Murine anaphylaxis to food requires cysteinyl leukotriene-mediated absorption of allergens in the gut

Food-specific IgE triggers life-threatening anaphylaxis; however, some people with food-specific IgE are asymptomatic upon allergen consumption. Using murine food allergy models, we discovered an unexpected pathway regulating the ability of food allergens to trigger anaphylaxis. C57BL/6 mice are uniquely resistant to anaphylaxis when challenged orally; we show that their gut barrier was impermeable to food allergens relative to anaphylaxis-susceptible strains, even prior to allergic sensitization. In a forward genetic screen, oral anaphylaxis resistance correlated with Dipeptidase1 (Dpep1) allelic variants. DPEP1 is expressed in intestinal epithelium and catabolizes leukotriene D4. Blocking DPEP1 with cilastatin enhanced allergen absorption in resistant mice. Conversely, pre-treatment of susceptible mice with a leukotriene synthesis inhibitor, zileuton, abrogated allergen absorption and subsequent oral anaphylaxis. Inhibiting leukotrienes may be a novel treatment for food allergy.