HMN 2025: What is the link of intestinal leukotrienes to oral anaphylaxis in mice

Yale University School of Medicine reports that cysteinyl leukotrienes released by intestinal mast cells are essential for anaphylaxis after food ingestion in mice, while responses to intravenous allergen challenge proceed without that requirement.

Food allergies are a growing medical problem in the industrialized world. In the most extreme cases, allergic reactions manifest as anaphylaxis, a life?threatening state of bronchoconstriction and hemodynamic collapse.

Previous mouse models often studied anaphylaxis through intravenous administration of food antigens, which is good at isolating systemic mechanisms of allergic shock, but bypasses the local exposure of food antigens in gut mucosal tissues.

In the study, “Intestinal mast cell–derived leukotrienes mediate the anaphylactic response to ingested antigens,” published in Science, researchers combined bulk and single?cell RNA sequencing, in vitro culture models, and flow cytometry to identify factors governing oral anaphylaxis susceptibility and severity.

Mouse experiments included multiple strains and genetically modified lines lacking leukotriene enzymes or receptors, as well as bone marrow chimeras.

Allergen exposure involved two models. Ovalbumin in alum was used for sensitization followed by repeated intragastric challenges to induce oral anaphylaxis. Peanut with cholera toxin served as an alternate allergen–adjuvant combination for testing oral challenge responses.

Passive IgE?dependent anaphylaxis models with intravenous and intragastric challenges were performed. Bone marrow chimera approaches tested hematopoietic contributions.

Oral challenge in the ovalbumin-alum model produced anaphylaxis that was dependent on IgE–Fc?R1? signaling and associated with expansion of intestinal mast cells. Passive IgE-dependent anaphylaxis confirmed that oral, but not intravenous, responses required leukotriene synthesis.

Peanut with cholera toxin did not cause a measurable drop in body temperature after oral challenge, though intravenous peanut challenge produced a detectable response.

Histamine’s role was tested using the H1 receptor (H1R) antagonist triprolidine. In oral anaphylaxis, triprolidine had little effect on body temperature changes, reducing severe drops only in some mice.

In contrast, the same treatment given before intravenous allergen challenge in the IgE-dependent model almost completely prevented anaphylaxis. These results indicate that oral reactions in this model do not rely primarily on histamine, pointing instead to a mechanism driven by leukotrienes.

Bone marrow chimera experiments showed that cysteinyl leukotrienes from hematopoietic cells were necessary for anaphylaxis after oral allergen exposure.

Zileuton treatment protected from oral antigen-induced responses without altering responses to intravenous challenge. Acute zileuton given 1 hour before challenge prevented body temperature decreases and improved allergen?inducible gastrointestinal transit time.

LTC4S knockout protected from oral challenge with complete protection from temperature drop and partial protection for transit changes, while intravenous responses remained largely unaltered.

Hematopoietic cysteinyl leukotrienes were required for ingested allergen–induced anaphylaxis, as shown in bone marrow chimera experiments. Passive models confirmed a selective requirement for LTC4S and CysLTR1 during IgE?dependent reactions after intragastric challenge but not after intravenous challenge.

CysLTR1 and CysLTR2 knockouts individually reduced intestinal mast cell expansion and mitigated gastrointestinal symptoms; acute blockade of individual receptors did not fully reproduce the protection achieved by aLOX5 inhibition.

The authors propose dual functions for cysteinyl leukotrienes in mice for promoting mucosal mast cell expansion and stimulating acute sensitization to oral anaphylaxis through signaling to epithelial cells, neurons, and group 2 innate lymphoid cells.

They conclude that local intestinal responses may be targetable as a therapeutic strategy to prevent anaphylaxis in severely food?allergic individuals.

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