Biological interpretation of the metabolic alterations detected in a murine model of allergic enteritis

ZUBELDIA- VARELA E; BLANCO- PEREZ F; BARKER- TEJEDA T C; ROJO D; VILLASEÑOR SOLÍS A; LAIÑO J; YU P; BARBAS C; VIETHS S; BARBER D; TODA M; PEREZ- GORDO M

Congreso; European Academy of Allergy and Clinical Immunology Hybrid Congress; 2021

European Academy of Allergy and Clinical Immunology

Background: Allergic enteritis (AE) is described as a T- cell mediated food allergy. However, patients with persistent AE often develop IgE, and the pathological mechanism is not well understood. Based on the hypothesis that high levels of IgE may influence metabolome and promote allergic inflammation, we have analysed and interpreted the metabolomic profiles of a novel AE model using IgE knock- in (IgEki) mice, which overexpress IgE instead of IgG1. Method: Mice were sensitized with ovalbumin (OVA) and challenged with egg white for 7 days. Faeces and serum samples from 1) wild type non- sensitized (WT) mice; 2) WT OVA- sensitized (WT/OVA) mice; 3) IgEki non- sensitized (IgEki) mice, and 4) IgEki OVAsensitized (IgEki/OVA) mice, were analysed by multiplatform untargeted metabolomics. Data treatment and biological interpretation were performed with specific software. Results: First, we studied the metabolism of WT/OVA mice and observed alterations in faces but not serum metabolites. WT mice responded to OVA by increasing the production of certain inflammatory mediators. Next, we explored the metabolism of IgEki mice, which showed a mild allergic inflammatory profile, with increased inflammatory mediators, but no clinical symptoms (e.g., weight loss). Besides, in the faeces of IgEki mice, several amino acids (e.g., aspartate, glutamate, and tryptophan) were reduced and alterations in glycerophospholipid and glycosphingolipid metabolisms were observed. Finally, the most severe model, the IgEki/OVA, was analysed. OVA sensitization of IgEki mice showed similar differences in the metabolomics profile when compared with either WT/OVA or IgEki mice. IgEki/OVA mice showed: a) increased serum Nmethylhistamine, which is a stable product of histamine metabolism and a proinflammatory biomarker of mast cell activation and degranulation in addition with several other metabolites, b) decreased Krebs’ cycle and Urea cycle metabolites, and c) decreased key microbial metabolites in faeces, such as butyric acid, pointing to a gut microbial alteration. These alterations demonstrate that IgEki/OVA mice exhibit a severe allergic profile of AE. Conclusion: This animal model provides valuable information to understand IgE- mediated exacerbation in AE since a severity gradient is observed in the four experimental groups, being the IgEki/OVA mice the most severe. Our data suggest that high IgE levels lead to the exacerbation of AE causing inflammation and severe disturbances in the gut microbiota and the energy metabolism.