W1740 Loss-of-Function Variants of the Epithelial Barrier Protein Filaggrin Predispose to Marked Atopic Co-Morbidity in Paediatric Inflammatory Bowel Disease

Abstract

Background: The gastric epithelial cell layer is a pivotal physical defence mechanism necessary for the integrity of gastric mucosa. Disruption of cell junctions and cell cytoskeleton, key elements in the efficiency of this barrier, leads to the initiation of gastric mucosal injury. Isoflavones, selective estrogen receptor modulators, exert their effects by selectively binding to estrogen receptors (ER), particularly ERβ, and are involved in the control of gastric mucosal homeostasis. ERβ are expressed mainly in the human gastric antrum and their role in the gastric physiological functions is still unknown. Aim: In this study we evaluated the effects of isoflavones, administrated as soy germ pasta, on gastric mucosal gene expression through an extensive microarray analysis in healthy individuals. Materials and Methods: Biologically active isoflavones (aglycones) were administrated using a 2% soy-germ pasta (SP) (Aliveris srl, Perugia, Italy). Equivalent conventional pasta (CP) was used as a control. 5 healthy volunteers (3 F, age: 30±3 years) consumed a standard diet containing CP (80gr/ daily) for 1 week followed by SP (80gr/daily; approx. 33mg of isoflavones) for 1 week. An upper endoscopy with biopsy was performed at the end of each week. Gastric samples were collected for microarray analysis and qRT-PCR. Biotin-labeled cRNA was obtained and hybridized to an Affymetrix HG-U133 Plus2.0 GeneChipArray according to standard procedures. Results: Microarray analysis highlighted a dramatic difference in gene expression after consumption of SP compared to CP. The gene list obtained was clearly efficient in separating the two groups at the end of the two different diets. Functional gene classification was performed based on different sources (GeneOntology, KEGG, SOURCE) with integrated information from the literature and 58 genes were included in 8 different gene categories: cytoskeleton, organization and biogenesis, cell-cell communication, contractility, signal transduction, stress response, transcription and other/unknown. Interestingly, one of these genes, PGTDS, which encodes an enzyme involved in prostaglandin synthesis, was 5-fold upregulated after SP administration compared to CP. Of note, while the expression of ERα and ERβ was not affected, 10 out of the 58 modulated genes contained one estrogen responsive element. Conclusion: This is the first evidence that isoflavones modulate the expression of genes involved in cell-cell and cell-extra cellular matrix adhesion process in human gastric mucosa, suggesting a potential role of isoflavones in gastric mucosal defense.