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\begin{document}

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



\author[1]{Lynn Vanhaecke}%
\author[1]{Ellen De Paepe}%
\author[1]{Vera Plekhova}%
\author[1]{Pablo Vangeenderhuysen}%
\author[2]{Nele Baeck}%
\author[3]{Dominique Bullens MA}%
\author[4]{Tania Claeys}%
\author[1]{Marilyn De Graeve}%
\author[5]{Kristien Kamoen}%
\author[6]{Anneleen Notebaert}%
\author[7]{Tom Van de Wiele}%
\author[1]{Wim Van Den Broeck}%
\author[8]{Koen Vanlede}%
\author[9]{Myriam Van Winckel}%
\author[9]{Lars Vereecke}%
\author[10]{Chris Elliott}%
\author[1]{Eric Cox}%
\affil[1]{Universiteit Gent Faculteit Diergeneeskunde}%
\affil[2]{AZ Jan Palfijn Gent AV}%
\affil[3]{Katholieke Universiteit Leuven Departement Microbiologie Immunologie en Transplantatie}%
\affil[4]{AZ Sint-Jan Brugge-Oostende AV}%
\affil[5]{AZ Maria Middelares vzw}%
\affil[6]{Sint-Vincentius Ziekenhuis vzw}%
\affil[7]{Universiteit Gent Faculteit Bio-Ingenieurswetenschappen}%
\affil[8]{Vitaz}%
\affil[9]{Universiteit Gent Faculteit Geneeskunde en Gezondheidswetenschappen}%
\affil[10]{Queen's University Belfast The Institute for Global Food Security}%


\vspace{-1em}



  
  \date{June 10, 2024}


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\selectlanguage{english}
\begin{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 \selectlanguage{greek}β-\selectlanguage{english}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 \emph{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-\selectlanguage{greek}γ\selectlanguage{english}) 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. \emph{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.%
\end{abstract}%



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\textbf{Hosted file}

\verb`Manuscript.docx`  available at \url{https://authorea.com/users/165649/articles/653732-integrated-gut-metabolome-and-microbiome-fingerprinting-reveals-that-dysbiosis-precedes-allergic-inflammation-in-ige-mediated-pediatric-cow-s-milk-allergy}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Allergy-Figure-1/Allergy-Figure-1}

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