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Integrated gut metabolome and microbiome fingerprinting reveals that dysbiosis precedes allergic inflammation in IgE-mediated pediatric cow's milk allergy
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  • Lynn Vanhaecke,
  • Ellen De Paepe,
  • Vera Plekhova,
  • Pablo Vangeenderhuysen,
  • Nele Baeck,
  • Dominique Bullens MA,
  • Tania Claeys,
  • Marilyn De Graeve,
  • Kristien Kamoen,
  • Anneleen Notebaert,
  • Tom Van de Wiele,
  • Wim Van Den Broeck,
  • Koen Vanlede,
  • Myriam Van Winckel,
  • Lars Vereecke,
  • Chris Elliott,
  • Eric Cox
Lynn Vanhaecke
Universiteit Gent Faculteit Diergeneeskunde

Corresponding Author:lynn.vanhaecke@ugent.be

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Ellen De Paepe
Universiteit Gent Faculteit Diergeneeskunde
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Vera Plekhova
Universiteit Gent Faculteit Diergeneeskunde
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Pablo Vangeenderhuysen
Universiteit Gent Faculteit Diergeneeskunde
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Nele Baeck
AZ Jan Palfijn Gent AV
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Dominique Bullens MA
Katholieke Universiteit Leuven Departement Microbiologie Immunologie en Transplantatie
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Tania Claeys
AZ Sint-Jan Brugge-Oostende AV
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Marilyn De Graeve
Universiteit Gent Faculteit Diergeneeskunde
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Kristien Kamoen
AZ Maria Middelares vzw
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Anneleen Notebaert
Sint-Vincentius Ziekenhuis vzw
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Tom Van de Wiele
Universiteit Gent Faculteit Bio-Ingenieurswetenschappen
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Wim Van Den Broeck
Universiteit Gent Faculteit Diergeneeskunde
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Koen Vanlede
Vitaz
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Myriam Van Winckel
Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen
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Lars Vereecke
Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen
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Chris Elliott
Queen's University Belfast The Institute for Global Food Security
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Eric Cox
Universiteit Gent Faculteit Diergeneeskunde
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Abstract

Background: IgE-mediated cow’s milk allergy (IgE-CMA) is one of the first allergies to arise in early childhood and may result from exposure to various milk allergens, of which β-lactoglobulin (BLG) and casein are the most important. Understanding the underlying mechanisms behind IgE-CMA is imperative for the discovery of novel biomarkers and the design of innovative treatment and prevention strategies. Methods: We report a longitudinal in vivo murine model, in which 2 mice strains (BALB/c and C57Bl/6) were sensitized to BLG using either cholera toxin or an oil emulsion (n=6 per group). After sensitization, mice were challenged orally, their clinical signs monitored, antibody (IgE and IgG1) and cytokine levels (IL-4 and IFN-γ) measured, and fecal samples subjected to metabolomics. The results of the murine models were further supported by fecal microbiome-metabolome data from our population of IgE-CMA (n=24) and healthy (n=23) children (Trial: NCT04249973), on which polar metabolomics, lipidomics and 16S rRNA metasequencing were performed. In vitro gastrointestinal digestions and multi-omics corroborated the microbial origin of proposed metabolic changes. Results: During sensitization, we observed multiple microbially derived metabolic alterations, most importantly bile acid, energy and tryptophan metabolites, that preceded allergic inflammation. The latter was reflected in a disturbed sphingolipid metabolism. We confirmed microbial dysbiosis, and its causal effect on metabolic alterations in our patient cohort, which was accompanied by metabolic signatures of low-grade inflammation. Conclusion: Our results indicate that gut dysbiosis precedes allergic inflammation and nurtures a chronic low-grade inflammation in children on elimination diets, opening important new opportunities for future prevention and treatment strategies.
07 Jul 2023Submitted to Allergy
10 Jul 2023Submission Checks Completed
10 Jul 2023Assigned to Editor
10 Jul 2023Review(s) Completed, Editorial Evaluation Pending
17 Jul 2023Reviewer(s) Assigned
08 Aug 2023Editorial Decision: Revise Minor
30 Oct 20231st Revision Received
30 Oct 2023Submission Checks Completed
30 Oct 2023Assigned to Editor
30 Oct 2023Review(s) Completed, Editorial Evaluation Pending
02 Nov 2023Reviewer(s) Assigned