Untargeted Metabolomic Profiling Identifies Disease-specific Profiles in Food Allergy

Abstract

Background. Food allergy (FA) affects an increasing proportion of children for reasons that remain obscure. Identification of pathogenic mechanisms involved in FA using untargeted metabolomic approaches may provide much needed diagnostic and prognostic disease biomarkers and improved treatment options.Methods. Mass spectrometry-based untargeted metabolomic profiling was performed on serum samples of children with either FA alone, asthma alone or both FA and asthma as well as healthy pediatric controls.Results. FA subjects exhibited a disease-specific metabolomic signature as compared to both control subjects and asthmatics. In particular, FA was uniquely associated with a marked decrease in sphingolipids, as well as a number of other lipid metabolites, in the face of normal frequencies of circulating natural killer T (NKT) cells. Specific comparison of FA and asthmatic subjects revealed differences in the microbiota-sensitive aromatic amino acid and secondary bile acid metabolism. Children with both FA and asthma exhibited a metabolomic profile that aligned with that of FA alone but not asthma. Among children with FA, distinct profiles were associated with history of severe reactions and presence of multiple FA. Conclusions.Children with FA display a disease-specific metabolomic profile that is informative of disease mechanisms and severity, and which dominates in the presence of asthma. Lower levels of sphingolipids and ceramides and other metabolomic alterations observed in FA children may reflect the interplay between an altered microbiota and immune cell subsets in the gut.

A Systematic Review of Metabolic Alterations Underlying IgE‐Mediated Food Allergy in Children

“…[35,40,[49][50][51] The latter was confirmed by altered lactate concentrations in blood of patients with IgE-FA and a history of anaphylaxis (Figure 3). [19] Additionally, a shift towards aerobic glycolysis can be hypothesized in immune cells as they are known to alter their metabolism to cope with the increasing demand resulting from the need to synthesize biological precursors associated with immune cell activation. Within the rapidly dividing and proliferating immune cells, glycolytic metabolism can be regarded as the most dominant and essential pathway to ensure adequate energy supply.…”

“…Marked alterations could be observed in feces of children who will develop IgE-FA, as well as in blood of patients already diagnosed with IgE-FA, more specifically in metabolites associated with de novo sphingolipid syntheses, including sphinganine, sphingomyelins, and ceramides. [19,34] Sphingolipids are major components of cellular membranes and participate in multiple cellular functions. They can be synthesized de novo as components of cellular membranes, derived from dietary sources or produced by Bacteroides species in the gut.…”

“…[57] Therefore, altered enzyme functionalities may hint towards an immune-regulatory role for this pathway, resulting in a systemic, non-allergen specific perturbation in Th17 response. [19,58]…”

“…[33,39] Both the kynurenine and indolic compound pathways are important in immune responses at mucosal barriers and contribute to intestinal homeostasis, due to direct downregulation of T cell activity or induction of various regulatory T (Treg) cells. [19,65] Metabolites within the indole pathway, a.o. indole propionate and 5-hydroxyindoleacetate (5-HIAA) were respectively increased and decreased in patients with a history of anaphylaxis or AM manifestations.…”

“…[16,17] Each allergic manifestation within the AM represents complex and diverse inflammatory conditions, with markedly heterogenous clinical phenotypes complicating diagnostics, especially in IgE-FA. [18,19] However, a correct diagnosis is essential in order to prevent both allergic reactions and unnecessary dietary restrictions, as the latter could result in nutritional imbalances and growth problems, especially in children. [20,21] The current diagnostic procedure relies on a thorough assessment of the clinical history of the patient, followed by additional diagnostic tests, including skin prick tests (SPT), immunoassays of serum food-specific IgE levels and, in some cases, a double-blinded placebo-controlled food challenge.…”