ReviewFrontiers in allergy2026
The AhR-TLR4 axis in non-IgE-mediated Cow's milk allergy: a systematic review with integrated multi-omics corroboration.
Review in Frontiers in allergy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 authors.
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Abstract
Background & aims: Non-IgE-mediated cow's milk allergy (non-IgE-CMPA) is the most prevalent form of CMPA in infancy; however, its pathogenesis is still poorly understood, which impedes the development of targeted nutritional strategies. Recent evidence suggests a connection between gut dysbiosis and immune dysregulation. Therefore, this systematic review, incorporating multi-omics corroboration, sought to clarify a pathogenic axis driven by dysbiosis and involving the aryl hydrocarbon receptor (AhR) and Toll-like receptor 4 (TLR4). Furthermore, the review aimed to evaluate related predictive biomarkers and potential therapeutic approaches. Methods: We synthesized evidence from 39 studies of infants (0-3 years) with physician-confirmed non-IgE-CMPA, following PRISMA guidelines. To visually corroborate key mechanistic pathways at cellular resolution, we performed an integrative analysis of publicly available single-cell RNA sequencing datasets from pediatric intestinal biopsies. Results: Non-IgE-mediated CMPA exhibits a distinct gut dysbiosis signature, characterized by decreased Bifidobacterium and increased Enterobacteriacea. This dysbiosis is associated with reduced microbial AhR ligands and TLR4 pathway in intestinal epithelial cells. A B/E ratio <0.5 at 3 months of age predicted persistent allergy (HR = 1.9, AUC = 0.82). scRNA-seq data confirmed IEC-specific upregulation of TLR4 co-receptors (CD14, LY96), activation of the NLRP3 inflammasome, and reduced expression of intestinal barrier integrity markers. Synbiotic intervention (LGG + HMOs) was associated with a 67% resolution of symptoms. Conclusion: Early-life gut dysbiosis may disrupt AhR-TLR4 crosstalk, leading to NLRP3-mediated inflammation and barrier dysfunction in non-IgE-mediated CMPA. Bradford Hill criteria suggest a causal relationship for this pathway. Furthermore, the B/E ratio holds promise for early risk stratification, and synbiotics represent a potential mechanism-guided nutritional strategy for restoring microbial-immune homeostasis. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/view/CRD42025104533, PROSPERO CRD420251045333.
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