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

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 ß-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.

Expanding the spectrum of MERS type 2 lesions, a particular form of encephalitis.

We report on a 13-year-old boy who presented with signs suggestive of encephalitis and in whom magnetic resonance imaging revealed lesions in the genu and splenium of the corpus callosum and symmetrical lesions bilaterally in the center semiovale. This clinical-radiologic entity was previously reported in the literature and was given the acronym MERS type 2 (mild encephalitis with reversible splenial) lesion. The clinical, radiologic, and biochemical characteristics of the patient with MERS type 2 lesions presented in this article show some differences with those in previously reported patients. His clinical recovery was particularly slow, cerebrospinal fluid was abnormal, and on magnetic resonance imaging the typical time course of MERS type 2 lesions resolving through a phase of solitary lesions in the splenium of the corpus callosum, the so-called type 1 lesions, was not seen. He is also the first patient in whom mycoplasma pneumoniae was found to be associated with MERS type 2 lesions. These findings further expand the spectrum of MERS type 2 lesions. The question raises whether the MERS type 2 lesion represents a new type of encephalitis or a particular radiologically recognizable subtype of postinfectious encephalitis. In the article, previously reported patients with MERS type 2 lesions are reviewed.