Precision synbiotic intervention with 2'-fucosyllactose and infant-derived Bifidobacterium modulates gut-immune axis and reduces disease risk in toddlers: a randomized controlled trial

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Abstract

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, double-blind, 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 × 1010 CFU + B. bifidum R0071 1.5 × 1010 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).

Abstract as published, via PubMed.