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A mouse study finds a gut “gatekeeper” that decides whether allergens can get through — and an existing drug that could block dangerous reactions before they start.
In A Nutshell
- In mice, a “gut gatekeeper” controls whether allergens can cross into the body and trigger a reaction.
- The protective version of this gatekeeper is linked to a more active enzyme (DPEP1) that clears chemical signals which open the gut barrier.
- Blocking those signals with an existing asthma drug (zileuton) stopped allergic reactions from oral exposure in mice.
- While promising, the findings are in mice; human safety and effectiveness are unknown.
CHICAGO — For millions of Americans with food allergies, eating can feel like walking through a minefield. Even people with the same allergy can have very different experiences; some react to the tiniest crumb, while others can handle small amounts without any symptoms. Now, scientists at Northwestern University and Yale have uncovered a clue in mice that could help explain this mystery.
Researchers discovered a biological pathway in the gut that acts like a bouncer, deciding which food proteins get past the intestinal wall to trigger an allergic reaction. And they found that an asthma drug already approved by the FDA, called zileuton, could block this process in mice, though it’s far too soon to say whether it would work in people.
How the Gut Blocks Allergens Before They Trigger Food Allergy Symptoms
The research focused on a group of inflammation-triggering molecules called cysteinyl leukotrienes. In mice, these molecules can open the gates for allergens, making it easier for them to cross the gut lining and set off the immune system. Block the molecules, and the gut stays on lockdown.
The clue came from two common types of lab mice. One type, dubbed C57BL/6, almost never reacted to peanut protein when it was eaten, even though their immune system clearly recognized it. The other type, C3H/HeJ, often had severe, body-wide reactions when given the same food.
Both strains made similar levels of antibodies and had healthy immune systems. The difference was in their guts. In one test using ovalbumin, a protein found in egg whites, the mice in the first group absorbed more than 100 times less ovalbumin than the other group, a striking difference in how much allergen slipped through.
The Gene and Enzyme That Decide If Allergens Get Through the Gut Barrier
When the team dug into the genetics, they found a key player: a gene called Dpep1. This gene makes an enzyme that normally breaks down the very molecules that help allergens cross the gut wall.
The “protected” mice had a version of this enzyme that cleared the signals quickly, keeping their gut barrier tight. The “vulnerable” mice had a version that left more of those signals hanging around, making it easier for allergens to sneak through.
To see what would happen if they interfered with this process, the scientists tried two drugs. One, cilastatin, blocks the protective enzyme. When resistant mice got it, more allergen got through their gut wall. The other, zileuton, stops the chemical signals from being made in the first place. When the vulnerable mice got zileuton before eating the allergen, they stayed symptom-free during oral testing.
New Food Allergy Treatment for People On the Horizon?
All of the main experiments were in mice, but there are hints the same mechanism could matter in humans. People and the “vulnerable” mice share the same version of the Dpep1 gene, and tissue samples from the human gut showed a similar pattern to those mice.
In a small group of children with peanut allergies, those who reacted to even tiny amounts of peanut showed increased activity in certain genes linked to producing the “open sesame” signals after eating peanut. This doesn’t prove cause and effect, but it lines up with what the mouse experiments found.
Right now, living with a food allergy mostly means avoiding the trigger food and keeping emergency medication like an EpiPen on hand. Some patients try oral immunotherapy to build tolerance, but it doesn’t work for everyone and can sometimes trigger dangerous reactions.
This study points to a different tactic: keep allergens from getting past the gut wall in the first place. In the mouse tests, a carefully timed dose of zileuton (given an hour before eating the allergen) completely blocked signs of a reaction from eating it. The drug didn’t help if the allergen was injected directly into the body, showing it works by protecting the gut rather than suppressing the immune system as a whole.
Zileuton is already approved for asthma, so we know it can be used safely in that context, but human trials would be needed before it could ever be used for food allergies.
It’s worth noting that some factors like exercise, alcohol, or certain medicines are known to make allergic reactions worse by making the gut wall leakier. Some of these also influence the same chemical signals found in this study, so it’s possible they connect — but that’s still just a theory.
For the roughly 32 million Americans with food allergies, this discovery offers a new way to think about prevention: not just calming down an overactive immune system, but also strengthening the gut’s front-line defenses.
Disclaimer: This article is based on a laboratory study conducted in mice. While the findings suggest a possible new way to prevent food allergy reactions, the results may not apply to humans. The drug mentioned (zileuton) is FDA-approved for asthma, but has not been tested for preventing food allergies in people. More research, including human clinical trials, is needed before any conclusions can be made about its safety or effectiveness for this purpose.
Paper Summary
Methodology
Researchers compared mouse strains that either developed severe allergic reactions or stayed symptom-free despite having allergy antibodies. They bred mice over several generations to pinpoint the genes involved, ran enzyme activity tests, used imaging to track protein movement through the gut, and measured inflammatory molecules. They tested both genetic changes and drugs that affected the pathway.
Results
In naïve mice, C57BL/6 absorbed more than 100× less OVA than C3H/HeJ. C57BL/6 also had higher DPEP1 activity, which breaks down CysLTs and limits allergen passage. Blocking DPEP1 with cilastatin increased allergen absorption in resistant mice. Stopping CysLT production with zileuton protected susceptible mice from allergic reactions in an oral challenge. The protection was dose-dependent and only applied when allergens entered through the gut.
Limitations
The study was done entirely in mice, with only small amounts of human tissue and blood data to support possible relevance. Human safety, dosing, and effectiveness would need to be tested in clinical trials. The experiments looked at short-term prevention, not long-term allergy control.
Funding and Disclosures
Funded by the Ira & Diana Riklis Family Research Award in Food Allergy, the Food Allergy Science Initiative (FASI) Inc., the Food Allergy Fund, several NIH grants, and the Nicholas Tierney Memorial GI Cancer Fund. Authors reported no competing interests.
Publication Information
Published August 7, 2025, in Science (Cysteinyl leukotrienes stimulate gut absorption of food allergens to promote anaphylaxis in mice), Laura R. Hoyt et al., Northwestern University Feinberg School of Medicine, Yale University School of Medicine, and others. DOI: 10.1126/science.adp0240.
