Romboutsia, Streptococcus spp., and Escherichia, with Streptococcus considered to be a key factor differentiating samples from patients with COPD from those from healthy individuals (65). The gut microbiota is particularly relevant to respiratory health. For example, exposure to gut commensal bacteria immediately after birth has been shown to promote the migration of group 3 innate lymphoid cells into the lungs of neonatal mice to help defend against pneumonia, whereas the same treatment in adult mice has limited effects on pneumonia susceptibility (66). Another study in mice demonstrated that colonization with gut microbes during the neonatal period reduces the likelihood of allergic asthma by preventing ovalbumin-induced aggregation of invariant natural killer T cells to the lungs and by reducing hypermethylation of the CC motif chemokine ligand 16 gene (67).

The administration of microbial metabolites, microbial components or probiotics to mice improves their immune response and survival when exposed to lung pathogens, with detectable changes in the microbiota of the gut and lungs (68). A study by Luoto et al (69) found that prebiotic treatment with a mixture of galacto-oligosaccharides and polydextrose, or probiotic supplementation with Lactobacillus rhamnosus GG (LGG), reduced the incidence of upper respiratory tract infections in preterm neonates. Similarly, Maldonado et al (70) observed a reduced incidence of respiratory and gastrointestinal infections in neonates following the administration of Lactobacillus fermentum and galacto-oligosaccharides. In addition, a meta-analysis of 23 trials and 6,269 children performed by Wang et al (71) demonstrated that probiotic supplementation reduced the incidence of upper respiratory tract infections, with the evidence rated as moderate quality.

Gastrointestinal symptoms such as loss of appetite, nausea and vomiting occur in 20–60% of patients with coronavirus disease 19 (COVID-19). These symptoms may appear earlier than respiratory symptoms exhibit an association with severe disease progression (72). Differences in the composition of the gut microbiota between individuals infected with COVID-19 and controls have been detected, with reductions of Faecalibacterium prausnitzii and Bifidobacterium bifidum (B. bifidum) populations in COVID-19-infected patients, which are inversely correlated with disease severity (73,74).

The remainder of this section examines the relationship between the gut microbiota and respiratory tract diseases, focusing on respiratory syncytial virus (RSV) infections, childhood asthma and cystic fibrosis.

Currently, traditional treatments for respiratory diseases rely heavily on antibiotics and antiviral drugs, which must be used with caution in infants and young children to avoid short- or long-term adverse effects. Widespread use of antibiotics can lead to serious issues, such as drug resistance, reduced therapeutic efficacy and a substantial societal burden (125). Probiotics have emerged as effective agents for the regulation of intestinal microecology and have gained attention in clinical studies for the prevention and treatment of respiratory diseases in children. Probiotics are generally defined as live microorganisms that can positively influence host health (126). They have been widely used as medicines, food additives or nutritional supplements for the prevention and treatment of pediatric diseases due to their recognized beneficial effects (127). Evidence-based medical findings have shown that oral probiotics are effective in preventing respiratory diseases and reducing recurrence rates in healthy children without any adverse side effects (128). Probiotic intake can promote a healthy upper respiratory microbiota and enhance resistance to viral invasion (129,130). The gut microbiota influences immune responses in multiple mucosal systems, playing a crucial role in the maintenance of physiological homeostasis and human health, while dysbiosis of the gut microbiota increases susceptibility to respiratory diseases (131). Although the etiology of respiratory diseases is multifaceted, the ability of probiotics to modulate microecological balance and immune responses has attracted considerable attention in treatment strategies for respiratory diseases (Fig. 2) (132).

Lactobacillus and Bifidobacterium are widely used probiotics that secrete a variety of beneficial compounds, including vitamins, short-chain fatty acids, bacteriocins and exopolysaccharides (133,134). Most children are susceptible to respiratory illnesses because their immature immune systema are not yet strong enough to combat the invasion of various pathogens. Probiotics play a crucial role in the prevention and treatment of respiratory diseases by inhibiting pathogens, enhancing host defenses such as the epithelial barrier, and modulating both innate and adaptive immunity (135).

Probiotics protect the integrity of the epithelial barrier by activating pattern recognition receptors on epithelial cells through microbe-associated molecular patterns that regulate tight and adhesion junctions (136). They also disrupt the microenvironments of pathogens through competition for epithelial cell adhesion sites, nutrient depletion and the secretions of antimicrobial compounds (137). In addition, probiotic metabolites play an important role in respiratory diseases by modulating the differentiation of immune cells and controlling the immune response via G protein-coupled receptors and histone deacetylases (138).

Gut-associated lymphoid tissue is an important component of the peripheral immune system, and probiotics have been shown to enhance systemic immunity and indirectly strengthen respiratory defense by the modulation of this tissue (139). They also mediate innate immune responses through pattern recognition receptors, particularly toll-like receptors (TLRs), which recognize and bind to pathogen-associated molecular patterns on the surface of pathogenic microorganisms and activate signaling pathways, such as the nuclear factor-κB and mitogen-activated protein kinase pathways, to regulate the secretion of pro-inflammatory cytokines (140). For example, Lactococcus lactis (L. lactis) enhances Th1 cell differentiation and upregulates the expression of cytokines IL-12, IFN-γ and TNF-α via TLR2, TLR3 and TLR9 pathways (141).

LGG is currently one of the most widely used probiotics due to its tolerance of stomach acid and bile. Studies have shown that LGG can regulate the balance of microbiota in the gut, reducing harmful bacteria such as Bacteroides and Proteus, and increasing beneficial bacteria such as Lactobacillus, Bifidobacterium and butyric acid-producing bacteria (142,143). In addition, LGG modulates the host immune system, helping to prevent and treat infections by triggering an inflammatory response and activating macrophages, which protect intestinal epithelial cells (144). Several studies have demonstrated that LGG has favorable preventive, therapeutic and curative effects on respiratory diseases in children. In a randomized trial involving 281 children, LGG significantly reduced the risk of upper respiratory tract infections and shortened the duration of respiratory symptoms (145), while a meta-analysis of four randomized controlled trials with 1,805 participants showed that LGG reduces the incidence of acute otitis media while also reducing antibiotic use (146). Other studies have demonstrated that LGG significantly reduces the overall risk of respiratory infection and shortens the duration of respiratory symptoms in children (147). However, although LGG significantly improves respiratory symptoms, it does not appear to inhibit viral activity in respiratory tract infections in children (148). Interestingly, in another randomized study involving 619 participants aged 2–6 years, LGG effectively relieved symptoms of upper respiratory tract infection, but was not effective in reducing the incidence of these infections (149). Despite the multifaceted health benefits of LGG, the results of the studies show some inconsistency, suggesting that the efficacy of probiotics may differ among individuals.

Bifidobacteria are a group of probiotics commonly found in the human gut, particularly in infants. Their numbers and species diversity tend to decline with age (150). Studies have shown that bifidobacteria play an important preventive role in the maintenance of a healthy gut microbiota by regulating gut microbial metabolism, promoting intestinal motility, adhering to and degrading harmful substances, and enhancing host immune function (151). B. longum has been shown to regulate the Th1/Th2 immune system balance. In a study in Malaysian preschool children, B. longum BB536 significantly increased the abundance of anti-inflammatory and immunomodulatory bacteria in the feces, thereby preventing upper respiratory tract diseases via modulation of the gut microbiota (152). Another study showed that the early administration of Bifidobacterium animalis subspecies Lactobacillus bifidus BB-12 to infants reduced the risk of early infections and respiratory tract infections (153).

Probiotic complexes are preparations containing multiple probiotic strains that regulate the composition and diversity of the intestinal flora, protect intestinal barrier function, and reduce inflammation and intestinal damage. Probiotic complexes have demonstrated superior efficacy than single strains in maintaining gut health, modulating immune function and single strain resistance issues (154). Probiotic complexes have shown the potential to play a positive role in the prevention and treatment of recurrent respiratory infections. For example, oral quadruple probiotic tablets containing B. bifidum, L. acidophilus, E. faecalis and Bacillus cereus not only increased the abundance of the beneficial gut bacteria B. bifidum and L. lactis, but also significantly reduced the mean annual frequency of acute respiratory infections and antibiotic use (155). Also, another probiotic preparation containing Bifidobacterium animalis subspecies Lactobacillus bifidus BB-12 and E. faecalis L3 significantly increased salivary immunoglobulin levels and reduced the risk of upper respiratory tract infections in healthy children (156). In addition, a nasal spray comprising Streptococcus salivarius 24SMB and Streptococcus oralis 89a was found to be effective in relieving the symptoms of recurrent respiratory infections in children (157). Another clinical study also supports the benefits of probiotic complexes, with a marked reduction in the incidence of respiratory infections in children treated with oral probiotics compared with placebo-treated controls, in addition to a lack of adverse effects (158).

Although numerous probiotic products have been shown to be safe, their use can also cause adverse reactions (159). Probiotics have been reported to cause gastrointestinal side effects, including diarrhea and bloating (160). In addition, probiotics may facilitate the lateral transfer of antibiotic resistance genes to other microorganisms (161,162). There have been some reports that probiotics can act as opportunistic pathogens in immunocompromised individuals, potentially leading to life-threatening diseases such as pneumonia, endocarditis and sepsis (163–165). Therefore, further research is necessary to evaluate probiotic therapies for respiratory diseases, particularly regarding individual differences and safety issues.

Certain probiotics have demonstrated beneficial effects. For example, a combination of Lactobacillus and B. bifidum has exhibited an association with reduced inflammation, and may have the ability to ameliorate inflammatory conditions (166). In addition, Lactobaccillus plantarum has been shown to regulate oxidative stress, inflammation and gut microbiota dysbiosis in vivo, while promoting intestinal motility and mucin production (167). Some of the key effects and underlying mechanisms of probiotic therapy are summarized in Table II (168–172). However, the mechanisms by which different probiotics exert their effects on the human body remain unclear, highlighting the need for further comprehensive research.

When considering any treatment, safety is a priority for pediatric populations. The comprehensive reporting of all adverse events, particularly long-term safety outcomes, is critical to meaningfully advance the evidence base in this area (173). A meta-analysis of COPD performed by Su et al (174) suggested that probiotics can improve lung function and structure, and reduce inflammation. However, the experimental results were suggested to have some limitations, particularly regarding the efficacy and safety of long-term probiotic use. Li et al (175) conducted a 12-week randomized controlled trial, which demonstrated that Bifidobacterium infantis YLGB-1496 exhibited excellent safety and tolerability in infants and effectively alleviated the gastrointestinal discomfort associated with respiratory diseases.

Further research is necessary to validate the long-term efficacy and safety of probiotics, even though a number of studies have indicated that probiotic therapy is safe (176–178).

The present review first described the development of gut microbiota in the early stages of life and their critical role in human health. It then introduced the gut-lung axis as an important bidirectional communication system, reviewed the relationship between the gut microbiota and three pediatric respiratory tract diseases, and concluded with a summary of probiotic therapies.

The concept of the gut-lung axis is crucial for understanding respiratory disease. The gut microbiota and human health interact with each other, but the underlying mechanisms remain unclear and require further study. The development of a healthy gut microbiota is strongly associated with respiratory health and the development of the immune system in children. Therefore, in-depth investigation of the gut microbiota composition and function during early childhood may help to predict future health, prevent diseases and clarify the underlying mechanisms.

Probiotic therapy offers a novel approach for the prevention and treatment of respiratory diseases. Increasing evidence suggests that probiotics can be used to relieve symptoms, reduce disease recurrence and reduce the use of antibiotics. Reducing antibiotic exposure is important in children, as antibiotics can lead to dysbiosis of the gut microbiota, leading to lower host resistance and contributing to the global issue of antibiotic resistance.

However, the limitations of probiotic treatments must be acknowledged. Their exact mechanisms remain unclear, and therapeutic effects may vary. In addition, the roles of probiotic preparations in the microenvironments of different diseases require further investigation. The development of more effective composite probiotic preparations appears to be a promising area of research. Although studies have shown that probiotic therapy is generally safe, with no serious side effects or adverse symptoms reported, safety assessments of probiotic treatments remain limited to certain populations; therefore, more research on safety is necessary. Finally, the lack of unified industry or clinical guidelines for probiotic use remains a barrier. The standardization of usage methods in daily life and clinical practice will be essential to expand the prospects for probiotic treatments in pediatric respiratory care.