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By Hannah Millington
Health Reporter
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For those with severe food allergies, just one morsel of the wrong thing can lead to a life-threatening reaction. A new understanding of how this begins could lead to better treatments, a study claims.
While scientists have long understood how injected allergens—bee stings, for example—trigger sever reactions—or "anaphylaxis"—it has been unclear how it begins in the gut after eating a food allergen.
Now, a team including researchers from Yale and Arizona State have pinpointed a surprising culprit: specialized immune cells in the intestine that produce powerful chemical messengers.
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These messengers can cause muscles in the airways and gut to contract, increase mucus production and boost inflammation. While they're already known to play a role in asthma attacks, this new study on mice suggests they're also key drivers of severe food allergy reactions.
It appears the way an allergen gets into the body—whether through the skin, bloodstream or gut—can shape the type of immune response involved.
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Around 33 million Americans have at least one food allergy, of which around half of adults and 42 percent of children have experienced a severe reaction.
"Until now, we assumed that anaphylaxis followed the same pathway regardless of where allergens entered the body, with histamine from mast cells [immune cells] as the main driver," said paper author Esther Borges Florsheim of the Arizona State University in a statement.
"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."
In both food and systemic allergies, mast cells play a key role. When they detect an allergen via antibodies called immunoglobulin E, or IgE, they burst open, releasing chemicals that cause swelling, low blood pressure and other symptoms.
In the bloodstream, the most important of these chemicals is histamine, which is why antihistamines can help in some allergic situations, the researchers explained.
However, the new research shows that when an allergen is ingested, mast cells in the intestinal lining respond differently.
They make relatively little histamine and instead ramp up production of cysteinyl leukotrienes, a family of inflammatory lipids already known to constrict airways in conditions like asthma.
In the gut lining, intestinal mast cells take cues from other nearby epithelial cells, shifting activity to make more leukotrienes and less histamine. Compared to mast cells elsewhere in the body, mast cells in the gut were primed to make leukotrienes.
Previous research found that blocking the IgE pathway—by removing IgE antibodies or the receptor they bind to on mast cells—protected against developing severe symptoms.
"This study identifies that anaphylaxis caused by food allergies is not all down to histamine, but that gut mast cells secrete leukotrienes instead, similar to the process in severe asthma attacks," Dr. Elena Salagean—an allergy consultant at Holistic Allergy, who was not involved in the present study—told Newsweek.
"The leukotriene release is then responsible for the features of food allergy-related anaphylaxis, such as the severe abdominal cramping feeling, the systemic cardiovascular changes, with low blood pressure crashes leading to feeling faint or collapsing along with a fast heart rate and the difficulty breathing,"
"Due to the tightening of muscles in the gut, it can also cause the feeling of needing to rush to the toilet with diarrhea."
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To confirm whether leukotrienes were really driving the reaction, the team used a drug called zileuton—which the FDA has approved for the treatment of asthma called—that blocks a crucial enzyme needed to make leukotrienes.
They discovered that the drug reduced allergy symptoms and provided protection from a dangerous drop in body temperature—which they said is a "hallmark of anaphylaxis."
Crucially, the same drug did not prevent reactions caused by allergens injected into the bloodstream. This shows that the gut allergic pathway is different from the whole-body allergic pathway and has its own chemical drivers, according to the researchers.
Current emergency treatments for severe allergic reactions, such as epinephrine, are aimed at quickly reversing symptoms once anaphylaxis starts. While antihistamines can help in mild reactions, they are far less effective for preventing severe events, especially those triggered by food.
The findings suggest targeting leukotrienes could offer a new preventive or therapeutic approach for food-triggered anaphylaxis.
"Food allergies that start in the gut may involve ingested allergens like milk, shellfish and peanuts, for example, and this experimental study indicates that these may more prominently trigger the leukotriene pathway," said Dr. Salagean.
"This finding highlights the gut as unique in how it senses allergens and potentially other harmful environmental challenges, such as food additives," said Florsheim. "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."
More research is needed to test whether the results from this study can be applied to humans. The team plan to study this next, as well as whether blocking the discovered pathways can reduce or prevent severe reactions in people with life-threatening food allergies.
Drugs that block leukotriene production (like zileuton) or leukotriene receptors (like montelukast, also commonly used for asthma) are already approved for other uses, which could speed up testing for food allergy applications, the study suggests.
"The mainstay of treatment, the EpiPen, still remains valid as this is powerful enough to override all the different anaphylaxis mechanisms and is the key treatment for acute anaphylaxis," added Dr. Salagean.
"The study does however shed light as to why antihistamines taken for food allergies may not be sufficiently strong to prevent or lead to improvement. The implications are that management of food-related allergy should also involve the use of anti-leukotriene therapies as well as anti-histamines."
Do you have a tip on a health story that Newsweek should be covering? Do you have a question about food allergies? Let us know via health@newsweek.com.
Correction 08/29/25, 6:01 a.m. ET: This article was updated to reflect the fact that the study was led from Yale, not ASU—and to correct an error in the paper reference.
Reference
Bachtel, N. D., Cullen, J. L., Liu, M., Erickson, S. A., Kutyavin, V. I., El-Naccache, D. W., Florsheim, E. B., Lim, J., Sullivan, Z. A., Imaeda, R., Hudak, A., Zhang, C., & Medzhitov, R. (2025). Intestinal mast cell–derived leukotrienes mediate the anaphylactic response to ingested antigens. Science, 389(6760). https://doi.org/10.1126/science.adp0246
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