Cysteinyl leukotrienes stimulate gut absorption of food allergens to promote anaphylaxis in mice

Food-specific immunoglobulin E (IgE) triggers life-threatening anaphylaxis; however, for unclear reasons, some people with food-specific IgE are asymptomatic upon allergen consumption. We studied strains of mice with different sensitivities to anaphylaxis when orally challenged with allergen to identify possible causes. In resistant C57BL/6 mice, intestinal goblet cells transported less food allergen than did anaphylaxis-susceptible strains, even before allergic sensitization. In a forward genetic screen, resistance was correlated with dipeptidase 1 (Dpep1) variants. DPEP1 is expressed in intestinal epithelium and catabolizes leukotriene D₄ (LtD₄). Blocking DPEP1 with cilastatin, deleting Dpep1, or administering LtD₄ orally enhanced allergen transport in resistant mice. Conversely, pretreatment of susceptible mice with a synthesis inhibitor, zileuton, abrogated allergen absorption and oral anaphylaxis, indicating that this could be an approach to treating food allergy.