Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage

Abstract

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1β in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

“…Bile acids are especially instrumental factors that highly aggravate NSAID-induced damage as there are reports showing that NSAID alone can trigger less macroscopic injuries in spite of increasing membrane permeability and inflammation in bile duct-ligated rats [142]. An interesting study revealed that insoluble dietary fibers and gliadin (contained in wheat gluten) lead to intestinal epithelial injury and increase in intestinal permeability mainly when mucus levels are low due to NSAID usage [143][144]. It was evident from the post hoc analysis of the data, obtained from Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) trial that small intestinal complications accounted for 40% of severe gastrointestinal complications in patients using NSAIDs [145].…”

Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

“…As a result of such initial disorders brought by COX inhibition and the topical effects on mitochondria, intestinal permeability is increased with the disruption of the barrier function, which facilitates the invasion of the small bowel by luminal injury factors such as enterobacteria and bile. Furthermore, recent studies have suggested that dietary factors are involved in increased intestinal permeability during the development of NSAIDs-induced damage: Insoluble dietary fibers contribute to the surface damage of the intestinal epithelium when the mucus is decreased by NSAIDs' administration [66], and gliadin, a component of wheat gluten, increases the intestinal permeability via the epidermal growth factor receptor-dependent signaling pathway [67]. All these events lead to promoting a series of inflammatory events sufficient for inducing macroscopic ulceration.…”

Rebamipide ameliorates indomethacin-induced small intestinal damage and proton pump inhibitor-induced exacerbation of this damage by modulation of small intestinal microbiota

“…and T.K.). For evaluation, a modified histological scoring system was used [ 25 ]. The histological score ranged from 0 to 13 and was divided into the following six categories: epithelium (0 = normal, 1 = flattened, 2 = loss of epithelial continuity, 3 = severe denudation), villus shape (0 = normal, 1 = short and rounded, 2 = extremely short and thick), villus tip (0 = normal, 1 = damaged, 2 = severely damaged), stroma (0 = normal, 1 = slightly retracted, 2 = severely retracted), inflammation (0 = no infiltration, 1 = mild infiltration, 2 = severe infiltration), and crypt status (0 = normal, 1 = mild crypt loss, 2 = severe crypt loss).…”