The Celiac‐Disease Superantigen Oligomerizes and Increases Permeability in an Enterocyte Cell Model

Celiac disease (CeD) is an autoimmune disorder triggered by gluten proteins, affecting approximately 1 % of the global population. The 33‐mer deamidated gliadin peptide (DGP) is a metabolically modified wheat‐gluten superantigen for CeD. Here, we demonstrate that the 33‐mer DGP spontaneously assembles into oligomers with a diameter of approximately 24 nm. The 33‐mer DGP oligomers present two main secondary structural motifs–a major polyproline II helix and a minor β‐sheet structure. Importantly, in the presence of 33‐mer DGP oligomers, there is a statistically significant increase in the permeability in the gut epithelial cell model Caco‐2, accompanied by the redistribution of zonula occludens‐1, a master tight junction protein. These findings provide novel molecular and supramolecular insights into the impact of 33‐mer DGP in CeD and highlight the relevance of gliadin peptide oligomerization. The 33‐mer deamidated gliadin peptide is formed in active celiac disease and related to T‐cell activation. We determined its oligomeric nature and found a significant increase in gut epithelial permeability mediated by the tight junction protein zonula occludens‐1. These findings shed light on this pathological peptide and its oligomers and have implications for advancing our understanding and treatment of celiac disease.