Integrated gut metabolome and microbiome fingerprinting reveals that dysbiosis precedes allergic inflammation in IgE-mediated pediatric cow's milk allergy

Ellen De Paepe, Vera Plekhova, Pablo Vangeenderhuysen, Nele Baeck, Dominique Bullens, 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 two 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 extrapolated to fecal microbiome-metabolome data from our population of IgE-CMA (n = 22) 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 mice sensitization, we observed multiple microbially derived metabolic alterations, most importantly bile acid, energy and tryptophan metabolites, that preceded allergic inflammation. We confirmed microbial dysbiosis, and its associated effect on metabolic alterations in our patient cohort, through in vitro digestions and multi-omics, 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.

Original languageEnglish
Number of pages15
JournalAllergy
Early online date09 Jan 2024
DOIs
Publication statusEarly online date - 09 Jan 2024

Keywords

  • 16S rRNA sequencing
  • cow's milk allergy
  • metabolomics
  • multi-omics
  • Immunology
  • Immunology and Allergy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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