Ke Chen

Gut microbiota dysbiosis has emerged as a key feature in pediatric acute lymphoblastic leukemia (ALL), driven by chemotherapy, antibiotic exposure, and treatment-related nutritional impairment. Increasing evidence indicates that disruption of microbial diversity and depletion of short-chain fatty acid–producing bacteria are closely associated with infectious complications, gastrointestinal toxicity, and potentially reduced treatment efficacy. This review synthesizes current evidence on the interplay between gut microbiota and pediatric ALL across four dimensions: clinical outcomes, treatment-related toxicity, pharmacological interactions, and prognosis. We further summarize how leukemia therapy reshapes microbial ecosystems through cytotoxic agents, antimicrobial exposure, and dietary alterations. In addition, we discuss microbiota-centered therapeutic strategies, including probiotics, prebiotics, synbiotics, postbiotics, dietary interventions, and fecal microbiota transplantation. While promising, these approaches require careful validation in pediatric oncology due to safety considerations and limited clinical trial data. Finally, we highlight methodological advances such as multi-omics integration and machine learning approaches, which may enable microbiome-based risk stratification and precision supportive care in the future. Overall, gut microbiota represents a potential modifiable factor influencing clinical outcomes in pediatric ALL.

The original version of this article has been updated.

Background: Early childhood represents a critical window for nutritional programming of immune function and microbiome establishment. While human milk oligosaccharides (HMOs) and probiotics individually demonstrate health benefits, their synergistic integration as synbiotics remains underexplored in toddler populations. This study aimed to evaluate whether a precision synbiotic combining 2′-fucosyllactose (2’-FL) with infant-adapted Bifidobacterium strains provides superior protection against common pediatric conditions compared with probiotics alone or placebo, and to elucidate underlying gut-immune mechanisms. Aim: To determine the efficacy of a 2’-FL-containing synbiotic on infectious and atopic disease incidence, gut microbiota composition, and intestinal immune markers in children aged 1–3 years. Methods: In this multicenter, doubleblind, placebo-controlled, three-arm trial, 390 healthy toddlers were randomized (1:1:1) to receive (1) synbiotic (2’-FL 1.0 g/day + B. infantis R0033 1.5 × 10 ⁹ CFU + B. bifidum R0071 1.5 × 10 ⁹ CFU); (2) probiotic (identical strains/doses); or (3) placebo (maltodextrin 1.5 g/day) for 12 weeks, with 12-week follow-up. Primary outcome was upper respiratory tract infections (URTIs) incidence over 24 weeks. Secondary outcomes included pneumonia, diarrhea, eczema, antibiotic use, gut microbiota (16S rRNA V3-V4 sequencing), and fecal immune biomarkers (calprotectin, sIgA, HBD-2, LL-37). Dietary intake was monitored to control nutritional confounders. Result: Synbiotic vs. placebo: URTI incidence reduced from 85.4 to 55.4% (adjusted risk ratio (aRR) 0.64, 95% CI 0.43–0.95; ARR 30.0%, NNT = 3.3; p = 0.028); pneumonia from 17.7 to 7.7% (RR 0.40, 0.17–0.94; p = 0.034); diarrhea from 17.7 to 10.0% (aRR 0.54, 0.30–0.95; p = 0.032); and eczema from 13.1 to 1.5% (aRR 0.12, 0.04–0.35; ARR 11.6%, NNT = 2.9; p < 0.001). Probiotic alone reduced only eczema (aRR 0.10, 0.03–0.40; p = 0.001). The synbiotic significantly altered gut beta-diversity (Bray-Curtis, p = 0.042) and enriched Bifidobacterium catenulatum and B. kashiwanohense species with conserved HMO utilization pathways. At 24 weeks, synbiotic reduced fecal calprotectin (62.7 ± 23.9 vs. 77.9 ± 24.6 μg/g; p = 0.004) and increased sIgA (1.37 ± 0.38 vs. 1.15 ± 0.49 mg/g; p = 0.014), indicating enhanced intestinal immune homeostasis. Conclusion: A 12-week precision synbiotic intervention combining 2’-FL with infant-derived Bifidobacterium strains significantly reduced the burden of respiratory infections, diarrhea, and atopic dermatitis in toddlers, with effects exceeding probiotics alone. These benefits were mediated by targeted gut microbiota modulation and enhanced mucosal immune function. This study provides evidence for integrative nutritional strategies in early childhood disease prevention and supports the development of next-generation synbiotic formulations. Clinical trial registration: This study was registered in the Chinese Clinical Trial Registry (ChiCTR2400088943) prior to enrollment ( https://www.chictr.org.cn/showprojEN.html?proj=235745 ).

Objective: To investigate the effects of a high-dose probiotic-lactoferrin (LF)-milk fat globule membrane (MFGM)-nucleotide combined formula on reducing the incidence risk of common diseases and related symptoms and improving growth and hemoglobin level in neonates born via cesarean section. Methods: This trial was a prospective, multicenter, open-label, randomized, controlled 3-month intervention study. A total of 150 eligible neonates were enrolled. All participants completed the full intervention and provided clinical data. All enrolled formula-feeding neonates were randomly assigned to either the intervention group (IG, n = 50) or the control group (CG, n = 50), and 50 exclusively breastfed neonates were assigned to the breastfeeding control group (BCG). The formula used in the IG contained 2 × 10 ⁹ CFU/100 g probiotics, 200 mg/100 g LF, added MFGM, and 55 mg/100 g nucleotides. In contrast, neonates in the CG were fed a formula containing 45–50 mg/100 g LF and 30–35 mg/100 g nucleotides, without probiotic or MFGM fortification. The primary outcome was the frequency of upper respiratory tract infections (URTIs). Secondary outcomes included the incidence of other respiratory, gastrointestinal, and allergic symptoms and diseases, as well as infant anthropometric indicators (including length, weight and head circumference) and the hemoglobin (Hb) concentration. Result: The incidence of URTIs over the 3-month intervention showed no significant difference among the three groups [the incidences of URTIs in CG, IG, and BCG: 22% (11/50), 18% (9/50), and 14% (7/50), respectively, χ ² = 1.084, p = 0.582] according to both intention-to-treat (TT) and per protocol (PP) analyses [incidence of URTIs in CG, IG, and BCG: 22.9% (11/48), 19.6% (9/46), and 14.9% (7/47), respectively, χ ² = 0.680, p = 0.712]. After the 3-month intervention, compared with infants in the CG, infants in the IG showed a reduced risk ration (RR) for functional dyspepsia [RR = 0.756, 95% confidence interval (95% CI) = 0.587–0.974] and eczema (RR = 0.647, 95% CI = 0.449–0.933). Hb levels in the CG and IG were both significantly higher than those in the BCG (107.35 ± 9.26 vs. 105.99 ± 7.01 vs. 101.42 ± 7.07 g/L for CG, IG, and BCG, respectively; F = 9.629, p < 0.001), with no statistically significant difference between the CG and IG. No significant differences in anthropometric indicators were observed among the three groups ( p > 0.05). Conclusion: This study found no adverse effects associated with 3-month supplementation of a high-dose probiotic-LF-MFGM-nucleotide combined formula, supporting its safety for term neonates delivered by cesarean section. The primary outcome, URTI incidence, did not differ significantly among groups. Exploratory analyses suggested lower risks of functional dyspepsia and eczema in the intervention group; however, these findings should be considered preliminary and require confirmation in larger adequately powered studies. The intervention was well tolerated and showed safety comparable to standard feeding practices.

A major theme emerging from the collection is the role of probiotics in modulating immune function and reducing infections in children. Several randomized controlled studies investigated Bifidobacterium longum subsp. infantis YLGB-1496 in young children, demonstrating beneficial effects on common pediatric illnesses, immune regulation, and gut microbiota composition (1,2). Improvements in respiratory symptoms, gastrointestinal health, and immune-related biomarkers suggest that early microbiota modulation may strengthen host defense during critical periods of immune maturation.These findings carry particular weight because early childhood represents a window of developmental vulnerability. Environmental exposures, feeding practices, antibiotic use, and microbial colonization patterns during this period may exert long-term health effects. The observed benefits of targeted bifidobacterial supplementation support the hypothesis that selective microbiota interventions can help optimize immune resilience.Respiratory health represented another important area of investigation. Several studies and reviews explored the relationship between probiotics and pediatric respiratory diseases, including recurrent upper respiratory tract infections (3)(4)(5). One randomized controlled trial evaluating probiotic supplementation in infants reported improvements in both respiratory and gastrointestinal outcomes, accompanied by favorable shifts in gut microbial composition and immune parameters (3).Narrative reviews also summarized accumulating evidence supporting strainspecific probiotics, particularly Lacticaseibacillus rhamnosus GG, in respiratory disease prevention (5,6). These studies contribute to the growing understanding of the gut-lung axis, the bidirectional network linking intestinal microbiota with pulmonary immune responses.The collection made important contributions to allergic disease prevention and immune modulation. Allergic disorders continue to increase among children globally, and microbiota dysbiosis has been proposed as a major contributing factor. One clinical study investigated Bifidobacterium lactis BLa80 supplementation in reducing eczema incidence and respiratory infections in early childhood, demonstrating beneficial effects on microbiota balance and immune regulation (7).Systematic and umbrella reviews evaluated current evidence regarding probiotics in atopic dermatitis prevention and management (8,9). While some strains showed encouraging preventive effects, the reviews emphasized substantial heterogeneity in study design, probiotic formulation, timing of intervention, and clinical endpoints.Gastrointestinal diseases remain among the most established applications of probiotics in pediatric medicine, and multiple articles expanded the evidence base. Acute gastroenteritis, antibiotic-associated diarrhea, and intestinal dysbiosis continue to represent major global health burdens in infants and young children.One systematic review evaluated the combined use of Saccharomyces boulardii CNCM I-745 and smectite in children with acute gastroenteritis, reporting favorable effects on symptom duration and recovery (10). Another multicenter clinical study explored probiotic co-treatment for antibiotic-associated diarrhea, demonstrating benefits in symptom control and treatment tolerance (11). Additional reviews summarized the role of probiotics in pediatric gastrointestinal disorders and necrotizing enterocolitis prevention (12)(13)(14).Several articles moved beyond traditional gastrointestinal endpoints to explore broader systemic implications of microbiota modulation. Researchers increasingly recognize that gut microbial communities influence not only digestion and immunity, but also metabolic, endocrine, and neurobehavioral pathways.A particularly noteworthy aspect of this Research Topic was the inclusion of studies investigating the microbiota-gut-brain axis and neurodevelopmental disorders. Reviews focusing on autism spectrum disorder summarized recent advances in dietary interventions, microbiota modulation, and probiotic strategies aimed at improving gastrointestinal and behavioral symptoms (15). Alterations in microbial diversity, intestinal permeability, microbial metabolites, and immune activation may contribute to autism-related pathophysiology.Another review explored the association between trans fatty acid exposure, gut microbiota dysbiosis, inflammation, and attention-deficit/hyperactivity disorder (ADHD) (16). By integrating nutritional, microbial, and neurodevelopmental perspectives, these contributions reflect the increasingly interdisciplinary nature of pediatric microbiome research.The Research Topic also addressed obesity and metabolic dysfunction in children. Several articles discussed how probiotic interventions may influence metabolic homeostasis, adiposity, inflammation, and intestinal barrier integrity (17).Beyond common pediatric conditions, the collection included studies in rare or specialized clinical settings. One systematic review explored microbiota-targeted interventions in children with Prader-Willi syndrome, highlighting emerging evidence that microbiota modulation may provide adjunctive therapeutic benefits in this challenging population (18).Another innovative contribution examined Lactiplantibacillus plantarum DSM 33464 in children with elevated blood lead levels. This randomized placebocontrolled trial suggested that probiotic supplementation may have detoxification-related potential through modulation of intestinal barrier function, microbial metabolism, and heavy metal handling (19).Several articles explored methodological and conceptual issues relevant to pediatric probiotic research, emphasizing the importance of strain characterization, genomic identification, viability assessment, dosage standardization, and long-term safety evaluation (20)(21)(22)(23). As probiotic research matures, precise taxonomic identification and mechanistic validation...

Background: Early childhood is a critical period for immune development, with eczema and respiratory infections representing common health challenges. This study investigated the efficacy of Bifidobacterium animalis subsp. lactis BLa80 in reducing these conditions potentially through gut microbiome modulation. Methods: In a randomized, double-blind, placebo-controlled trial, 360 formula-fed infants and children aged below 3 years old with elevated allergy risk received daily B. lactis BLa80 (5 × 10 ⁹ CFU) or placebo for 180 days. Primary outcomes included eczema incidence and symptom burden, with secondary outcomes assessing respiratory infections, gastrointestinal symptoms, gut microbiota composition (16S rRNA sequencing), functional pathways (KEGG analysis), and fecal immune markers (ELISA). Results: The probiotic group demonstrated significantly reduced eczema incidence (27.6% vs. 69.5%, RR: 0.398, p < 0.001) and upper respiratory tract infections (19.4% vs. 42.5%, RR: 0.457, p < 0.001). Significant reductions were observed in symptom burden, including nasal congestion, vomiting, milk aspiration, and irritability. Microbiota profiling showed enrichment of beneficial taxa ( Akkermansia, Fusicatenibacter ) with enhanced metabolic pathways including tryptophan metabolism, vitamin biosynthesis, and xenobiotic degradation. Immunological profiling showed maintained human beta-defensin-2 ( p = 0.005), increased secretory IgA ( p < 0.001), and reduced calprotectin ( p < 0.001). Conclusions: B. lactis BLa80 supplementation effectively reduces eczema and respiratory infections associated with gut microbiome remodeling that may enhance barrier function, immune regulation, and metabolic capacity, supporting its use as a preventive nutritional strategy in early childhood. Clinical Trial Registration: ChiCTR2300074956.

Background Recurrent respiratory tract infections (RRTIs) in children are associated with substantial morbidity and healthcare burden. Modulation of the gut microbiota via probiotics represents a potential adjunctive strategy to prevent recurrent infections. This study evaluated the efficacy and safety of Bifidobacterium animalis subsp. lactis XLTG11 and Lactobacillus plantarum CCFM8661 in children with RRTIs. Methods In a double-blind, randomized, placebo-controlled trial, 120 children with RRTIs received either daily probiotic supplementation (1 × 10¹⁰ CFU/day; n = 60) or placebo (n = 60) for 3 months, with a 6-month follow-up. Primary outcome was clinical efficacy; secondary outcomes included gut microbiota composition (16 S rRNA sequencing) and plasma immune biomarkers (IgA, IgG, IgM, C3, C4). Results Probiotics significantly improved clinical efficacy compared with placebo in both per-protocol [82.1% vs. 64.2%, p = 0.033] and intention-to-treat analyses [76.7% vs. 56.7%, p = 0.020]. Children in the probiotic group experienced fewer and shorter respiratory episodes, including fever, cough, and pharyngeal congestion (all p < 0.05). Probiotic supplementation increased beneficial taxa (B. breve, L. plantarum, S. salivarius, W. cetiin) and reduced potentially pathogenic taxa (Anaerostipes, Vibrio). IgG and IgM levels remained stable or decreased in the probiotic group, contrasting with increases in the placebo group, indicating a balanced humoral response. No adverse events were reported. Conclusions Daily administration of XLTG11 and CCFM8661 for three months is safe and improves clinical outcomes in children with RRTIs, reducing new respiratory episodes and modulating gut microbiota and immune function. These findings support strain-specific probiotics as a viable adjunctive therapy in pediatric respiratory infections.

Background: Respiratory, gastrointestinal, and allergic diseases can significantly affect children’s physical and mental health and quality of life.Purpose: This study aimed to assess the safety of Bifidobacterium animalis subsp. lactis BLa80, its preventive effects on morbidities related to respiratory, gastrointestinal, and allergic diseases, and its impact on the gut microbiome of children during the study period.Methods: Healthy children aged 0–3 years were randomly assigned to an intervention group (IG; n=180) or control group (CG; n=180). Participants received probiotics or placebo for 3 months, followed by a 3-month follow-up period. Children in the IG received one oral probiotic sachet daily for 90 consecutive days starting on the first day of the intervention. Each sachet contained maltodextrin and the BLa80 strain at 5×109 colony-forming units (CFUs). Children in the CG received placebo sachets containing maltodextrin only. The primary outcome measure was eczema morbidity during the 6-month study period. Secondary outcomes included acute upper respiratory tract infections (URTIs) and acute tracheitis/bronchitis. Fecal gut microbiota profiles were assessed by 16S rRNA sequencing. Fecal immune biomarkers including calprotectin, human beta-defensin-2 (HBD-2), cathelicidin (LL-37), and secretory immunoglobulin A were also determined. This study was registered with the China Clinical Trial Center (ChiCTR2300074956).Results: Per-protocol analyses were conducted of 156 and 164 subjects in the IG and CG, respectively. The morbidity rate of eczema during the 6-month period was significantly lower in the IG versus CG (intention-to-treat analysis: 26.1% [47 of 180] vs. 66.7% [120 of 180], P<0.01; per-protocol analysis: 30.1% [47 of 156] vs. 73.2% [120 of 164], P<0.01). Probiotic supplementation was also associated with a lower risk of URTIs (IG vs. CG: 40.3% vs. 20.7%; risk ratio [RR], 0.752; 95% confidence interval [CI], 0.653–0.866) and acute tracheitis/bronchitis (18.8% vs. 9.5%; RR, 0.897; 95% CI, 0.825–0.977). Bla80 intervention increased the relative abundance of Bifidobacterium bifidum, Bifidobacterium kashiwanohense PV20-2, Bifidobacterium longum, and Enterococcus dispar ATCC (American Type Culture Collection) 51266 while decreasing the abundance of Bacteroides thetaiotaomicron. Postintervention, the IG had significantly lower concentrations of LL-37 (3,509.31±587.89 pg/g vs. 3,720.82±614.90 pg/g, P=0.006) and HBD-2 (202.36±56.35 pg/g vs. 222.65±56.23 pg/g, P=0.005) than the CG. No serious adverse events were reported in either group.Conclusion: The daily administration of BLa80 at 5×109 CFU for 3 months in children aged 0–3 years reduced therisk of eczema, URTIs, and acute tracheitis/bronchitis and beneficially altered the gut microbiome composition, fecal immune biomarkers, and functional gene composition without any adverse effects.