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

Qiaozhi Zhang; Hui Wang; Shenyu Zhang; Mingwu Chen; Zhongshan Gao; Jinlyu Sun; Jizhou Wang; Linglin Fu

doi:10.1016/j.jaci.2024.02.023

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

J Allergy Clin Immunol. 2024 Mar 24:S0091-6749(24)00293-8. doi: 10.1016/j.jaci.2024.02.023. Online ahead of print.

Authors

Qiaozhi Zhang¹, Hui Wang¹, Shenyu Zhang², Mingwu Chen³, Zhongshan Gao⁴, Jinlyu Sun⁵, Jizhou Wang⁶, Linglin Fu⁷

Affiliations

¹ Food Safety Key Laboratory of Zhejiang Province, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China.
² Department of Hepatobiliary Surgery, the First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, China.
³ Department of Pediatrics, the First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, China.
⁴ Allergy Research Center, Zhejiang University, Hangzhou, China.
⁵ Allergy Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶ Department of Hepatobiliary Surgery, the First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, China. Electronic address: wangjizhou1984@hotmail.com.
⁷ Food Safety Key Laboratory of Zhejiang Province, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China. Electronic address: fulinglin@zjgsu.edu.cn.

PMID: 38522626
DOI: 10.1016/j.jaci.2024.02.023

Abstract

Background: A 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.

Objective: We aimed to uncover the metabolic signatures associated with clinical milk allergy (MA) and sensitized tolerance using metabolomics.

Methods: We characterized the serum metabolic and immunologic profiles of children with clinical IgE-mediated MA (n = 30) or milk-sensitized tolerance (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).

Results: Metabolomic profiling confirmed the presence of a distinct metabolic signature that discriminated children with MA from those with milk-sensitized tolerance. 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 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.

Conclusions: By 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 pathologic mechanisms underlying childhood allergy and suggest potential therapeutic targets.

Keywords: Amino acid metabolism; biomarker; food allergy; metabolomics; sensitized tolerance.