Modulating a Novel Neuroepithelial Circuit in Food Allergy to Repair Barrier Dysfunction With Larazotide Acetate and Neuregulin-1

Overview

Food allergy (FA) affects 18% of the population and is driven by type-2 inflammation, epithelial barrier dysfunction, and tight junction (TJ) disruption. Recent studies identify Zonulin and Resistin-like-Molecule-beta (RELMb) as parallel disruptors of TJs through PKC-a activation. While Zonulin acts through established receptors, RELMb's receptor remains undefined; however, emerging evidence implicates ErbB3 as a potential candidate. This study aimed to (1) define RELMb-induced gut barrier disruption, (2) identify ErbB3 as RELMb's receptor, (3) determine competitive interactions between RELMb and ErbB3 canonical ligand Neuregulin-1 (NRG1), (4) evaluate therapeutic applications of Zonulin antagonist Larazotide Acetate (LA) with NRG1 in FA. Murine intestinal organoids derived from IL4raF709 and IL4raF709Retnlb-/- mice were treated with IL-13, RELMb, LA, and NRG1. RELMb increased Claudin-13/Claudin-15 (p<0.01) and alarmin IL-25/TSLP expression (p<0.01), reflecting a compensatory response to barrier leak, with RELMb-/- organoids displaying blunted alarmin transcription (p<0.0001). LA restored RELMb (p<0.01), alarmin (p<0.001), and TJ expression (p<0.01). AlphaFold-Multimer, PyMOL, and PRODIGY docking demonstrated RELMb binds with substantial affinity to ErbB3 extracellular domains 1 and 3, overlapping NRG1 binding sites. Immunofluorescence confirmed RELMb-ErbB3 colocalization, while NRG1 competitively displaced RELMb from the receptor, normalizing TJ and cytokine expression (p<0.001). Combined LA/NRG1 treatment produced the greatest restoration of epithelial integrity (p<0.001). These findings define a novel RELMb-ErbB3-NRG1 neuroepithelial circuit modulating gut permeability and highlight LA/NRG1 as a novel co-therapy to restore FA barrier and immune homeostasis.

Awards (1)

• Second Award of $2,400 $2,400

Competition history

• ISEF 2026 Biomedical and Health Sciences · Entry BMED054

Resources

• ISEF abstract page ↗

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