In recent years, ambient ionization mass spectrometry (AIMS) including laser ablation rapid evaporation IMS (LA-REIMS), has enabled direct biofluid metabolome analysis. AIMS procedures are however still hampered by both analytical, i.e., matrix effects, and practical, i.e., sample transport stability, drawbacks that impede metabolome coverage. In this study, we aimed at developing biofluid-specific metabolome sampling membranes (MetaSAMP®s) that offer a directly applicable and stabilizing substrate for AIMS. Customized rectal, salivary and urinary MetaSAMP®s consisting of electrospun nanofibrous membranes of blended hydrophilic (polyvinylpyrrolidone and polyacrylonitrile) and lipophilic (polystyrene) polymers supported metabolite ab-, ad-, and desorption. Moreover, MetaSAMP® demonstrated superior metabolome coverage and transport stability compared to crude biofluid analysis and was successfully validated in two pediatric cohorts (MetaBEAse, N=234 and OPERA, N=101). By integrating anthropometric and (patho)physiological with MetaSAMP®-AIMS metabolome data, we obtained significant weight-driven predictions and clinical correlations. In conclusion, MetaSAMP® holds great clinical application potential for on-the-spot metabolic health stratification.
Understanding the underlying mechanisms behind IgE-mediated cow’s milk allergy (IgE-CMA) is imperative for the discovery of novel biomarkers and the design of innovative treatment and prevention strategies. Here, we report data on the gut microbiome, metabolome, and lipidome of 81 children affected by food allergies, including CMA and healthy controls. Moreover, we developed a mouse model that mimicked IgE CMA best, BALB/c mice sensitized with ß-lactoglobulin using cholera toxin. During sensitization, we observed multiple microbially derived metabolic alterations, most importantly bile acid and tryptophan metabolites, that preceded allergic inflammation, while this inflammation was reflected in a disturbed sphingomyelin and histamine metabolism. We endorsed the microbial origin of these metabolites by in vitro colonic digestions and confirmed the microbial dysbiosis in our patient cohort, which was accompanied by metabolic signatures of low-grade inflammation. Our results suggest that gut dysbiosis precedes allergic inflammation, opening new opportunities for future prevention and treatment strategies. Trial: NCT04249973.
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.
While rapid analysis of the human biofluid metabolome is now possible using ambient ionization mass spectrometry (AIMS), these procedures are hampered by in-source matrix effects and reduced sample stability impeding metabolome coverage while remaining relatively labor-intensive. In this study, we aimed at developing biofluid-specific metabolome sampling membranes (MetaSAMP®s, WO2021/191467) that offer a directly applicable and stabilizing substrate for AIMS. Customized rectal, salivary and urinary MetaSAMP®s consisting of multilayered electrospun nanofibrous membranes of blended hydrophilic (polyvinylpyrrolidone and polyacrylonitrile) and lipophilic (polystyrene) polymers supported adequate metabolite ab- , ad-, and desorption. Moreover, MetaSAMP® demonstrated superior metabolome coverage and transport stability compared to crude biofluid analysis and was successfully validated in two pediatric cohorts (MetaBEAse, n=234, feces and urine; OPERA, n=138, saliva). By integrating anthropometric and (patho)physiological with MetaSAMP®-AIMS metabolome data, we obtained significant weight-driven predictions and clinical correlations. In conclusion, MetaSAMP® holds great clinical application potential for on-the-spot metabolic health stratification.
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