Cellular and molecular gastroenterology and hepatology · 2026
Single-Cell Mapping of the Gut Epithelium Reveals Paneth Cell Dysfunction and Lysozyme Deficiency in Peanut Allergy.
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Clough Katelyn M, Gomez-Martinez Ismael, Cannon Gabrielle, VanLandingham Nathan K, Chettoor Maria R, Khaled Zena, Kennedy Sophia, Schaner Matthew R, Huan Benjamin, Lau Gwen W, Lian Grace, Silverstein Sophie, Beasley Caroline, Weaver David S, Lacorte Ariana M, Furey Brady, Mir Sabina A, Madren Jillann A, White Kristen K, Hepperla Austin J, Furey Terrence S, Steinbach Erin C, Sheikh Shehzad Z
Аннотация
BACKGROUND AND AIMS: A growing body of evidence links intestinal epithelial cell barrier dysfunction to the development of food allergies. We previously showed that the peanut allergy-susceptible CC027 mouse has increased intestinal permeability. To understand the heterogeneity of the intestinal barrier in peanut allergy susceptibility, we used scRNA-seq to generate a high-resolution single-cell atlas of the small intestinal epithelium in the naïve CC027 mouse. This can be used to inform patient findings and provide a resource for understanding how epithelial cells contribute to peanut allergy pathogenesis.
METHODS: We generated a high-resolution single-cell atlas of the intestinal epithelium of allergy-susceptible, naïve CC027 mice and allergy-prone but orally resistant, naïve C3H/HeJ mice. Histology studies in gastrointestinal tissues from mice and human patients with or without peanut allergy corroborated our findings.
RESULTS: Naïve CC027 mice exhibited a reduced proportion of interferon-responsive absorptive enterocytes compared to naïve C3H/HeJ mice, reduced numbers of EECs, and increased numbers of goblet and tuft cells. We found a complete absence of the Paneth cell antimicrobial peptide lysozyme 1 (Lyz1) transcript and enrichment of mitochondrial stress pathways in peanut unexposed CC027 mice. Paneth cells from CC027 mice exhibited signs of cell stress by electron microscopy. In patients with peanut allergy, small intestinal biopsies demonstrated decreased Paneth cell-specific LYZ protein expression.
CONCLUSION: We establish a single-cell atlas of the intestinal epithelium in a translationally relevant peanut allergy-susceptible mouse model and show a link between intestinal permeability, epithelial-derived interferon responses, and Paneth cell dysfunction in maintaining immune tolerance to dietary antigens.
METHODS: We generated a high-resolution single-cell atlas of the intestinal epithelium of allergy-susceptible, naïve CC027 mice and allergy-prone but orally resistant, naïve C3H/HeJ mice. Histology studies in gastrointestinal tissues from mice and human patients with or without peanut allergy corroborated our findings.
RESULTS: Naïve CC027 mice exhibited a reduced proportion of interferon-responsive absorptive enterocytes compared to naïve C3H/HeJ mice, reduced numbers of EECs, and increased numbers of goblet and tuft cells. We found a complete absence of the Paneth cell antimicrobial peptide lysozyme 1 (Lyz1) transcript and enrichment of mitochondrial stress pathways in peanut unexposed CC027 mice. Paneth cells from CC027 mice exhibited signs of cell stress by electron microscopy. In patients with peanut allergy, small intestinal biopsies demonstrated decreased Paneth cell-specific LYZ protein expression.
CONCLUSION: We establish a single-cell atlas of the intestinal epithelium in a translationally relevant peanut allergy-susceptible mouse model and show a link between intestinal permeability, epithelial-derived interferon responses, and Paneth cell dysfunction in maintaining immune tolerance to dietary antigens.