Food allergies affect over half a billion people worldwide, and severe cases can lead to anaphylaxis — a rapid allergic reaction that can result in breathing difficulties, low blood pressure, and even death.
While scientists have understood how injected allergens such as insect stings cause anaphylaxis, the mechanism behind food-induced anaphylaxis in the gut has been less clear. Now, researchers from Arizona State University (ASU), working with Yale University and other partners, have identified specialized immune cells in the intestine as a key factor.
These intestinal immune cells produce chemical messengers known for causing muscle contractions in airways and the gut, increasing mucus production, and promoting inflammation. These messengers are already linked to asthma attacks. According to research published in Science, these same molecules also play a significant role in triggering severe food allergy reactions that start in the gut.
The study was supported by the Howard Hughes Medical Institute, the National Institutes of Health, and other funding agencies.
“Until now, we assumed that anaphylaxis followed the same pathway regardless of where allergens entered the body, with histamine from mast cells as the main driver,” says ASU researcher Esther Borges Florsheim. “Our study shows that when allergens are ingested, a specialized set of mast cells in the gut don’t release histamine — instead, they produce lipid-based molecules called leukotrienes. These molecules, rather than histamine, trigger anaphylaxis in the gastrointestinal tract.”
Florsheim is part of ASU’s Biodesign Center for Health Through Microbiomes and serves as an assistant professor at the School of Life Sciences.
In both food-related and systemic allergies, mast cells detect allergens via IgE antibodies and release chemicals that cause symptoms like swelling and low blood pressure. In bloodstream-triggered reactions, histamine is most important; this is why antihistamines help some patients. The new research finds that when allergens are ingested, intestinal mast cells mainly produce cysteinyl leukotrienes instead of histamine. These lipids are already known to constrict airways during asthma attacks.
Intestinal mast cells take signals from nearby epithelial cells that prompt them to increase leukotriene production while reducing histamine output. Genetic and chemical analysis revealed several subtypes of these mast cells within the gut compared to those found elsewhere in the body.
Previous studies showed blocking IgE pathways could prevent severe symptoms from developing.
To test if leukotrienes were driving these reactions, researchers used zileuton—an FDA-approved drug for asthma—which blocks a key enzyme needed for leukotriene production. The drug reduced allergy symptoms and protected against dangerous drops in body temperature—a marker of anaphylaxis—when allergens were ingested but not when injected into the bloodstream. This finding highlights distinct mechanisms between gut-triggered and systemic allergic responses.
Current emergency treatments like epinephrine aim to reverse symptoms after onset; antihistamines are less effective at preventing severe events from food triggers.
The findings suggest targeting leukotrienes could offer new preventive or therapeutic options for food-triggered anaphylaxis. More research is needed before applying these results to humans; however, drugs like zileuton or montelukast (already approved for asthma) may speed up future clinical testing for food allergies.
Beyond clinical applications, this work changes scientific understanding of allergic reactions by showing that how an allergen enters the body—through skin, blood or gut—affects immune response type.
“This finding highlights the gut as unique in how it senses allergens and potentially other harmful environmental challenges, such as food additives,” Florsheim says. “It also helps explain a long-standing puzzle: why levels of food-specific antibodies, especially IgE, do not reliably predict the risk of food allergy.”
Researchers plan further studies on whether similar mast cell populations exist in human intestines and if blocking their action can prevent severe reactions among people with life-threatening food allergies.
Arizona State University has been recognized nationally for its innovative advancements for eight consecutive years by U.S. News & World Report.
