Nrf2 ACTIVATION PREVENTS PRO-OXIDANT SIGNS IN A MOUSE MODEL OF GLIADIN-INDUCED ENTEROPATHY

AIMS. Gliadin-induced toxicity on intestinal cytoprotective mechanisms (nuclear factor erythroid 2-related factor2, Nrf2) and the protective effects elicited by Conjugated Linoleic Acid (CLA) mixture of cis9,trans11 (c9) and trans10,cis12 (t10) isomers was evidenced in HLA-DQ8-transgenic mice (DQ8). Herein the association between the ability to improve Nrf2-mediated defences and the protective effect against in our animal model of gluten-induced enteropathy was investigated. METHODS The different ability of CLA to activate Nrf2 enzymes (Glutathione reductase, GSR; Glutathione transferase, GST and NAD(P)H:quinone oxidoreductase NQO1) was investigated in animals supplemented with c9 or t10 (520 mg kg/bw/day) for two weeks. Gluten-induced enteropathy was induced in DQ8 mice by three intra-gastric administration of gliadin (20 mg kg/bw) and indomethacin intake (15 mg/L in drinking water) for ten days (GI). DQ8 mice treated with wheat albumin-globulin fraction were used as control (AI) and final group consisting of animals pre-treated with c9 before GI challenge (c9+GI) was used. Nrf2-activated defences were evaluated by combining enzymatic and quantitative real-time PCR assays. RESULTS The activity of Nrf2-activated enzymes and the mRNA levels of GST were significantly improved by c9 (p <0.01) but not by t10 intake. GI treatment resulted in significant pro-oxidant and toxic effects on duodenal Nrf2-mediates cyto-protections while only minor effects were measured in the duodenum of AI animals. Notably, pro-oxidant and pro-apoptotic effects resulting from GI intake were inhibited by c9 pre-treatment. CONCUSION Nrf2-mediated antioxidant/detoxifying defences are activated by supplementation with low doses of c9 isomer and pre-treatment with c9 has preventive effects against pro-oxidant and pro-inflammatory signs of gliadin-induced enteropathy. Presented data indicates the Nrf2 pathway as a molecular target for decreasing disease activity in celiac disease patients.