Digestive Diseases and Sciences

, Volume 52, Issue 9, pp 2015–2021 | Cite as

Oxidative Stress and Pathogenesis of Inflammatory Bowel Disease: An Epiphenomenon or the Cause?

  • Ali Rezaie
  • Robyn D. Parker
  • Mohammad AbdollahiEmail author
Review Article


Crohn’s disease (CD) and ulcerative colitis (UC), known as inflammatory bowel disease (IBD), are fairly common chronic inflammatory conditions of the gastrointestinal tract. Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species are produced in abnormally high levels in IBD. Their destructive effects may contribute to the initiation and/or propagation of the disease. We provided an extensive overview on the evidences from animal and human literature linking oxidative stress to IBD and its activity. Moreover, the effects of antioxidant therapy on IBD patients in randomized, controlled trials were reviewed and the need for further studies elaborated. We also summarized the evidence in support for causality of oxidative stress in IBD.


Animal Crohn’s disease Human Inflammatory bowel disease Oxidative stress Ulcerative colitis 


  1. 1.
    Brandtzaeg P, Haraldsen G, Rugtveit J (1997) Immunopathology of human inflammatory bowel disease. Semin Immunopathol 18(4):555–589CrossRefGoogle Scholar
  2. 2.
    Spitz DR, et al. (2004) Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastasis Rev 23(3–4):311–322PubMedCrossRefGoogle Scholar
  3. 3.
    Mueller S (2000) Sensitive and nonenzymatic measurement of hydrogen peroxide in biological systems. Free Radic Biol Med 29(5):410–415PubMedCrossRefGoogle Scholar
  4. 4.
    Togashi H, et al. (2000) Analysis of hepatic oxidative stress status by electron spin resonance spectroscopy and imaging. Free Radic Biol Med 28(6):846–853PubMedCrossRefGoogle Scholar
  5. 5.
    Faulkner K, Fridovich I (1993) Luminol and lucigenin as detectors for O2. Free Radic Biol Med 15(4):447–451PubMedCrossRefGoogle Scholar
  6. 6.
    Briggs RT, et al. (1986) Superoxide production by polymorphonuclear leukocytes. A cytochemical approach. Histochemistry 84(4–6):371–378PubMedCrossRefGoogle Scholar
  7. 7.
    Pick E, Keisari Y (1980) A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J Immunol Methods 38(1–2):161–170PubMedCrossRefGoogle Scholar
  8. 8.
    Halliwell B, Whiteman M (2004) Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br J Pharmacol 142(2):231–255PubMedCrossRefGoogle Scholar
  9. 9.
    Collins AR, Horvathova E (2001) Oxidative DNA damage, antioxidants and DNA repair: applications of the comet assay. Biochem Soc Trans 29(Pt 2):337–341PubMedCrossRefGoogle Scholar
  10. 10.
    Dalle-Donne I, et al. (2003) Protein carbonylation in human diseases. Trends Mol Med 9(4):169–176PubMedCrossRefGoogle Scholar
  11. 11.
    Hoffmann JC, et al. (2002) Animal models of inflammatory bowel disease: an overview. Pathobiology 70(3):121–130PubMedCrossRefGoogle Scholar
  12. 12.
    Esworthy RS, et al. (2001) Mice with combined disruption of Gpx1 and Gpx2 genes have colitis. Am J Physiol Gastrointest Liver Physiol 281(3):G848–855PubMedGoogle Scholar
  13. 13.
    Forrest CM, et al. (2003) Levels of purine, kynurenine and lipid peroxidation products in patients with inflammatory bowel disease. Adv Exp Med Biol 527:395–400PubMedGoogle Scholar
  14. 14.
    Geerling BJ, et al. (1999) The relation between antioxidant status and alterations in fatty acid profile in patients with Crohn’s disease and controls. Scand J Gastroenterol 34(11):1108–1116PubMedCrossRefGoogle Scholar
  15. 15.
    Genser D, et al. (1999) Status of lipidsoluble antioxidants and TRAP in patients with Crohn’s disease and healthy controls. Eur J Clin Nutr 53(9):675–679PubMedCrossRefGoogle Scholar
  16. 16.
    Koutroubakis IE, et al. (2004) Decreased total and corrected antioxidant capacity in patients with inflammatory bowel disease. Dig Dis Sci 49(9):1433–1437PubMedCrossRefGoogle Scholar
  17. 17.
    Wendland BE, et al. (2001) Lipid peroxidation and plasma antioxidant micronutrients in Crohn’s disease. Am J Clin Nutr 74(2):259–264PubMedGoogle Scholar
  18. 18.
    Erichsen K, et al. (2003) Ferrous fumarate deteriorated plasma antioxidant status in patients with Crohn’s disease. Scand J Gastroenterol 38(5):543–548PubMedCrossRefGoogle Scholar
  19. 19.
    Holmes EW, et al. (1998) Glutathione content of colonic mucosa: evidence for oxidative damage in active ulcerative colitis. Dig Dis Sci 43(5):1088–1095PubMedCrossRefGoogle Scholar
  20. 20.
    Rezaie A, Eshghtork A, Zamani M, Dehghan G, Taghavi B, Nikfar S, Daryani N, Abdollahi M. Alterations in salivary antioxidants, nitric oxide, and transforming growth factor-beta1 in relation to disease activity in Crohn’s disease patients. Ann N Y Acad Sci (in press)Google Scholar
  21. 21.
    Miles AM, Grisham MB (1994) Antioxidant properties of aminosalicylates. Methods Enzymol 234:555–572PubMedCrossRefGoogle Scholar
  22. 22.
    Aghdassi E, et al. (2003) Antioxidant vitamin supplementation in Crohn’s disease decreases oxidative stress: a randomized controlled trial. Am J Gastroenterol 98(2):348–353PubMedGoogle Scholar
  23. 23.
    Trebble TM, et al. (2005) High-dose fish oil and antioxidants in Crohn’s disease and the response of bone turnover: a randomised controlled trial. Br J Nutr 94(2): 253–261PubMedCrossRefGoogle Scholar
  24. 24.
    Trebble TM, et al. (2004) Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease. Am J Clin Nutr 80(5):1137–1144PubMedGoogle Scholar
  25. 25.
    Geerling BJ, et al. (2000) Nutritional supplementation with N-3 fatty acids and antioxidants in patients with Crohn’s disease in remission: effects on antioxidant status and fatty acid profile. Inflamm Bowel Dis 6(2):77–84PubMedCrossRefGoogle Scholar
  26. 26.
    Seidner DL, et al. (2005) An oral supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis: a randomized, controlled trial. Clin Gastroenterol Hepatol 3(4):358–369PubMedCrossRefGoogle Scholar
  27. 27.
    Hendrickson BA, Gokhale R, Cho JH (2002) Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev 15(1):79–94PubMedCrossRefGoogle Scholar
  28. 28.
    Meyer CT, et al. (1981) Hydrogen peroxide colitis: a report of three patients. J Clin Gastroenterol 3(1):31–35PubMedCrossRefGoogle Scholar
  29. 29.
    Bilotta JJ, Waye JD (1989) Hydrogen peroxide enteritis: the “snow white” sign. Gastrointest Endosc 35(5):428–430PubMedCrossRefGoogle Scholar
  30. 30.
    Riedle B, Kerjaschki D (1997) Reactive oxygen species cause direct damage of Engelbreth-Holm-Swarm matrix. Am J Pathol 151(1):215–231PubMedGoogle Scholar
  31. 31.
    Rao RK, et al. (1997) Oxidant-induced disruption of intestinal epithelial barrier function: role of protein tyrosine phosphorylation. Am J Physiol 273(4 Pt 1):G812–G823PubMedGoogle Scholar
  32. 32.
    Fries W, et al. (2005) Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn’s disease in Southern Italy. Am J Gastroenterol 100(12):2730–2736PubMedCrossRefGoogle Scholar
  33. 33.
    Buhner S, et al. (2006) Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020insC mutation? Gut 55(3):342–347PubMedCrossRefGoogle Scholar
  34. 34.
    Ding X, et al. (2005) Inducible nitric oxide synthase-dependent DNA damage in mouse model of inflammatory bowel disease. Cancer Sci 96(3):157–163PubMedCrossRefGoogle Scholar
  35. 35.
    Tham DM, Whitin JC, Cohen HJ (2002) Increased expression of extracellular glutathione peroxidase in mice with dextran sodium sulfate-induced experimental colitis. Pediatr Res 51(5):641–646PubMedGoogle Scholar
  36. 36.
    Ardite E, et al. (2000) Replenishment of glutathione levels improves mucosal function in experimental acute colitis. Lab Invest 80(5):735–744PubMedGoogle Scholar
  37. 37.
    Nieto N, et al. (2000) Experimental ulcerative colitis impairs antioxidant defense system in rat intestine. Dig Dis Sci 45(9):1820–1827PubMedCrossRefGoogle Scholar
  38. 38.
    Ghazanfari GMB, Yasa N, Ashtaral-Nakhai L, Mohammadirad A, Nikfar S, Dehghan G, Shetab-Boushehri V, Jamshidi H, Khorasani R, Salehnia A, Abdollahi M (2006) Biochemical and histopathological evidences for beneficial effects of Satureja khuzestanica jamzad essential oil on the mouse model of inflammatory bowel diseases. Toxicology Mechanisms Methods 16(7):365–372CrossRefPubMedGoogle Scholar
  39. 39.
    Ghafari HYN, Mohammadirad A, Dehghan G, Zamani MJ, Nikfar S, Khorasani S, Minaie B, Abdollahi M (2006 Jun) Protection by Ziziphora clinopoides of acetic acid-induced toxic bowel inflammation through reduction of cellular lipid peroxidation and myeloperoxidase activity. Human Experimental Toxicol 25:325–332CrossRefGoogle Scholar
  40. 40.
    Jahanshahi G, et al. (2004) Alterations in antioxidant power and levels of epidermal growth factor and nitric oxide in saliva of patients with inflammatory bowel diseases. Dig Dis Sci 49(11–12):1752–1757PubMedCrossRefGoogle Scholar
  41. 41.
    Barbosa DS, et al. (2003) Decreased oxidative stress in patients with ulcerative colitis supplemented with fish oil omega-3 fatty acids. Nutrition 19(10):837–842PubMedCrossRefGoogle Scholar
  42. 42.
    Kruidenier L, et al. (2003) Intestinal oxidative damage in inflammatory bowel disease: semi-quantification, localization, and association with mucosal antioxidants. J Pathol 201(1):28–36PubMedCrossRefGoogle Scholar
  43. 43.
    Tuzun A, et al. (2002) Oxidative stress and antioxidant capacity in patients with inflammatory bowel disease. Clin Biochem 35(7):569–572PubMedCrossRefGoogle Scholar
  44. 44.
    Sampietro GM, et al. (2002) Oxidative stress, vitamin A and vitamin E behaviour in patients submitted to conservative surgery for complicated Crohn’s disease. Dig Liver Dis 34(10):696–701PubMedCrossRefGoogle Scholar
  45. 45.
    D’Odorico A, et al. (2001) Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease. Scand J Gastroenterol 36(12):1289–1294PubMedCrossRefGoogle Scholar
  46. 46.
    Levy E, et al. (2000) Altered lipid profile, lipoprotein composition, and oxidant and antioxidant status in pediatric Crohn’s disease. Am J Clin Nutr 71(3):807–815PubMedGoogle Scholar
  47. 47.
    Chiarpotto E, et al. (1997) Oxidative damage and transforming growth factor beta 1 expression in pretumoral and tumoral lesions of human intestine. Free Radic Biol Med 22(5):889–894PubMedCrossRefGoogle Scholar
  48. 48.
    Lih-Brody L, et al. (1996) Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig Dis Sci 41(10):2078–2086PubMedCrossRefGoogle Scholar
  49. 49.
    Cao W, et al. (2004) Hydrogen peroxide contributes to motor dysfunction in ulcerative colitis. Am J Physiol Gastrointest Liver Physiol 286(5):G833–G843PubMedCrossRefGoogle Scholar
  50. 50.
    Pelli MA, et al. (1999) Breath alkanes determination in ulcerative colitis and Crohn’s disease. Dis Colon Rectum 42(1):71–76PubMedCrossRefGoogle Scholar
  51. 51.
    Hatoum OA, et al. (2003) Acquired microvascular dysfunction in inflammatory bowel disease: loss of nitric oxide-mediated vasodilation. Gastroenterology 125(1):58–69PubMedCrossRefGoogle Scholar
  52. 52.
    Koch TR, et al. (2000) Total antioxidant capacity of colon in patients with chronic ulcerative colitis. Dig Dis Sci 45(9):1814–1819PubMedCrossRefGoogle Scholar
  53. 53.
    Tsunada S, et al. (2003) Redox imbalance in the colonic mucosa of ulcerative colitis. Scand J Gastroenterol 38(9):1002–1003PubMedCrossRefGoogle Scholar
  54. 54.
    Kruidenier L, et al. (2003) Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease. J Pathol 201(1):17–27PubMedCrossRefGoogle Scholar
  55. 55.
    Szanto I, et al. (2005) Expression of NOX1, a superoxide-generating NADPH oxidase, in colon cancer and inflammatory bowel disease. J Pathol 207(2):164–176PubMedCrossRefGoogle Scholar
  56. 56.
    Buffinton GD, Doe WF (1995) Depleted mucosal antioxidant defenses in inflammatory bowel disease. Free Radic Biol Med 19(6):911–918PubMedCrossRefGoogle Scholar
  57. 57.
    Reimund JM, et al. (2000) Antioxidant and immune status in active Crohn’s disease: a possible relationship. Clin Nutr 19(1):43–48PubMedCrossRefGoogle Scholar
  58. 58.
    Hoffenberg EJ, et al. (1997) Circulating antioxidant concentrations in children with inflammatory bowel disease. Am J Clin Nutr 65(5):1482–1488PubMedGoogle Scholar
  59. 59.
    Fernandez-Banares F, et al. (1989) Vitamin status in patients with inflammatory bowel disease. Am J Gastroenterol 84(7):744–748PubMedGoogle Scholar
  60. 60.
    Kuroki F, et al. (1993) Multiple vitamin status in Crohn’s disease. Correlation with disease activity. Dig Dis Sci 38(9):1614–1618PubMedCrossRefGoogle Scholar
  61. 61.
    Hinks LJ, et al. (1988) Reduced concentrations of selenium in mild Crohn’s disease. J Clin Pathol 41(2):198–201PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Ali Rezaie
    • 1
  • Robyn D. Parker
    • 1
  • Mohammad Abdollahi
    • 2
    Email author
  1. 1.Department of Community Health MedicineFaculty of Medicine, University of CalgaryCalgaryCanada
  2. 2.Faculty of Pharmacy, and Pharmaceutical Sciences Research CenterTehran University of Medical SciencesTehranIran

Personalised recommendations