Transcriptional and Ultrastructural Analyses Suggest Novel Insights into Epithelial Barrier Impairment in Celiac Disease

Agnieszka Sowińska,Bożena Cukrowska,Beata Oralewska,Elżbieta Czarnowska,Michael Scharl,Marek Woynarowski,Yasser Morsy,Marcin Wawrzyniak,Joanna B Bierła,Sylwia Szymańska,Maria Ejmont,Ewa Konopka

doi:10.3390/cells9020516

Agnieszka Sowińska, Bożena Cukrowska + Show 10 more

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https://doi.org/10.3390/cells9020516

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Abstract

Disruption of epithelial junctional complex (EJC), especially tight junctions (TJ), resulting in increased intestinal permeability, is supposed to activate the enhanced immune response to gluten and to induce the development of celiac disease (CD). This study is aimed to present the role of EJC in CD pathogenesis. To analyze differentially expressed genes the next-generation mRNA sequencing data from CD326+ epithelial cells isolated from non-celiac and celiac patients were involved. Ultrastructural studies with morphometry of EJC were done in potential CD, newly recognized active CD, and non-celiac controls. The transcriptional analysis suggested disturbances of epithelium and the most significant gene ontology enriched terms in epithelial cells from CD patients related to the plasma membrane, extracellular exome, extracellular region, and extracellular space. Ultrastructural analyses showed significantly tighter TJ, anomalies in desmosomes, dilatations of intercellular space, and shorter microvilli in potential and active CD compared to controls. Enterocytes of fetal-like type and significantly wider adherence junctions were observed only in active CD. In conclusion, the results do not support the hypothesis that an increased passage of gluten peptides by unsealing TJ precedes CD development. However, increased intestinal permeability due to abnormality of epithelium might play a role in CD onset.

Highlights

Celiac disease (CD) is an autoimmune-mediated disorder with characteristic histological changes in the small intestine and serum specific antibodies, which is triggered by the ingestion of gluten from wheat, barley, and rye in genetically predisposed individuals [1]
CD326+ epithelial cells from active celiac disease (CD) biopsies were compared with CD326+ epithelial cells from five biopsies of control patients
As epithelium and epithelial junctional complex (EJC) can be visualized by transmission electron microscopy, further research was directed into ultrastructural analyses

Summary

Introduction

Celiac disease (CD) is an autoimmune-mediated disorder with characteristic histological changes in the small intestine and serum specific antibodies, which is triggered by the ingestion of gluten from wheat, barley, and rye in genetically predisposed individuals [1]. The gluten from food products after digestion in the intestinal lumen generates small peptides, which are transferred through the epithelial barrier into lamina propria. This passage can take place using two different routes: the transcellular transport mediated by endocytosis on the luminal side of enterocytes or the paracellular transfer depend on the epithelial junctional complex (EJC). It is supposed that the dysfunction of tight junctions (TJ)—the most apical unit between neighboring epithelial cells—induces the transport of immunogenic gluten peptides into lamina propria and increases activation of the immune response leading to CD development [5]. Zonulin signaling leads to disassembling of junctional proteins and cytoskeleton rearrangement resulting in the disruption of TJ [6]

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