Northwestern Medicine scientists have identified a breakthrough approach to preventing life-threatening food allergy reactions using Zileuton, an FDA-approved asthma medication. The research, published in Science, demonstrates that blocking a newly discovered biological pathway can nearly eliminate anaphylaxis in mice, potentially offering new hope for millions of people living with food allergies.
Novel Pathway Discovery Links Gut Inflammation to Anaphylaxis
The discovery emerged from a comprehensive forward genetic screen conducted over several years, where researchers bred generations of mice to identify genes responsible for food allergy susceptibility. This systematic approach revealed that the DPEP1 gene plays a previously unknown but essential role in regulating anaphylaxis through its control of leukotrienes in the gut.
"The discovery of the new pathway came after a yearslong forward genetic screen, a process where scientists breed generations of mice to narrow down the specific genes responsible for biological differences, such as susceptibility to food allergy," the researchers explained. Once they identified that DPEP1 controlled these inflammatory molecules already targeted by asthma drugs, they tested Zileuton's effectiveness.
Dramatic Protection Against Food-Induced Anaphylaxis
The results exceeded expectations when mice received Zileuton before oral exposure to peanut extract. Dr. Stephanie Eisenbarth, director of the Center for Human Immunobiology and chief of the Division of Allergy and Immunology at Northwestern University Feinberg School of Medicine, described the outcome as "actually shocking how well Zileuton worked."
The treatment achieved remarkable efficacy, with 95% of previously susceptible mice showing almost no symptoms of anaphylaxis after Zileuton administration. Co-senior author Dr. Adam Williams, associate professor of medicine in allergy and immunology, emphasized the dramatic reversal: "The treatment reversed their risk from 95% susceptible to 95% protected."
Addressing Critical Unmet Medical Need
Food allergies affect more than 33 million people in the United States—nearly one in 10 individuals—and rates continue rising. Current treatment options remain severely limited, with only two FDA-approved therapies available for certain food allergies and no cure.
The existing treatments include oral immunotherapy for peanut allergy, which doesn't work for everyone and can itself trigger anaphylaxis, and omalizumab, a costly injection that also isn't effective for all allergic patients. Predicting an allergic individual's risk of anaphylaxis and preventing severe reactions from accidental exposure remains challenging with current approaches.
Preventive Protection Through Pathway Blocking
Zileuton offers a fundamentally different therapeutic strategy—a simple pill that temporarily shields allergic individuals by blocking the body's anaphylactic pathway before activation. This preventive approach could prove particularly valuable in situations where allergen exposure cannot be controlled.
"This is a totally different, out-of-the-box approach to treat food allergy, unlike anything we've tried before," Williams explained. "We've seen tragic, even fatal reactions from hidden ingredients like ground peanuts in a sauce. For parents sending their child to a birthday party, or for anyone flying where they can't control what's being served, this could be a powerful protective drug."
Clinical Translation Underway
The Northwestern team launched a small early-stage clinical trial in July to evaluate whether blocking this newly identified pathway with Zileuton produces similar protective effects in humans. This represents a critical step toward translating the promising preclinical findings into clinical practice.
Solving Long-Standing Diagnostic Puzzles
The research also provides insights into a persistent clinical mystery: why some individuals test positive for food allergens but experience no symptoms when consuming the food. This discrepancy between diagnostic tests and clinical tolerance has challenged clinicians and caused stress for patients.
"Let's say you're told you're allergic to peanuts based on a blood test, but you've eaten peanuts your whole life without any problems," Eisenbarth noted. "This pathway we discovered may be one explanation for why some of those people are protected."
Current diagnostic tests only estimate allergy risk rather than tolerance, creating uncertainty for both patients and healthcare providers. The newly identified pathway may help explain these individual differences in food allergy susceptibility.
Broader Research Implications
The findings open new avenues for understanding food allergy development and individual variation in allergic responses. "Our findings open a whole new area for future research into how people develop food allergies in the first place, and why some react while others don't," Eisenbarth said.
The research demonstrates the value of long-term scientific investment in unexpected directions. Eisenbarth reflected on the discovery's unpredictable nature: "If you'd asked me five or six years ago to guess the pathway that would lead to this discovery, I never would have picked this gene or the leukotriene molecules."
The study appears alongside complementary research led by Dr. Ruslan Medzhitov at Yale University, which independently discovered the same leukotriene pathway regulating food allergy in mice through a different experimental approach, strengthening confidence in the findings' validity and significance.
