Metabolomics identifies phenotypic biomarkers of amino acid metabolism in milk allergy and sensitized tolerance

Abstract

BackgroundA substantial proportion of sensitized individuals tolerate suspected foods without developing allergic symptoms; this phenomenon is known as sensitized tolerance. The immunogenic and metabolic features underlying the sensitized-tolerant phenotype remain largely unknown. ObjectiveIn this study, we aimed to uncover the metabolic signatures associated with clinical milk allergy and sensitized tolerance using metabolomics. MethodsWe characterized the serum metabolic and immunological profiles of children with clinical IgE-mediated milk allergy (MA; n = 30) or milk-sensitized tolerance (MST; n = 20) and healthy controls (n = 21). A comparative analysis was performed to identify dysregulated pathways associated with the clinical manifestations of food allergy. We also analyzed specific biomarkers indicative of different sensitization phenotypes in children with MA. The candidate metabolites were validated in an independent quantification cohort (n = 41). ResultsMetabolomic profiling confirmed the presence of a distinct metabolic signature that discriminated children with MA from those with MST. Amino acid metabolites generated via arginine, proline, and glutathione metabolism were uniquely altered in children with sensitized tolerance. Arginine depletion and metabolism through the polyamine pathway to fuel glutamate synthesis were closely associated with the suppression of clinical symptoms in the presence of allergen-specific IgE. In children with MA, the polysensitized state was characterized by disturbances in tryptophan metabolism. ConclusionsBy combining untargeted metabolomics with targeted validation in an independent quantification cohort, we identified candidate metabolites as phenotypic and diagnostic biomarkers of food allergy. Our results provide insights into the pathological mechanisms underlying childhood allergy and suggest potential therapeutic targets.