These studies uncover mechanisms for food allergy sensitization and anaphylaxis in neonatal mice that are consistent with features of human early-life exposures and genetics in patients with clinical food allergy and demonstrate that changes in barrier function drive development of anaphylaxis to food allergen.

Concomitant dramatic increase in prevalence of allergic and metabolic diseases is part of a modern epidemic afflicting technologically advanced societies. While clinical evidence points to clear associations between various metabolic factors and atopic disease, there is still a very limited understanding of the mechanisms that link the two. Dysregulation of central metabolism in metabolic syndrome, obesity, diabetes, and dyslipidemia has a systemic impact on multiple tissues and organs, including cells of the epithelial barrier. While much of epithelial research in allergy has focused on the immune-driven processes, a growing number of recent studies have begun to elucidate the role of metabolic components of disease. This review will revisit clinical evidence for the relationship between metabolic and allergic diseases, as well as discuss potential mechanisms driving metabolic dysfunction of the epithelial barrier. Among them, novel studies highlight links between dysregulation of the insulin pathway, glucose metabolism, and loss of epithelial differentiation in asthma. Studies of mitochondrial structure and bioenergetics in lean and obese asthmatic phenotypes recently came to light to provide a novel framework linking changes in tricarboxylic acid cycle and oxidative phosphorylation with arginine metabolism and nitric oxide bioavailability. New research established connections between arachidonate metabolism, autophagy, and airway disease, as well as systemic dyslipidemia in atopic dermatitis and ceramide changes in the epidermis. Taken together, studies of metabolism have a great potential to open doors to a new class of therapeutic strategies, better characterization of disease endotypes, as well as enable a systems biology approach to mechanisms of allergic disease.

Glucose is a key source of energy in systemic and cellular metabolism and has known pro-inflammatory properties. Metabolic disorders (diabetes, insulin resistance) associate with asthma and other allergic diseases. This study sought to understand the role of hyperglycemia in the allergic response. First, we injected fasted Balbc/J mice intraperitoneally (i.p.) with 2g/kg dextrose to test whether hyperglycemia promotes antigen sensitization. Within one hour of injection, we detected a rapid increase in blood glucose levels followed by an increase in expression of inflammatory markers Il1β, Tslp, and Cxcl9 in peritoneal tissue. Concurrently, MHCII+ cells infiltrated the peritoneum. Control experiments showed that inflammatory responses were not due to hyperosmotic effects. To determine whether glucose promotes allergic response, we sensitized mice to chicken egg ovalbumin (OVA) using either alum (standard adjuvant), dextrose, or a vehicle control. Both alum/OVA and dextrose/OVA treated mice mounted lung allergic inflammation in response to inhaled OVA antigen. Dextrose/OVA mice had OVA-specific IgE production similar to alum/OVA group, demonstrating glucose’s ability to promote sensitization. Total cellular infiltrates, bronchoalveolar lavage (BAL) eosinophils, and lung expression of IL-4, IL-13 and IL-33 in dextrose-sensitized mice were equal to or surpassing allergic inflammatory responses in mice given standard adjuvant. Finally, in a separate mouse tolerance model we demonstrated that hyperglycemia impairs development of tolerogenic response to innocuous OVA antigen. These results demonstrate a potentially critical role for glucose dysregulation in loss of tolerance and promotion of allergy.

Glucose is a key source of energy in systemic and cellular metabolism and has known pro-inflammatory properties. It has recently been acknowledged that associations exist between metabolic disorders (diabetes, insulin resistance, obesity), asthma and other allergic diseases. As the prevalence of both metabolic and allergic disorders increases, it is important to understand how metabolism can influence the development of allergy. First, we injected fasted wild type Balbc/J mice intraperitoneally (i.p.) with 2g/kg dextrose (standard hyperglycemic challenge) to test whether hyperglycemia promotes inflammation favoring antigen sensitization. Within one hour of injection, we detected a rapid increase in blood glucose levels (up to 130 mg/dL) followed by an increase in Il1β, Tslp, Cxcl9, and Siglec5 gene expression in the peritoneal tissue compared to vehicle controls. Within 2 hours post injection, IL-1β protein was detected in peritoneal cellular infiltrate. In order to determine whether glucose-induced inflammation promotes allergic response, we sensitized mice by i.p. to chicken egg ovalbumin (OVA) using either alum (standard adjuvant), dextrose or vehicle control. Both alum/OVA and dextrose/OVA mounted lung allergic inflammation in response to inhaled OVA antigen. Dextrose/OVA mice had OVA-specific IgE production similar to alum/OVA group, demonstrating ability to promote sensitization. Remarkably, total cellular infiltrates, bronchoalveolar lavage eosinophils, lung expression of IL-4, IL-13 and IL-33 in dextrose-sensitized mice were equal or surpassing allergic inflammatory responses in mice given standard adjuvant. These results demonstrate a potentially critical role for glucose in promotion of allergy.