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The rising prevalence and treatment resistance of obesity urges further exploration of underlying metabolic processes. This is especially important at a young age, when metabolic and psychological development, are ongoing. The gastrointestinal metabolome contains a multitude of endogenous and environmental potentially disease-causative agents. The origins of specific compounds are mostly known, i.e., the gastrointestinal microbiome, food and drug intake, lifestyle, etc. The key drivers of most metabolites in relation to the pathophysiology of overweight and obesity remain however poorly understood. Using stool and saliva collected from the deeply characterized OPERA cohort (n=112, age 8-18, 54% boys, 30% overweight), UHPLC-HRMS-based metabolomics and lipidomics and 16s rDNA sequencing data were obtained. In parallel, food and drug intake, anthropometrics, lifestyle, psychological and clinical markers were gathered. Individual fecal metabolite and lipid levels were quantitively predicted based on microbial OTUs, using supervised training (random forest regressor). The top 50 prediction coefficients (R2) on the set of 21,435 features ranged from 0.26-0.48 and thus in the same range as Bar et al. (2020, Nature) for the serum metabolome. The salivary metabolome (9,044 features) was also significantly (FDR q

In Westernized societies, food allergies are a growing epidemic and are considered a major cost to our health care system. Cow’s milk allergy (CMA) is one of the first allergies to occur in early childhood and may occur to various milk proteins or allergens, of which beta-lactoglobulin (BLG) and casein are the most important. In this study, two different protocols (using cholera toxin (CT) or an oil emulsion) were used to sensitize two different strains of mice (Balb/C and C57Bl/6; n=6 per group) to BLG. After sensitization, mice were challenged orally and their clinical signs monitored. Plasma and spleen cells were collected for antibody (IgE and IgG1) and cytokine (IL-10 and IFN-γ) analysis, while fecal samples were subjected to metabolomics. The results of this murine experiment served to corroborate the microbiome-metabolome findings in a cohort of children with IgE mediated CMA (IgE-CMA) (n=23) and healthy brothers and sisters (n=24) on which polar metabolomics [1], lipidomics [2] and 16S rRNA sequencing [3] were performed. Signs of anaphylaxis and discomfort were respectively observed in the Balb/C mice receiving BLG and CT and the C57Bl/6 mice receiving BLG in oil. In Balb/C mice receiving BLG and CT, elevated fecal histamine levels and altered energy metabolism were observed. In the C57Bl/6 group receiving BLG in oil, tryptophan metabolism (p=0.0018), reflected by increased levels of 3-hydroxykynunerin and kynurenic acid, was most significantly affected. In addition, impaired TCA cycle (p=0.017) and bile acid biosynthesis (p=0.021) were observed in this group. In children with IgE-mediated CMA, tryptophan (p=0.0011) and bile acid (p=0.019) metabolism were significantly impaired, in addition to several pathways within energy metabolism. Alterations in tryptophan and bile acid metabolism have been linked to microbial dysbiosis, which was confirmed by differences in alpha and beta diversity in children with CMA (p=0.03 and 0.034, respectively). It is hypothesized that this dysbiosis and its concomitant metabolic disturbances are a direct consequence of sensitization and as such precede CMA mediated inflammation, as no metabolic signs of dysbiosis were observed in control mice. Our results suggest that metabolic alterations in C57Bl/6 mice sensitized with BLG in an oil emulsion optimally resemble those of IgE-CMA in children, whereas CT may represent a more accurate model of anaphylaxis. Furthermore, we hypothesize that sensitization is the true causal factor of microbial dysbiosis observed in food allergies. More in-depth data exploration through multi-omics, to map microbiome-metabolome-lipidome interactions, is currently ongoing.