RRTIs are highly prevalent respiratory diseases affecting pediatric populations worldwide, particularly young children. According to international research data, approximately 10%–15% of children experience RRTIs at some point, representing about one-third of cases seen in primary pediatric care settings and accounting for between 8% and 18% of acute hospitalizations related to respiratory infections. Preschool-aged children are especially susceptible, experiencing an average annual occurrence rate ranging from six to ten viral colds (1). Globally, these infections claim the lives of approximately four million individuals each year while remaining the leading cause of mortality among those under six years old (2). Following the onset of RRTIs, common symptoms include fever and cough. If left untreated, they can lead to a decline in lung function among affected children, significantly impacting their health as well as growth and development (3). During early childhood, RRTIs often result in frequent medical consultations and emergency room visits while exerting a substantial influence on both affected children's quality of life and that of their families. Additionally, it frequently disrupts schooling activities (4). Enhanced resistance levels and concerns over treatment effectiveness often arise from the heavy reliance on antibiotics and antiviral drugs in conventional treatments for RRTIs. The inappropriate use of antibiotics has led to a significant increase in rates of bacterial resistance, resulting not only in elevated patient mortality but also imposing substantial economic pressure on healthcare systems (5).

Probiotics are commonly defined as living microorganisms that confer positive health effects on the host when present in sufficient quantities (6). In recent years, public attention towards probiotics has continued to rise due to the increasing recognition of their various beneficial effects in the field of health (7). According to statistics, the global probiotic market is projected to exceed $90 billion by 2026. Probiotics have been extensively used as pharmaceuticals, food additives or nutritional supplements for preventing and treating pediatric diseases (8). By modulating the cellular and humoral immune mechanisms, probiotics can enhance their immune defense capability (9). The research findings of evidence-based medicine suggest that oral probiotics effectively prevent respiratory tract infections and reduce recurrence rates in healthy children, without any observed adverse side effects (10, 11). Probiotics are highly esteemed for their diverse effects, particularly their antiviral properties. Recently, probiotics with antiviral capabilities have been incorporated into dairy products and fermented foods to assist in preventing viral infections (12). Evidence suggests that the utilization of probiotics can diminish the susceptibility to upper respiratory tract infections and facilitate the establishment of a robust microbiota environment in the upper respiratory tract that exhibits resistance against viral intrusion (13, 14).

The human gut microbiome represents a complex community of microorganisms residing within the gastrointestinal tract, encompassing an estimated range of 500–1,000 distinct bacterial species (15). Dysbiosis within this microbial ecosystem weakens host defense mechanisms against drug resistance and pathogenic bacteria colonization, increasing susceptibility to pathogens (15). Studies on human microbiota have revealed that intestinal flora can affect immune responses in multiple mucosal systems and facilitate systemic immune maturation (16), playing a crucial role in maintaining physiological equilibrium and influencing human health. Multiple studies (17, 18) have demonstrated a direct correlation between intestinal dysbiosis and impairment of the intestinal mucosal barrier integrity, resulting in an increased susceptibility to pulmonary infections. Recent investigations have extensively elucidated the link between imbalanced gut microbiota composition and RRTIs. The etiology of RRTIs is multifaceted. However, probiotics are widely acknowledged for their capacity to modulate both microecology and immune responses (19). These microorganisms can stimulate antigen-presenting cells (APCs), regulate cytokine secretion, and immunoglobulin production levels, while also reinforcing the protective layer on intestinal mucosal cells. Moreover, they exert influence over mucus generation while conferring resistance against invading pathogens or viruses (20). The objective of this review is to provide a comprehensive overview of current research advancements on probiotics in preventing and treating RRTIs in children. Additionally, it proposes several innovative strategies to address the limitations associated with probiotic therapies for RRTIs. This involves delving deeper into the underlying mechanisms, summarizing findings from clinical trials, addressing existing challenges, and identifying key areas for future research. By synthesizing findings from multiple studies, this review seeks to offer clinicians, researchers, and policymakers a multifaceted perspective that promotes evidence-based utilization of probiotics in pediatric healthcare while also highlighting areas requiring further investigation.

Currently, there is no global consensus on the diagnostic criteria for RRTIs in children. Different countries have varying definitions for RRTIs; however, the methods employed to diagnose them are consistent and based on infection frequency (Figure 1). Most scholars tend to define childhood RRTIs as eight or more documented respiratory infections per year in children under 3 years old, and six or more episodes in children over 3 years old (21, 22). RRTIs encompass both recurrent upper respiratory tract infections and recurrent lower respiratory tract infections (23). While there is no consensus on the exact definition of relapse, certain specific respiratory diseases have precise and unambiguous criteria for relapse. For instance, infectious rhinitis occurring more than five times per year is considered a recurrence in cases of recurrent upper respiratory tract infections, while acute otitis media recurring three times within six months or four times within twelve months also qualifies as a relapse (22). Recurrent lower respiratory tract infections are defined as bronchitis, bronchiolitis, or pneumonia occurring three or more times per year (24). In healthy individuals, a symbiotic and mutually regulated dynamic equilibrium exists between the microorganisms in the respiratory tract and intestine and their hosts, which is crucial for maintaining normal physiological functions. However, when pathogenic microorganisms invade the human body, this delicate microbial balance can be disrupted, resulting in the development of pathological conditions (25). Due to their less responsive immature immune systems towards environmental pathogens (26), children often encounter respiratory tract infections. The intestine functions as a pivotal immunological organ crucial for the maturation and differentiation of immune cells (27). The intestinal microbiota can modulate the cells of the intestinal epithelium, facilitating immune tissue development associated with the intestinal mucosa and activating receptors on immune cells (28). It not only plays a local regulatory role in the mucosal immune system but also has a pivotal regulatory role in cell-mediated systemic immune response (29). In addition to aiding nutrient absorption, gut microbiota defends against infections by competing for resources with pathogens or secreting antibacterial substances that eradicate pathogens (30). The gut-lung axis refers to bidirectional communication established between intestinal microorganisms and their metabolites, which regulate or exchange information between intestinal and lung tissues via circulation through blood and lymphatic systems (31). Previous studies have demonstrated that this regulatory network influences respiratory diseases through its impact on gut microbiota (32). Additionally, histoembryological evidence confirms that both the intestine and respiratory tract originate from common embryonic tissue known as the foregut of the gastrum, with their mucosal inner walls being continuous (33). Due to the thinner intestinal wall, higher permeability, and weaker barrier function in children with RRTIs, allergens such as toxins and incompletely digested products may enter the body through the intestine and subsequently reach the lungs via blood circulation. Several studies have compared populations of Bifidobacterium and Lactobacillus in the gut of children with RRTIs to healthy children, revealing a significant reduction. This dysbiosis in intestinal microbiota leads to decreased levels of IgA-dominated immunoglobulins (34).

Probiotics are defined as “living microorganisms that confer health benefits to the host when administered in sufficient quantities” (35). Lactobacillus and Bifidobacteria, which are widely used in the field of probiotics (36), secrete various beneficial compounds like vitamins, short-chain fatty acids (SCFAs), bacteriocins, and exopolysaccharides (EPS) that contribute to their positive effects (37). Most children develop RRTIs due to their immature immune system during development, and typically there is no underlying disease present during this period (23). Certain probiotics strains play a crucial role in preventing and treating respiratory diseases by inhibiting pathogen growth and harmful bacteria, producing antimicrobial substances, enhancing the defense function of the epithelial cell barrier, and importantly regulating immune system activity (22), thereby impacting both innate and adaptive immunity in the host (Figure 2). Recent studies have unveiled a correlation between dysbiosis of intestinal flora and RRTIs. For instance, strains such as Lactobacillus rhamnosus and Escherichia coli Nissle 1917 can activate pattern recognition receptors (PRRs) on epithelial cells through microbially associated molecular patterns to regulate tight junctions and adhesion junctions, thereby preserving the integrity of the epithelial barrier (38). The probiotics inhibit the proliferation of pathogenic bacteria by competing for adhesion sites on epithelial cells or depleting their essential nutrients, while simultaneously secreting antibacterial substances to establish an unfavorable microenvironment for pathogen survival (39). Additionally, probiotic metabolites like SCFAs modulate the differentiation of immune cells and control excessive immune responses by interacting with G protein-coupled receptors (GPCRs) and inhibiting histone deacetylases (HDACs), thereby playing a crucial role in immune response, inflammation, and lung disease development (40). Moreover, probiotics can exhibit antiviral effects through direct interaction with viruses or the generation of antiviral metabolites while stimulating the host's immune system response (41). Gut-associated lymphoid tissue (GALTs) is a vital part of the peripheral immune system that houses around 80% of active immune cells. Probiotics have the potential to enhance systemic immunity by modulating GALTs' response, indirectly strengthening the respiratory tract's defense capabilities (42). Upon encountering intestinal microbiota, infectious pathogens, as well as ingested or inhaled antigens, GALTs facilitate frequent interactions between immune cells and these antigens, thus triggering an ongoing immune response that encompasses germ-center (GC) formation within intestinal microbiota and subsequent responses to pathogen invasion (43). The specific mechanism involves the encapsulation of GALTs by microfold (M) cells, facilitating their targeted delivery to dendritic cells (DCs) and subsequent antigen exposure, thereby initiating immune responses from T and B cells in the mucosa (44). Furthermore, probiotics mediate the innate immune response through PRRs, particularly toll-like receptors (TLRs), which recognize and bind to pathogen-associated molecular patterns (PAMPs) on the surface of pathogenic microorganisms. This interaction triggers the activation of signaling pathways such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) (45, 46). As a result, this process modulates the secretion of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), thereby regulating host-pathogen interactions and influencing the immune and inflammatory responses. Lactococcus lactis can initiate signal transduction in DCs through the TLR2, TLR3, and TLR9 pathways, thereby promoting DC maturation, enhancing Th1 cell differentiation, and upregulating the expression of IL-12, IFN-γ, and TNF-α (47). Additionally, probiotics have been shown to induce clonal expansion of IgA-producing B cells by elevating IL-6 levels in a TLR2-dependent manner (37). Therefore, they serve as a preventive and therapeutic strategy against respiratory infections.

Probiotics, which are a consortium of living bacteria, exert beneficial effects on the human body by modulating the gut microbiome, enhancing immune function, and improving digestive health. Although numerous probiotic products have demonstrated safety (92), their usage may also lead to certain adverse reactions. Currently, there is no globally unified standard for evaluating probiotics due to ongoing advancements in safety assessments across different countries. The utilization of probiotics may pose several potential risks and adverse effects. For example, some clinical reports have indicated that probiotics can lead to gastrointestinal side effects such as diarrhea and bloating (93). In addition, it is imperative to acknowledge the potential for horizontal gene transfer of antibiotic resistance genes from probiotic strains to other microorganisms. In 1998, viable probiotic bacteria were identified as donors in the conjugative transfer of antibiotic resistance (AR) genes, a phenomenon subsequently corroborated by additional studies confirming the intestinal transfer capability of AR genes (94). Moreover, AR gene transfer can also occur through transformation via free DNA or phage-mediated transduction (95). As highlighted in the preceding clinical application section, probiotics generally have exhibited a relatively favorable safety profile among healthy pediatric populations. However, it has been reported that certain probiotic strains may act as opportunistic pathogens in immunocompromised individuals, potentially leading to adverse effects such as life-threatening conditions like pneumonia (96), endocarditis (97), and sepsis (98). To ensure the safe application of probiotics, it is crucial to perform whole genome sequencing of probiotic strains. This method not only facilitates strain-level identification but also enables the detection of virulence factors, pathogenicity determinants, and AR genes, thereby enhancing the safety and efficacy of probiotic use (95).

The present review comprehensively analyzes recent advancements in using probiotics for preventing and treating RRTIs in pediatric patients. Multiple studies have demonstrated that probiotics exert a favorable influence on reducing the incidence of RRTIs and alleviating symptoms by modulating the gut microbiome, enhancing immune system functionality, attenuating inflammatory response, and other underlying mechanisms. In terms of prevention, multiple randomized controlled trials have consistently demonstrated the significant efficacy of specific strains of probiotic supplementation in reducing the incidence and duration of RRTIs in children. Moreover, probiotics have also been found to effectively decrease antibiotic usage frequency, thereby mitigating risks associated with adverse reactions and resistance. Regarding treatment, although available evidence is not as robust as that for prevention studies, preliminary research suggests that probiotics may expedite recovery from respiratory infections by enhancing host immune function. However, it should be noted that considerable variation exists in the efficacy of different strains and combinations necessitating further high-quality investigations to determine optimal treatment options. Despite showing promise in preventing and treating RRTIs in children, several challenges and unresolved issues still persist. For example, further investigation is required regarding aspects such as optimal dosage, duration, strain selection, and suitability for specific pediatric populations concerning probiotics. Moreover, significant gaps persist in understanding the long-term effects of probiotics on pediatric populations, particularly in children with chronic or recurrent conditions. When administering probiotics, it is imperative to conduct a comprehensive evaluation of individual differences, lifestyle factors, genetic backgrounds, potential risks, and long-term outcomes to ensure both the safety and efficacy of these interventions. The significance of whole-genome sequencing as an indispensable tool for evaluating the safety of probiotic strains cannot be overstated. It not only enhances strain identification for production tracing and infection investigation but also facilitates the classification and assessment of associated risks. Additionally, it enables the detection of potential virulence, pathogenicity, or antibiotic resistance genes within genomes. Probiotic formulations must ensure safety regarding purity, potency, and composition through rigorous testing protocols to prevent contamination, especially with live organisms. Stricter testing measures are imperative for products intended for vulnerable populations. In conclusion, while probiotics hold promising prospects in preventing and treating RTIs in children, their efficacy and safety necessitate verification through additional clinical trials. Future research ought to concentrate on identifying the optimal combination and usage strategies for probiotics, as well as exploring their integration with other interventions (e.g., vaccination, nutritional support) to provide more comprehensive approaches towards safeguarding children's health.