The danger starts in the gut. Arizona State University and Yale researchers have discovered that specialized intestinal mast cells, not histamine, are the real culprits behind food-induced anaphylaxis. Published in Science, the study shows that instead of releasing histamine, these gut mast cells flood the body with lipid molecules called leukotrienes, triggering the dangerous reaction that makes severe food allergies so life-threatening.

A Different Chemical Pathway

Food allergies affect more than half a billion people worldwide, and anaphylaxis can be fatal within minutes. Until now, most research focused on how injected allergens, such as insect venom, provoke systemic reactions. But the new study shows the gut is different. There, mast cells don’t behave like their bloodstream counterparts.

“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,” said Esther Borges Florsheim of ASU. “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.”

Those leukotrienes, already infamous in asthma attacks, constrict airways, tighten gut muscles, and dial up mucus production. The result: a cascading storm that can stop breathing or collapse blood pressure. Same dangerous outcome, but through a very different route.

From Mouse Models to Medicine Cabinet

To test the idea, researchers used mice engineered to lack the enzymes that make leukotrienes. The animals were protected from oral allergen-induced anaphylaxis. They also tried zileuton, an FDA-approved asthma drug that blocks leukotriene synthesis. It dampened allergic symptoms and prevented the plummeting body temperature that signals shock. Crucially, zileuton worked only for food-induced reactions, not when allergens were injected directly into the bloodstream. That distinction matters.

“This finding highlights the gut as unique in how it senses allergens and potentially other harmful environmental challenges, such as food additives,” Florsheim said. “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.”

Changing the Allergy Playbook

Today, people with severe allergies rely on epinephrine auto-injectors as a last line of defense. Antihistamines can ease hives or mild swelling, but they are blunt instruments against food-triggered anaphylaxis. The new work suggests leukotriene-blocking drugs — already approved and prescribed for asthma under names like montelukast — could be repurposed to prevent or treat life-threatening food reactions.

It also reframes how immunologists think about allergic disease. Not all allergens enter the body the same way, and not all mast cells are equal. Intestinal mast cells, tuned by epithelial signals, follow a script of their own, producing little histamine but plenty of leukotrienes. That difference could be exploited for safer, faster treatments. For now at least, the mouse data are a strong proof of concept.

Takeaway

The study doesn’t just uncover a new mechanism. It offers a therapeutic opening, one that could shift food allergy care from reactive to preventive. If confirmed in humans, targeting leukotrienes could save lives — and give families living with severe food allergies a reason to breathe easier.

Journal: Science
DOI: 10.1126/science.adp0246