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Oxidative stress, DNA stability and evoked inflammatory signaling in young celiac patients consuming a gluten-free diet

European Journal of Nutrition volume 59, pages 1577–1584 (2020)Cite this article

Abstract

Purpose

Celiac disease (CD) is a multifactorial, autoimmune, gluten-sensitive inflammatory disorder of the small intestine. Taking into account the pathogenesis of CD, a strict gluten-free diet (GFD) is the only treatment able to restore epithelium integrity and eliminate complications. The current study was designed to assess whether the use of a GFD is sufficient for maintaining a correct oxidative/antioxidant balance and ameliorating the evoked inflammatory signaling in young patients with CD.

Methods

The study covered 80 children, aged between 7 and 18 years, attending the Gastroenterology Service of the Gastroenterology, Hepatology and Child Nutrition Service from the Virgen de las Nieves Hospital in Granada. Children with CD diagnosed were included in the celiac group who followed a strict GFD for 2 years (n = 40) and the control group (n = 40) included healthy children, with negative serological screening. Soluble superoxide dismutase 1 and 2, total antioxidant status, 8-hydroxy-2′-deoxyguanosine, cortisol, melatonin and inflammatory parameters in plasma, 15-F2t-isoprostanes in urine, and DNA breaks in peripheral blood lymphocytes were analysed.

Results

No differences were found in oxidative stress between CD patients and controls; however, IFN-γ, IL-1α, IP-10 and TNF-β were higher in the CD patients. VEGF was also higher than in the control group.

Conclusion

The GFD in the CD patients is enough to reduce the oxidative stress; however, in the case of the inflammatory signaling, the initial exposure to gluten prior to stablish the GFD is strong enough to induce an inflammatory state which is maintained (even when consuming the GFD); meanwhile the increase in VEGF recorded in the CD group could be a compensatory mechanism to restore the damaged mucosa and duodenal villous atrophy, due to its role in endothelial activation and generation of new functional and stable vascular networks.

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References

  1. Green PH, Lebwohl B (2011) Mesalamine for refractory celiac disease: an old medicine for a new disease. J Clin Gastroenterol 45(1):1–3

    PubMed  Google Scholar 

  2. Zimmer KP, Fischer I, Mothes T, Weissen-Plenz G, Schmitz M, Wieser H, Büning J, Lerch MM, Ciclitira PC, Weber P, Naim HY (2010) Endocytotic segregation of gliadin peptide 31–49 in enterocytes. Gut 59:300–310

    CAS  PubMed  Google Scholar 

  3. Stojiljkovic V, Todorovic A, Radlovic N, Pejic S, Mladenovic M, Kasapovic J, Pajović SB (2007) Antioxidant enzymes, glutathione and lipid peroxidation in peripheral blood of children affected by coeliac disease. Ann Clin Biochem 44:537–543

    PubMed  Google Scholar 

  4. Pascual V, Dieli-Crimi R, López-Palacios N, Bodas A, Medrano LM, Núñez C (2014) Inflammatory bowel disease and celiac disease: overlaps and differences. World J Gastroenterol 20:4846–4856

    PubMed  PubMed Central  Google Scholar 

  5. Green PHR, Jabri B (2006) Celiac disease. Ann Rev Med 57:207–221

    CAS  PubMed  Google Scholar 

  6. Högberg L, Webb C, Fälth-Magnusson K, Forslund T, Magnusson KE, Danielsson L, Ivarsson A, Sandström O, Sundqvist T (2011) Children with screening-detected coeliac disease show increased levels of nitric oxide products in urine. Acta Paediatr 100:1023–1027

    PubMed  Google Scholar 

  7. Palova-Jelinkova L, Danova K, Drasarovv H, Dvorak M, Funda DP, Fundova P, Kotrbova-Kozak A, Cerna M, Kamanova J, Martin SF, Freudenberg M, Tuckova L (2013) Pepsin digest of wheat gliadin fraction increases production of IL-1β via TLR4/MyD88/TRIF/MAPK/NF- κB signaling pathway and an NLRP3 inflammasome activation. PloS One 8:e62426

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Abadie V, Jabri B (2014) IL-15: a central regulator of celiac disease immunopathology. Immunol Rev 260:221–234

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Serena G, Camhi S, Sturgeon C, Yan S, Fasano A (2015) The role of gluten in celiac disease and type 1 diabetes. Nutrients 7:7143–7162

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Dandekar A, Mendez R, Zhang K (2015) Cross talk between ER stress, oxidative stress, and inflammation in health and disease. Methods Mol Biol 1292:205–214

    CAS  PubMed  Google Scholar 

  11. Makharia GK (2014) Current and emerging therapy for celiac disease. Front Med (Lausanne) 1:6

    Google Scholar 

  12. Ferretti G, Bacchetti T, Masciangelo S, Saturni L (2012) Celiac disease, inflammation and oxidative damage: a nutrigenetic approach. Nutrients 4(4):243–257

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Husby S, Koletzko IR, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Mäki M, Ribes-Koninckx C, Ventura A, Zimmer KP, ESPGHAN Working Group on Coeliac Disease Diagnosis, ESPGHAN Gastroenterology Committee, European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (2012) European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 54:136–160

    CAS  PubMed  Google Scholar 

  14. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH (2000) Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320:1240–1243

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Diaz-Castro J, Alferez MJ, Lopez-Aliaga I, Nestares T, Granados S, Barrionuevo M, Campos MS (2008) Influence of nutritional iron deficiency anemia on DNA stability and lipid peroxidation in rats. Nutrition 24(11–12):1167–1173

    CAS  PubMed  Google Scholar 

  16. Dugas B, Dugas N, Conti M, Calenda A, Pino P, Thomas Y, Mazier D, Vouldoukis I (2003) Wheat gliadin promotes the interleukin-4-induced IgE production by normal human peripheral mononuclear cells through a redox-dependent mechanism. Cytokine 21:270–280

    CAS  PubMed  Google Scholar 

  17. Luciani A, Villella VR, Vasaturo A, Giardino I, Pettoello-Mantovani M, Guido S, Cexus ON, Peake N, Londei M, Quaratino S, Maiuri L (2010) Lysosomal accumulation of gliadin p31–43 peptide induces oxidative stress and tissue transglutaminase-mediated PPARgamma downregulation intestinal epithelial cells and coeliac mucosa. Gut 59:311–319

    PubMed  Google Scholar 

  18. Katar M, Ozugurlu AF, Ozyurt H, Benli I (2014) Evaluation of glutathione peroxidase and superoxide dismutase enzyme polymorphisms in celiac disease patients. Genet Mol Res 13:1030–1037

    CAS  PubMed  Google Scholar 

  19. Marnett LJ (2000) Oxyradicals and DNA damage. Carcinogenesis 21:361–370

    CAS  PubMed  Google Scholar 

  20. Diosdado B, van Oort E, Wijmenga C (2005) Coelionomics: towards under-standing the molecular pathology of coeliac disease. Clin Chem Lab Med 43:685–695

    CAS  PubMed  Google Scholar 

  21. Olinski R, Gackowski D, Rozalski R, Foksinski M, Bialkowski K (2003) Oxidative DNA damage in cancer patients: a cause or a consequence of the disease development? Mutat Res 531:177–190

    CAS  PubMed  Google Scholar 

  22. Haddad JJ, Olver RE, Land SC (2000) Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells. J Biol Chem 275:21130–21139

    CAS  PubMed  Google Scholar 

  23. Moss SF, Attia L, Scholes JV, Walters JR, Holt PR (1996) Increased small intestinal apoptosis in coeliac disease. Gut 39:811–817

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Jabri B, Sollid LM (2017) T Cells in celiac disease. J Immunol 198:3005–3014

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Green PHR, Cellier C (2007) Celiac disease. N Engl J Med 357:1731–1743

    CAS  PubMed  Google Scholar 

  26. Meresse B, Malamut G, Cerf-Bensussan N (2012) Celiac disease: an immunological jigsaw. Immunity 36:907–919

    CAS  PubMed  Google Scholar 

  27. Abadie V, Discepolo V, Jabri B (2012) Intraepithelial lymphocytes in celiac disease immunopathology. Semin Immunopathol 34:551–556

    CAS  PubMed  Google Scholar 

  28. Goldstein NS, Underhill J (2001) Morphologic features suggestive of gluten sensitivity in architecturally normal duodenal biopsy specimens. Am J Clin Pathol 116:63–71

    CAS  PubMed  Google Scholar 

  29. Steenholt JV, Nielsen C, Baudewijn L, Staal A, Rasmussen KS, Sabir HJ, Barington T, Husby S, Toft-Hansen H (2017) The composition of T cell subtypes in duodenal biopsies are altered in coeliac disease patients. PLoS One 12:1–17

    Google Scholar 

  30. Tuire I, Marja-Leena L, Teea S, Katri H, Jukka P, Päivi S, Heini H, Markku M, Pekka C, Katri K (2012) Persistent duodenal intraepithelial lymphocytosis despite a long- term strict gluten- free diet in celiac disease. Am J Gastroenterol 107:1563–1569

    PubMed  Google Scholar 

  31. Kutlu T, Brousse N, Rambaud C, Le Deist F, Schmitz J, Cerf-Bensussan N (1993) Numbers of T cell receptor (TCR) alpha beta+ but not of TCR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut 34:208–214

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen Y, Chou K, Fuchs E, Havran WL, Boismenu R (2002) Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci USA 99:14338–14343

    CAS  PubMed  Google Scholar 

  33. Piatek-Guziewicz A, Ptak-Belowska A, Przybylska-Felus M, Pasko P, Zagrodzki P, Brzozowski T, Mach T, Zwolinska-Wcislo M (2017) Intestinal parameters of oxidative imbalance in celiac adults with extraintestinal manifestations. World J Gastroenterol 23(44):7849–7862

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Wapenaar MC, van Belzen MJ, Fransen JH, Sarasqueta AF, Houwen RH, Meijer JW, Mulder CJ, Wijmenga C (2004) The interferon gamma gene in celiac disease: augmented expression correlates with tissue damage but no evidence for genetic susceptibility. J Autoimmun 23:183–190

    CAS  PubMed  Google Scholar 

  35. Nilsen EM, Lundin KE, Krajci P, Scott H, Sollid LM, Brandtzaeg P (1995) Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 37:766–776

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kumar V, Gutierrez-Achury J, Kanduri K, Almeida R, Hrdlickova B, Zhernakova DV, Westra HJ, Karjalainen J, Ricaño-Ponce I, Li Y, Stachurska A, Tigchelaar EF, Abdulahad WH, Lähdesmäki H, Hofker MH, Zhernakova A, Franke L, Lahesmaa R, Wijmenga C, Withoff S (2015) Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels. Hum Mol Genet 24(2):397–409

    CAS  PubMed  Google Scholar 

  37. Lanzini A, Lanzarotto F, Villanacci V, Mora A, Bertolazzi S, Turini D, Carella G, Malagoli A, Ferrante G, Cesana BM, Ricci C (2009) Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet. Aliment Pharmacol Ther 29:1299–1308

    CAS  PubMed  Google Scholar 

  38. Lebwohl B, Granath F, Ekbom A, Smedby KE, Murray JA, Neugut AI, Green PH, Ludvigsson JF (2013) Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population based cohort study. Ann Intern Med 159:169–175

    PubMed  PubMed Central  Google Scholar 

  39. McNicholl B, Egan-Mitchell B, Stevens F, Keane R, Baker S, McCarthy CF, Fottrell PF (1976) Mucosal recovery in treated childhood celiac disease (gluten-sensitive enteropathy). J Pediatr 89:418–424

    CAS  PubMed  Google Scholar 

  40. Wahab PJ, Meijer JW, Mulder CJ (2002) Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery. Am J Clin Pathol 118:459–463

    PubMed  Google Scholar 

  41. Yla-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J (2007) Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 49(10):1015–1026

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by Andalusian Government, Excellence Research Project no P12-AGR-2581. Carlota Muriel-Neyra and Jorge Moreno-Fernandez are grateful to the Excellence Ph.D. Program “Nutrición y Ciencias de los Alimentos” from the University of Granada. The authors also thank the patients for their participation in the current study and Ms. Susan Stevenson for her efficient support in the revision with the English language.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Pharmacy, Campus Universitario de Cartuja, University of Granada, 18071, Granada, Spain

    Javier Diaz-Castro, Carlota Muriel-Neyra, Jorge Moreno-Fernandez & Teresa Nestares

  2. Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, Granada, Spain

    Javier Diaz-Castro, Carlota Muriel-Neyra, Jorge Moreno-Fernandez & Teresa Nestares

  3. Gastroenterology, Hepatology and Child Nutrition Service, University Hospital Virgen de las Nieves, Granada, Spain

    Rafael Martin-Masot & José Maldonado

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  1. Javier Diaz-Castro
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Correspondence to Teresa Nestares.

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The authors declare no conflict of interest. The funding sponsor had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

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Diaz-Castro, J., Muriel-Neyra, C., Martin-Masot, R. et al. Oxidative stress, DNA stability and evoked inflammatory signaling in young celiac patients consuming a gluten-free diet. Eur J Nutr 59, 1577–1584 (2020). https://doi.org/10.1007/s00394-019-02013-5

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Keywords

  • Celiac disease
  • Gluten-free diet
  • Oxidative stress
  • Inflammatory signaling