Metabolomics identifies phenotypic biomarkers of amino acid metabolism in milk allergy and sensitized tolerance - 18/04/24

Doi : 10.1016/j.jaci.2024.02.023

Qiaozhi Zhang, PhD ^a, Hui Wang, BS ^a, Shenyu Zhang, MM ^b, Mingwu Chen, MD ^c, Zhongshan Gao, MD ^d, Jinlyu Sun, MD ^e, Jizhou Wang, MD ^b,^⁎ , Linglin Fu, PhD ^a,^⁎
^a Food Safety Key Laboratory of Zhejiang Province, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
^b Department of Hepatobiliary Surgery, the First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, China
^c Department of Pediatrics, the First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, China
^d Allergy Research Center, Zhejiang University, Hangzhou, China
^e 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

^∗Corresponding authors: Linglin Fu, PhD, School of Food Science and Biotechnology, Zhejiang Gongshang University, 18 Xue Zheng St, Hangzhou 310018, Zhejiang Province, China.School of Food Science and BiotechnologyZhejiang Gongshang University18 Xue Zheng StHangzhouZhejiang Province310018China^∗Jizhou Wang, MD, Department of Hepatobiliary Surgery, First Affiliated Hospital of University of Science and Technology of China, Hefei 230036, China.Department of Hepatobiliary SurgeryFirst Affiliated Hospital of University of Science and Technology of ChinaHefei230036China

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 18 April 2024

Graphical abstract

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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.

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Key words : Amino acid metabolism, biomarker, food allergy, metabolomics, sensitized tolerance

Abbreviations used : AUC, Bos d 5, Bos d 8, CMA, DEM, FA, GABA, HC, MA, MA_Mono, MA_Poly, MST, PLS-DA, sIgE, SPT, UPLC-MS/MS