A peanut butter sandwich is a common meal for many, yet for the 1.6 million children in the U.S. with peanut allergy, even minor exposure can provoke a severe, potentially fatal reaction. Scientists have long sought to explain why some children develop this allergy while others do not. A new study from the University of North Carolina School of Medicine proposes that the answer may lie in the gut lining—not the peanut itself—but in a missing protein that weakens the intestine’s defenses before a child encounters the allergen.
The research, published in Cellular and Molecular Gastroenterology and Hepatology, was led by graduate student Katelyn (Katie) Clough and her colleagues. Using single-cell RNA sequencing, they mapped every cell type in the small intestinal lining of mice genetically predisposed to peanut allergy. Their findings revealed that a specialized cell population called Paneth cells, normally responsible for producing antimicrobial proteins to safeguard the gut, were deficient in lysozyme 1 (Lyz1), an enzyme essential for maintaining gut health.
This deficiency was not accidental. The allergy-prone mouse strain, CC027, inherited its chromosome 10 from a wild mouse species lacking the Lyz1 gene entirely. The team then examined intestinal biopsies from children with peanut allergy and found fewer lysozyme-producing Paneth cells compared to non-allergic children. The defect appeared even before any peanut exposure, indicating that the gut’s barrier was already compromised.
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Clough noted that these Paneth cell changes were present in mice that had never been exposed to peanuts. “This tells us the gut is already in an altered state before any allergic challenge. The barrier defect may come first, and allergy follows.”
Disruptions in the gut’s cellular structure
The study extended beyond Paneth cells by sequencing thousands of intestinal cells from both allergy-susceptible and resistant mice. The results uncovered broader disruptions in the gut’s epithelial layer of allergy-prone mice, even before peanut exposure:
- A specialized population of interferon-responsive absorptive enterocytes was depleted, weakening the gut’s antiviral defenses.
- Goblet cells, which produce mucus to protect the intestine, were overproduced, while enteroendocrine cells, critical for regulating gut permeability, were reduced.
- Tuft cells, known to trigger type 2 allergic immune responses, were increased and exhibited higher levels of allergic immune receptors such as IL-4Rα.
- Under electron microscopy, Paneth cells showed signs of stress, including dilated endoplasmic reticulum and dysmorphic secretory granules, consistent with secretory dysfunction, in addition to decreased production of the antimicrobial protein lysozyme-1.
The absence of lysozyme has wider implications. Lysozyme helps regulate the gut microbiome by targeting bacteria that can promote allergic reactions. Both Lyz1-deficient mice and allergy-susceptible CC027 mice shared an overgrowth of specific bacterial genera, including Ruminococcus and Akkermansia, microbes linked to type 2 immune skewing, the same pathway driving peanut allergy.
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Erin Steinbach, an assistant professor in UNC’s Division of Rheumatology, Allergy & Immunology, emphasized that the gut epithelium may not merely be a passive observer in allergy development but the primary driver. “A genetic loss of a single antimicrobial protein in Paneth cells cascades into microbiome changes, immune skewing, and a gut barrier primed for allergy. That is a mechanistic chain in which we can potentially intervene.”
The team is now expanding the study to a larger pediatric cohort and testing whether restoring lysozyme function or adjusting the microbiome in human gut models can reverse the barrier defects seen in allergy-susceptible individuals.