IL-33/ST2 signalling in pediatric food allergy and eosinophilic gastrointestinal disorders: a systematic review of human and preclinical evidence

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Abstract
Background: Interleukin-33 (IL-33) is an epithelial-derived member of the IL-1 cytokine family that functions as an alarmin and signals through the ST2 receptor, upstream of type 2 inflammation. Together with thymic stromal lymphopoietin (TSLP) and IL-25, it constitutes an epithelial alarmin triad that orchestrates barrier-related immune responses. Despite substantial mechanistic data, the specific role of IL-33 as a biomarker and therapeutic target in pediatric food-related allergic disease remains insufficiently defined. Objective: This systematic review aims to synthesize current evidence on serum and tissue IL-33 in pediatric IgE-mediated food allergy and eosinophilic gastrointestinal disorders (EGIDs), to delineate its association with disease severity, clinical phenotype and oral immunotherapy (OIT) outcomes, and to critically appraise the IL-33/ST2 axis as a candidate biomarker and therapeutic target within the broader epithelial alarmin network. Methods: A systematic search of PubMed/MEDLINE, Web of Science, Scopus and the Cochrane Library (2010–2026) identified pediatric clinical studies quantifying IL-33 or IL-33/ST2 in food allergy or EGIDs, alongside murine and in vitro studies directly interrogating IL-33-dependent mechanisms in food allergy models. Eligible studies were screened and extracted according to predefined PICO criteria. Results: Fourteen studies fulfilled the inclusion criteria (four pediatric clinical cohorts, ten direct preclinical murine or in vitro studies). Across murine models, keratinocyte-derived IL-33 consistently activated a skin-to-gut axis driving intestinal mast-cell expansion and IgE-independent food anaphylaxis, which was abrogated by genetic or pharmacologic ST2 blockade. In a small case-control study of nine children with eosinophilic gastroenteritis, serum IL-33 and TSLP were increased during active disease and declined after dietary elimination. In pediatric eosinophilic esophagitis, IL-33 was increased in tissue but not consistently in serum. Conversely, serum IL-33 demonstrated limited discriminatory value in IgE-mediated food allergy. Conclusions: IL-33 emerges as a context-dependent yet non-redundant component of the epithelial alarmin circuitry in pediatric food-related allergic disease, as candidate biomarker of epithelial inflammation in pediatric EGIDs. However, current clinical evidence is limited and requires validation in larger prospective cohorts.

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