Probiotic, prebiotic, and synbiotic interventions targeting the early-life gut-brain axis: A systematic review of...

Early life represents a critical window for maturation of the gut microbiota, mucosal immunity, and neuroimmune pathways underpinning the gut-brain axis (GBA). Probiotic, prebiotic, and synbiotic interventions have been proposed to modulate these processes; however, their mechanistic effects on GBA-relevant biomarkers in humans remain unclear. We conducted a systematic review of randomized controlled trials (RCTs) evaluating microbiota-directed interventions in infants aged 0-36 months, focusing on biological pathways implicated in gut-brain communication. Searches of PubMed/MEDLINE, Scopus, and Web of Science identified six eligible RCTs including 1148 randomized participants, of whom 923 contributed data to at least one GBA-relevant biomarker. Outcomes were synthesized across six mechanistic domains: intestinal microbiota composition and functional proxies, microbial metabolites, mucosal immunity, systemic cytokines, intestinal inflammation and permeability, and hypothalamic-pituitary-adrenal (HPA) axis activity. Across trials, interventions were associated with localized mucosal effects, including selective enrichment of Bifidobacterium and Lactobacillus, modest reductions in fecal pH, and modest, variably reported increases in fecal secretory sIgA. In contrast, short-chain fatty acids (SCFAs) were inconsistently reported and showed no robust between-group differences. Systemic cytokines, fecal calprotectin, permeability markers, basal salivary cortisol, and neurodevelopmental outcomes remained unchanged. Methodological heterogeneity, frequent values below assay detection limits, and developmental variability precluded quantitative meta-analysis. Available RCT evidence, although limited and heterogeneous, suggests that early-life microbiota-directed interventions may be associated with compartmentalized microbial and mucosal immune modulation without measurable propagation to systemic neuroimmune or neurodevelopmental pathways in healthy or mildly symptomatic infants. These findings support a model of developmental neuroimmune gating within the early-life GBA, defined here as the physiological restriction of signal propagation from mucosal to systemic and central pathways during early life, and highlight the need for standardized biomarker frameworks, dynamic neuroendocrine assessments, and studies in higher-risk populations to clarify mechanistic relevance.