New Insights into Food Allergy: Intestinal Leukotrienes Drive Oral Anaphylaxis Beyond Histamine

Recent research from Yale University School of Medicine reveals that cysteinyl leukotrienes produced by intestinal mast cells play a crucial role in triggering anaphylaxis after food ingestion in mice. Unlike systemic allergic reactions triggered by intravenous allergens, the study found that oral reactions rely heavily on leukotriene synthesis rather than histamine. Using advanced techniques such as bulk and single-cell RNA sequencing, along with in vitro and in vivo models, scientists identified that leukotrienes are essential mediators facilitating intestinal mast cell expansion and sensitization to food antigens. In mouse models sensitized with ovalbumin in alum or peanut with cholera toxin, oral challenges led to significant drops in body temperature, which were dependent on IgE-FcεR1α signaling pathways. Notably, blockade of histamine receptors only mitigated intravenous allergic responses and had minimal impact on oral anaphylaxis, highlighting leukotrienes' predominant role in gut-mediated reactions. Therapeutic interventions with zileuton, a leukotriene synthesis inhibitor, effectively prevented temperature drops and gastrointestinal symptoms in mice following oral allergen exposure. Genetic knockouts of LTC4S and pharmacological blockade of leukotriene receptors significantly reduced or abolished oral anaphylactic responses, indicating their potential as targets for preventing food-induced allergic reactions. These findings suggest that targeting intestinal leukotrienes may represent a promising strategy to prevent severe food allergies, especially in individuals with heightened sensitivity. The study underscores the importance of local mucosal responses and opens new avenues for managing food allergies through specialized therapies aimed at leukotriene pathways.