In a groundbreaking advancement in food allergy research, scientists at Northwestern University have uncovered a previously unknown biological pathway that dramatically alters the trajectory of anaphylactic responses to food allergens in mice. This pioneering study reveals that targeting the gene DPEP1, through the use of the FDA-approved asthma drug Zileuton, can nearly abolish life-threatening allergic reactions in animal models. The results, published in the prestigious journal Science, offer a beacon of hope for millions worldwide who live under the constant threat of severe food allergies.
The discovery originated from an exhaustive genetic investigation involving a forward genetic screen, wherein multiple generations of mice were bred and analyzed to isolate genetic determinants tied to food allergy susceptibility. Researchers pinpointed the DPEP1 gene as a crucial regulator of anaphylaxis, highlighting its unexpected role in modulating leukotriene production within the gastrointestinal tract. Leukotrienes, well-known inflammatory mediators traditionally implicated in asthma pathology, emerged as central players in the gut’s immune response to ingested allergens.
By administering Zileuton, a leukotriene production inhibitor long approved for managing asthma, the team was able to effectively block this newly identified anaphylactic pathway in mice. Upon oral challenge with peanut extract—a common and potent food allergen—the pretreated mice exhibited a drastic reduction in clinical symptoms, shifting from a 95% susceptibility to severe anaphylaxis down to a 95% protection threshold. This transformative outcome underscores the drug’s therapeutic potential as a prophylactic agent against food-induced anaphylaxis.
The mechanism by which DPEP1 influences allergic sensitization and reaction is particularly noteworthy. As a dipeptidase enzyme, DPEP1 modulates leukotriene activity in the gut, thereby impacting the absorption and immunogenic presentation of allergens. This pathway’s elucidation positions leukotrienes not only as downstream effectors of inflammation but as integral mediators of allergen uptake, thus redefining their role in food allergy pathogenesis.
Current treatment paradigms for food allergies remain limited and imperfect. Oral immunotherapies, often targeting peanut allergies, entail gradual desensitization but carry risks of triggering anaphylaxis themselves and offer protection only during treatment periods. Additionally, monoclonal antibody therapies, such as omalizumab, provide benefits for some but fall short of broad efficacy and come with substantial costs. Hence, an easily administered oral medication that prevents anaphylaxis preemptively represents a paradigm shift in disease management.
Dr. Stephanie Eisenbarth, a co-senior author and director of the Center for Human Immunobiology at Northwestern, reflected on the unexpected nature of the findings. “The efficacy of Zileuton in this context was truly astonishing,” she remarked, emphasizing the serendipitous identification of a gene and pathway previously unassociated with food allergy risk. The research team’s approach, leveraging decades of genetic screening and molecular analyses, exemplifies the innovative routes required to tackle complex immunologic disorders.
The translational impact of these findings is immediate, with Northwestern having initiated a phase 1 clinical trial in July to evaluate the safety and efficacy of Zileuton in individuals with food allergies. This trial aims to confirm whether the promising results in murine models can be replicated in humans, potentially heralding a new therapeutic avenue that circumvents the risks and limitations of existing treatments.
Beyond its clinical implications, the study also addresses a perplexing phenomenon frequently encountered in allergy diagnostics: individuals testing positive for food allergen sensitization yet experiencing no adverse symptoms upon exposure. Dr. Eisenbarth posits that variations in this newly identified pathway may explain why some people demonstrate tolerance despite immunologic evidence of allergy, a finding that could refine diagnostic algorithms and patient counseling in the future.
The team’s comprehensive approach integrated expertise from immunology, molecular biology, and clinical medicine, underscoring the collaborative nature of contemporary biomedical research. The work was accomplished with support from various funding agencies, including the National Institute of Allergy and Infectious Diseases and dedicated food allergy research foundations, reflecting the critical role of sustained investment in uncovering novel disease mechanisms.
Complementing this study, concurrent research from Yale University led by Dr. Ruslan Medzhitov independently confirmed the importance of leukotriene pathways in gut-mediated food allergy through alternative methodologies. The convergence of findings from distinct investigative routes reinforces the robustness of leukotrienes as therapeutic targets and validates leukotriene inhibition as a viable clinical strategy.
In conclusion, this landmark study not only delineates a hitherto unrecognized mechanism of food allergen absorption and anaphylaxis but also identifies a readily available pharmacologic agent capable of disrupting this process. Should clinical trials confirm these results in humans, Zileuton may revolutionize food allergy prevention, providing a simple, effective prophylactic option and significantly reducing the morbidity and mortality associated with food-induced anaphylaxis.
Subject of Research: Food allergy mechanisms; role of DPEP1 gene and leukotriene pathway in anaphylaxis; therapeutic potential of leukotriene inhibition.
Article Title: Cysteinyl leukotrienes stimulate gut absorption of food allergens to promote anaphylaxis in mice
News Publication Date: 7-Aug-2025
Web References:
http://dx.doi.org/10.1126/science.adp0240
References:
- Northwestern Medicine study published in Science (10.1126/science.adp0240)
- Related research by Dr. Ruslan Medzhitov at Yale University (concurrent Science publication)
Image Credits: Northwestern University
Keywords: Allergies, Allergens, Allergic reactions, Peanuts
