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Loss of tolerance in cow milk allergic endotypes is linked to allergen-specific CD4+ T cell subset outgrowth and microbial dysbioses

ABSTRACT: Cow milk allergy (CMA) is the most prevalent pediatric food allergy, presenting in IgE and non-IgE mediated forms. Currently, the CD4+ T cell inflammatory responses underlying non-IgE CMA remain poorly characterized. By applying an allergen-reactive CD4+ T cell sorting and differential gene expression analysis approach, we characterized the CD4+ T cell subsets associated with both IgE and non-IgE mediated CMA endotypes and assessed their associations with gut bacterial compositions. Analysis of conventional (Tcon) and regulatory (Treg) CD4+ T cells revealed an expansion of inflammatory Tcon in CMA subjects, coincident with TH-like subset polarization and alterations in Treg signaling pathways. TH2-skewing was dominant in IgE mediated allergies, whereas subjects with non-IgE mediated allergies exhibited a CD4+ T cell compartment dominated by a novel TH response. Microbial dysbiosis was observed across all CMA endotypes, and network mapping revealed significant associations between a decrease in butyrate producing bacteria and the presence of inflammatory TH-like subsets. These insights link the composition of the allergen-reactive Tcon/Treg compartment to CMA pathology and identifies differences in bacterial dysbioses associated with specific disease endotypes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303756 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:<h4><strong>BACKGROUND: </strong>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.</h4><h4><strong>METHODS: </strong>We report a longitudinal <em>in vivo</em> 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.</h4><h4><strong>RESULTS: </strong>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 <em>in vitro</em> digestions and multi-omics, which was accompanied by metabolic signatures of low-grade inflammation.</h4><h4><strong>CONCLUSION: </strong>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.</h4>

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Loss of tolerance in cow milk allergic endotypes is linked to allergen-specific CD4+ T cell subset outgrowth and microbial dysbioses

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