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

代谢组 微生物群 免疫学 免疫球蛋白E 牛奶过敏 失调 过敏 代谢组学 炎症 敏化 肠道菌群 瘤胃球菌 生物 食物过敏 医学 抗体 生物信息学
作者
Lynn Vanhaecke,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,Christopher T. Elliott,Eric Cox
出处
期刊:Authorea - Authorea
标识
DOI:10.22541/au.168895277.71396238/v1
摘要

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.

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