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.

Parental Catastrophizing and Goal Pursuit in the Context of Child Chronic Pain: A Daily Diary Study.

Background: Despite daily variability in children's chronic pain experiences, little is known about how parents' emotions and goals toward their child's pain are influenced by these daily changes. This diary study examined how daily child pain intensity (as perceived by parents) moderates the associations between parental catastrophic thoughts about child pain on the one hand, and daily parental distress and parents' goals with regard to their child's pain (pain control vs. activity engagement) on the other hand. Method: Participants were 25 parents of 20 different children (N = 18; 90% girls). Children, aged 8-14 years (M = 9.5, SD = 2.09), experienced either chronic headache or functional abdominal pain with an average pain duration of 22.5 months (SD = 24.5 months). Daily parental responses (i.e., perceived child pain intensity, distress and goal endorsement) were collected through a 3-week daily diary (resulting in 413 valid diary reports). Parents completed the Pain Catastrophizing Scale for Parents prior to starting the diary (PCS-P general) and a daily measure (PCS-P daily) included in the diary. To account for the interdependence of the data, the data were analyzed using multilevel modeling. Results: Perceived daily child pain intensity moderated the impact of parental general and daily catastrophic thoughts on parents' daily distress. Only for parents experiencing low general catastrophic thoughts an increase in distress was observed on days when they perceived their child's pain intensity as high. For all parents, high levels of perceived child pain intensity were related to more distress on days where parents reported high levels of catastrophic thinking (i.e., PCS-P daily). Perceived daily child pain intensity also moderated the impact of parental general catastrophic thinking on parents' daily endorsement of goals. Parents with high levels of general catastrophic thinking reported a lower focus on child pain control on days when child pain intensity was perceived to be low. Parents with low general catastrophic thinking reported lower endorsement of the activity engagement goal on days where the child's pain intensity was perceived to be low. Conclusion: These findings highlight the complexity of daily fluctuations in parental distress and goals regarding their child's pain. Clinical implications and future directions are critically assessed.