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

Date Published: February 20, 2019

Publisher: Public Library of Science

Author(s): Sunao Shimada, Tetsuya Tanigawa, Toshio Watanabe, Akinobu Nakata, Naoki Sugimura, Shigehiro Itani, Akira Higashimori, Yuji Nadatani, Koji Otani, Koichi Taira, Shuhei Hosomi, Yasuaki Nagami, Fumio Tanaka, Noriko Kamata, Hirokazu Yamagami, Masatsugu Shiba, Yasuhiro Fujiwara, Karol Sestak.

http://doi.org/10.1371/journal.pone.0211436

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.

Partial Text

The recent widespread use of video capsule endoscopy and balloon-assisted enteroscopy revealed that non-steroidal anti-inflammatory drugs (NSAIDs) induce small-intestinal damage.[1–4] Our recent study showed that 25% of patients with rheumatoid arthritis who took NSAIDs for more than 3 months had mild small-intestinal damage, and more important, 27.8% of patients had severe damage and decreased hemoglobin levels.[5] Although misoprostol and rebamipide are reported to be potential therapeutic and prophylactic agents for NSAID-induced small-intestinal damage,[6, 7] clarification of dietary factors associated with NSAID-induced small intestinal damage is also important for making therapeutic and prophylactic strategies against the disease as well as chemopreventive strategy.

In the present study, we demonstrated that gliadin exacerbates NSAID-induced small-intestinal damage. Gliadin increased intestinal paracellular permeability through the upregulation of EGFR phosphorylation, which is involved in the mechanism by which gliadin exacerbates NSAID-induced small intestinal damage.

 

Source:

http://doi.org/10.1371/journal.pone.0211436

 

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