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Differential DNA methylation in infants with Ig E mediated and non-Ig E mediated cow’s milk allergy and its association with acquired tolerance

ABSTRACT: Background: Cow's milk allergy (CMA) is one of the most common food allergies (FA) in childhood. This condition can be IgE-mediated, non-IgE-mediated, or a combination of both. Diagnosis involves clinical history in conjunction with sensitization tests. However, these tests have limited predictive value, making the oral food challenge (OFC) the gold standard for diagnosis. Recent research has focused on identifying biomarkers, including DNA methylation patterns, for FA diagnosis. The aim of this study is to investigate the differences in DNA methylation associated with distinct patterns of CMA, to identify novel diagnostic biomarkers. Methods: Genome-wide DNA methylation profiling was performed on blood samples from infants with IgE-mediated CMA (CMAIE), non-IgE-mediated CMA (CMANIE), and non-allergic controls, at baseline and after 6 months of a exclusion diet in CMA groups. These results were then correlated with tolerance acquisition following the restrictive diet. Results: A total of 19 infants were enrolled (10 CMAIE, 6 CMANIE, and 3 controls). Significant differentially methylated regions (DMRs) annotated to both genes and promoters were identified in all groups, and a clear separation of the samples into their respective groups was observed. Furthermore, DMRs in promoters and genes were identified in tolerant CMAIE children after the exclusion diet, being associated to tolerance. Discussion: Differential DNA methylation in CMA children is a useful diagnostic biomarker, and it could also be valuable in predicting the resolution of such pathologies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289021 | GEO | 2025/12/17

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>

Project description:Background & Aims: Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied and the mechanisms by which this vitamin exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers. Methods: Hypergastrinemic mice (INS-GAS) infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer, with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation-sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements and immunohistochemistry (IHC) with anti-5-methylcytosine. We also profiled gene expression in the same tissues. Results: We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and IHC for lymphocyte markers. Conclusions: We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to reverse global loss of methylation and suppress inflammation. Study the difference in gene expression between transgenic hypergastrinemic (INS-GAS) mice fed a folate-supplemented diet and a diet with normal folate content. Because folate had a substantial protective effect, we matched the animals not only by folate status but also by dysplasia score (DYS). The degree of dysplasia was scored on a 1-4 scale. True replicates are not included. The first five samples are from folate supplemented animals, and the latter five are from controls on regular chow.

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Differential DNA methylation in infants with Ig E mediated and non-Ig E mediated cow’s milk allergy and its association with acquired tolerance

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