Dig Dis Sci (2007) 52:2015–2021
DOI 10.1007/s10620-006-9622-2
R EVIEW ARTICLE
Oxidative Stress and Pathogenesis of Inflammatory Bowel
Disease: An Epiphenomenon or the Cause?
Ali Rezaie · Robyn D. Parker · Mohammad Abdollahi
Received: 14 September 2006 / Accepted: 14 September 2006 / Published online: 3 April 2007


C Springer Science+Business Media, LLC 2007
Abstract Crohn’s disease (CD) and ulcerative colitis (UC),
known as inflammatory bowel disease (IBD), are fairly com-
mon chronic inflammatory conditions of the gastrointestinal
tract. Although the exact etiology of IBD remains uncer-
tain, dysfunctional immunoregulation of the gut is believed
to be the main culprit. Amongst the immunoregulatory fac-
tors, 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 pro-
vided 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.
Keywords Animal . Crohn’s disease . Human .
Inflammatory bowel disease . Oxidative stress . Ulcerative
colitis
Inflammatory bowel diseases (i.e., ulcerative colitis (UC)
and Crohn’s disease (CD)) are characterized by chronic
or relapsing immune activation and inflammation within
the gastrointestinal tract. Despite extensive research, an in-
A. Rezaie · R. D. Parker
Department of Community Health Medicine, Faculty
of Medicine, University of Calgary,
Calgary, Canada
M. Abdollahi (
)
Faculty of Pharmacy, and Pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences,
P.O. Box 14155-6451, Tehran, Iran
e-mail: mohammad.abdollahi@utoronto.ca
tegrated, pathophysiologic model of the initiation and/or
propagation of IBD have not emerged. It is generally hy-
pothesized that IBD is caused by gastrointestinal tract im-
mune dysregulation, because the disease is accompanied
by a considerable infiltration of inflammatory cells in gut
mucosa [1].
However, the specific pathways leading to cellular dam-
age are not completely understood. Oxidative stress is a po-
tential etiological and/or triggering factor for IBD, because
the detrimental effects of reactive oxygen molecules (ROM)
have been well established in the inflammation process [2].
In this review, we assess the evidence from animal and hu-
man literature that links oxidative stress (OS) to IBD and its
activity. We also evaluate the effect of antioxidant therapy
on IBD.z
Oxidative Stress: Definition and measurement
Reactive oxygen species (ROS), which form as natural
byproducts of the normal metabolism of oxygen, are highly
reactive molecules as a result of the presence of unpaired
electrons. To regulate the destructive effects of ROS, vital
tissues are equipped with an intricate antioxidant defense
system. Oxidative stress arises when there is a marked im-
balance between the production of ROS and their removal
by antioxidants.
Numerous techniques, with varying precision, are avail-
able to measure ROS or the reduction of antioxidants. Be-
cause ROS have short biologic half-lives, attempts to directly
quantify their levels are limited to electron spin resonance
spectroscopy [3, 4] and chemiluminescence [5], expensive
techniques that are restricted in their application. Histochem-
istry [6] and colorimetric assays [7], which are easily used
in tissue studies, lack sufficient sensitivity and specificity.
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2016
The presence of ROS is generally measured indirectly by
the levels of oxidatively damaged molecules. Lipid oxida-
tion can be assessed in a variety of tissues and fluids by
measuring levels of thiobarbituric acid reactive substances
(TBARS), diene conjugation, isoprostanes, and breath alka-
nes [8]. Oxidative DNA damage is usually evaluated by mea-
suring the concentration of 8-hydroxy-2‘–deoxyguanosine
(8OHdG) [9]. Free–radical attack on proteins generates prod-
ucts, such as 3–nitrotyrosine, 3–chlorotyrosine, and para-
hydroxyphenylacetaldehyde [8], but the most frequently
used biomarkers of protein damage are carbonyl groups [10].
Antioxidants can be categorized into nonenzymatic and
enzymatic ROS scavengers.
Nonenzymatic antioxidants include dietary compounds,
such as vitamins (C and E) and minerals (selenium and
zinc) and also glutathione, uric acid, and ubiquinol. Superox-
ide desmutase (SOD), catalase, and glutathione peroxidase
(GPO) are the main enzymatic antioxidants [8]. The sum of
all known and unknown endogenous and exogenous antioxi-
dants in a medium is usually called total antioxidant capacity
(TAC) and gives a holistic view of antioxidant status.
Oxidative stress and inflammatory bowel disease
Animal studies
None of the current animal models of IBD is ideal, and
attempts to create an experimental model of human IBD
using toxic chemicals have limited capability in reproducing
the disease because of complicated genetic, immunologic,
environmental, and psychologic factors that are considered
to contribute to the pathophysiology of IBD [11]. However,
several studies have been conducted to evaluate the status of
ROMs in animal models (Table 1), which unanimously show
abnormal levels of antioxidants or oxidized molecules.
The most striking evidence in animal studies comes from
genetic knockout mice lacking the antioxidant enzyme of
Table 1 Studies considering
the presence of oxidative stress Study Model
in IBD animal models
Ding et al. [34] Transfer of CD4 + T cells to severe
combined immunodeficiency animals
Tham et al. [35] Dextran sodium sulfate (DSS)
Ardite et al. [36] trinitrobenzenesulfonic acid in 50% ethanol
Nieto et al. [37] DSS
Ghazanfari et al. [38] Acetic acid
Ghafari et al. [39] Acetic acid
Note. Only studies with healthy
control subjects are included.
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Dig Dis Sci (2007) 52:2015–2021
glutathione peroxidase. These animals develop a crypt de-
structive colitis similar to UC as early as 11 days of age
[12].
Human studies
Presence of excessive reactive oxygen metabolites
in human tissues
The presence of ROMs or the molecules damaged by ROMs
have been extensively studied in patients with IBD (Table 2).
Although some conflicting results exist, it seems that pa-
tients with IBD demonstrate excessive oxidized molecules
compared with healthy control subjects in a variety of or-
ganic systems (e.g., gastrointestinal tract, blood, and respi-
ratory system). Interestingly, this effect seems to be more
pronounced in patients with CD. Use of imprecise tech-
niques, such as a simple TBA test and/or small sample size,
could be the source of inconsistency in the studies that failed
to show any evidence of oxidative stress.
Presence of an antioxidant imbalance in human tissues
In reaction to mild oxidative stress, tissues often respond by
producing more antioxidants; however, severe persistent ox-
idative stress depletes body antioxidant resources and over-
takes its ability to produce more antioxidants, leading to
lower antioxidant levels. Therefore, interpretation of antiox-
idant concentrations without knowing the status of ROS and
course of the disease would be biased.
Expression of antioxidants has been investigated in sev-
eral studies in various organs (Table 3). Although the change
in antioxidant levels is conflicting among the studies, the
imperative point is the presence of an imbalance in antioxi-
dant concentration, attesting the fact that vital organs in IBD
patients are oxidatively stressed.
Species Result
Mouse 8-OXdG ↑
Mouse Glutathion peroxidase ↑
Mouse Glutathione ↓
Mouse Glutathion peroxidase ↑
Glutathione ↓
SOD ↑
Catalase ↑
Mouse Lipid peroxidation↑
Myeloperoxidase ↑
Mouse Lipid peroxidation↑
Myeloperoxidase ↑
Dig Dis Sci (2007) 52:2015–2021 2017

Table 2 Human studies considering the presence of ROMs

Study No. of patients Type of IBD Specimen Results

Rezaie et al. [20] 28 CD Saliva Lipid peroxidation ↑

Jahanshahi et al. [40] 30 CD & UC Saliva Lipid peroxidation: CD ↑, UC nd
Forrest et al. [13] 12 CD & UC Serum Lipid peroxidation: CD ↑↑, UC ↑
Barbosa et al. [41] 9 UC Plasma Lipid peroxidation nd
Kruidenier et al. [42] 34 CD & UC Colon biopsy Lipid peroxidation: CD ↑, UC ↑
Tuzun et al. [43] 47 CD & UC Plasma Lipid peroxidation: CD nd, UC nd
Sampietro et al. [44] 20 CD Serum Lipid peroxidation: CD↑
D’Odorico et al. [45] 81 UC & CD Plasma 8-OHdG ↑
Wendland et al. [17] 37 CD Exhaled air & plasma Breath pentane, ethane & F2 -isoprostane ↑
Levy et al. [46] 22 CD Plasma Lipid peroxidation ↑
Chiarpotto et al. [47] 10 CD Colon tissue Lipid peroxidation ↑
Lih-Brody et al. [48] 67 CD & UC Colon tissue ROMs (chemiluminescence): CD ↑, UC ↑
8-OHdG: CD ↑
Cao et al. [49] 9 UC Colon tissue H2 O2 : UC ↑
Pelli et al. [50] 20 UC & CD Exhaled air Ethane: CD ↑, UC ↑
Propane: CD ↑, UC ↑
Pentane: CD ↑, UC ↑
Hatoum et al. [51] 33 CD & UC Colon mucosal arterioles ROMs (chemiluminescence): UC ↑
Koch et al. [52] 15 UC Colon tissue Lipid peroxidation : UC nd

Note. nd No statistical difference compared with controls. Only controlled studies are included.

Correlation of oxidative stress with IBD activity
The majority of studies that examined the relationship be-
tween IBD severity and oxidative stress markers failed to
show any significant correlation [13–18]. However, Holmes
et al. [19] observed a 1.7–fold increase of colon oxidized
glutathione in active UC compared with inactive UC pa-
tients. In our recent study of 28 patients with CD [20], we
showed that CD activity index significantly correlates with
TAC, lipid peroxidation, and their interaction (r2 = 0.625,
r2 = 0.8, F test P < 0.00005). This novel finding that
TAC and ROS modify the other’s effects in determination
of CD severity may explain the inability of previous studies
to reach a meaningful relationship between oxidative stress
markers and disease activity because both ROS and antioxi-
dant defense condition should be considered in determining
the severity of IBD.
Specific antioxidant randomized, controlled trials
in patients with IBD
In consideration of the strong evidence of OS in IBD, an-
tioxidant therapy deserves a place in its treatment. In fact,
the oldest and most commonly used drug for treatment of
patients with IBD, 5–aminosalicylic acid, has shown ROS
scavenging capabilities [21]. Conversely, only a few random-
ized, controlled trials RCTs have been conducted to examine
the efficacy of specific antioxidants in IBD. Given the multi-
faceted nature of OS and complex pathophysiology of IBD,
there are numerous known and unknown confounders and
effect modifiers influencing the association between the dis-
ease and OS. Therefore, only RCTs could bring us reliable
answers for the effect of antioxidants in IBD patients.
Aghdassi et al. [22] treated stable but oxidatively stressed
CD patients (n = 57; CD activity index < 180) with vitamin
E (800 IU) and vitamin C (1,000 mg) or placebo for a period
of 4 weeks. During supplementation, oxidative stress mark-
ers, such as breath pentane and ethane output, plasma lipid
peroxidation, and F2 –isoprostane, significantly decreased.
Although disease activity remained stable during the course
of the trial, it should be considered that participants had mild
or controlled (in remission) disease, therefore, detecting a
significant difference in disease activity index would have
been difficult if not impossible in only 57 patients. More-
over, a follow-up of 4 weeks seems to be too short to detect
a meaningful difference among both arms of the study.
In another RCT with a longer term but a far smaller dose
of antioxidant nutrients, Trebble et al. [23, 24] investigated
the effect of fish oil and antioxidants (i.e., β-carotene 150
µg, selenium 200 µg, vitamin E 30 mg, and vitamin C 90
mg) vs. placebo on 61 patients for 24 weeks. Supplementa-
tion was associated with reduction in plasma arachidonic
acid, interferon-δ, and prostaglandin E2 . No differences
were detected in activity of the disease or indices of bone
turnover.
During a 3–month period, Geerling et al. [25] evalu-
ated the effects of antioxidants (e.g., selenium 12.4 µg, β–
carotene 150 µg, vitamin E 4 mg, and vitamin C 20 mg)
and n–3 fatty acids on 25 patients with CD currently in
remission. TAC and SOD activity significantly increased,

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2018 Dig Dis Sci (2007) 52:2015–2021

Table 3 Human studies considering the concentration of various antioxidants

Study No. of patients Type of IBD Specimen Results

Rezaie et al. [20] 28 CD Saliva TAC ↓

Jahanshahi et al. [40] 30 CD & UC Saliva TAC: CD ↓, UC nd
Koutroubakis et al. [16] 201 CD & UC Serum TAC: CD ↓, UC ↓
Corrected TAC: CD ↓, UC ↓
Barbosa et al. [41] 9 UC Plasma TAC ↓
SOD ↑
Tsunada et al. [53] 24 UC Colon biopsy Glutathione ↓
Oxidized glutathione ↑
Kruidenier et al. [54] 34 CD & UC Colon biopsy SOD ↑
Glutathione nd
Catalase ↑
Gluthatione peroxidase ↑
Erichsen et al. [18] 10 CD Plasma Vit C nd
Vit E nd
β Carotene ↓
Tuzun et al. [43] 47 CD & UC Plasma Gluthatione peroxidase: CD ↑, UC ↑
Sampietro et al. [44] 20 CD Serum Vit E ↓
D’Odorico et al. [45] 81 UC & CD Plasma Vit E ↓
β Carotene ↓
Wendland et al. [17] 37 CD Exhaled air & plasma Plasma β Carotene, Vit C, Vit A ↓
Koch et al. [52] 15 UC Colon tissue TAC: UC nd
Holmes et al. [19] 19 UC Colon biopsy Glutathione nd
Oxidized glutathione ↑
Szanto et al. [55] 14 CD & UC Colon tissue NOX1 expression(a ROM-producing
NADPH oxidase): CD ↑, UC ↑
Buffinton et al. [56] 8 UC & CD Colon tissue TAC: CD ↓, UC ↓
Vit E: CD nd, UC nd
Glutathione: CD nd, UC nd
Reimund et al. [57] 26 CD Plasma Glutathione peroxidase ↓
Selenium ↓
SOD nd
Geerling et al. [25] 62 CD Serum β-Carotene ↓
Vit E nd
Vit C ↓
Selenium ↓
SOD ↓
Glutathione peroxidase ↓
Genser et al. [15] 24 CD Plasma β-Carotene ↓
α-Carotene ↓
Vit E nd
TAC ↓
Hoffenberg et al. [58] 24 CD & UC Plasma Glutathione peroxidase: CD ↑, UC ↑
Vit C: CD ↓, UC ↓
Vit E: CD ↑, UC ↑
Fernandez-Banares et al. [59] 23 CD & UC Serum β-Carotene: CD ↓, UC ↓
Vit C: CD ↓, UC ↓
Kuroki et al. [60] 24 CD Serum Vit E ↓
Vit C nd
Hinks et al. [61] 20 CD Serum Selenium ↓
Geerling et al. [14] 32 CD Serum β-Carotene ↓
Vit E ↓
Vit C ↓
Selenium ↓

Note. nd No statistical difference compared with controls. Only controlled studies are included.

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Dig Dis Sci (2007) 52:2015–2021
whereas activity of glutathione peroxidase reduced after an-
tioxidant supplementation. No change was observed between
the groups considering lipid peroxidation or disease activity.
Siedner et al. [26] randomized 121 patients with mild-to-
moderate UC to placebo or oral supplement enriched with
various nutrients, such as vitamin E (72 IU), vitamin C (156
mg), β-carotene (1185 µg), selenium (30 µg), and fish
oil. Both groups showed significant clinical improvement at
6 months of follow-up. Patients given the supplementation
had a significantly greater rate of decrease in corticosteroid
dose. No marker of OS was measured in this study.
With the exception of the first trial, all the studies used
doses of antioxidants far lower than one could expect to
produce a dramatic change in OS status or clinical course of
patients with IBD. In addition, all the trials used antioxidants
with medium potency, which again questions the ability of
these nutrients to be remarkably effective in chronic disease,
such as IBD.
Conclusions
The influx of inflammatory cells within the intestinal mu-
cosa mediates the tissue injury in IBD. Once the intestinal
epithelial barrier is damaged, it allows the luminal highly
immunogenic bacterial antigens to enter the normally sterile
submucosal layers, initiating a destructive cascade of im-
mune response. Regarding the triggering pathogenesis for
the accumulation of inflammatory cells in IBD, several im-
munologic hypotheses have been postulated but all remain
ill-defined, noncomprehensive, and impractical in therapeu-
tic advancements [27].
This review provides a great body of evidence that IBD
is accompanied by increased levels of ROMs and decreased
concentration of related antioxidants; however, does this as-
sociation bear an etiologic relationship for oxidative stress in
the intestinal inflammation, or are ROMs just a side-product
of the inflammation process? The following statements ad-
dress the evidence in favor of a causal relationship:
r Oxidizing agents are capable of inducing the clinical and
histologic features of IBD. Hydrogen peroxide (H2 O2 ) en-
emas, a potent oxidant, were being administered for man-
agement of fecal impaction before the 1980s; however,
its use was abandoned because of several case reports of
colitis after administration [28, 29].
r Mice deficient in glutathione peroxidase genes, an impor-
tant intrinsic antioxidant enzyme, develop symptoms and
pathology consistent with IBD [12].
r ROMs can disintegrate the colonic epithelium and increase
mucosal permeability [30, 31]. Moreover, it has been
shown that patients with CD even in quiescent stage and
40% of their first-degree relatives have increased intesti-
2019
nal permeability without any actual inflammation [32, 33].
The fact that OS is present before the cascade of colonic
inflammation starts argues against ROMs as byproducts of
the colonic inflammatory process.
r The presence of “effect modification” between TAC and
lipid peroxidation in our recent study emphasizes that ox-
idative stress has a role in pathophysiology of CD rather
than a nonspecific marker of inflammation [20].
Although none of the above provide a rigid basis for
causality, it is likely that OS has an etiologic role in IBD.
However, whether the OS markers are useful in monitoring
disease activity or determining prognosis remains uncertain.
Therapeutic applicability of antioxidants must be elucidated
in future, randomized, clinical trials. We recommend using
high-dose potent antioxidants, a long follow-up period, and
emphasis on moderate and severe cases of IBD.
References
1. Brandtzaeg P, Haraldsen G, Rugtveit J (1997) Immunopathol-
ogy of human inflammatory bowel disease. Semin Immunopathol
18(4):555–589
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):311–322
3. Mueller S (2000) Sensitive and nonenzymatic measurement of
hydrogen peroxide in biological systems. Free Radic Biol Med
29(5):410–415
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):846–853
5. Faulkner K, Fridovich I (1993) Luminol and lucigenin as detectors
for O2. Free Radic Biol Med 15(4):447–451
6. Briggs RT, et al. (1986) Superoxide production by polymorphonu-
clear leukocytes. A cytochemical approach. Histochemistry 84(4–
6):371–378
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):161–170
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):231–255
9. Collins AR, Horvathova E (2001) Oxidative DNA damage, antiox-
idants and DNA repair: applications of the comet assay. Biochem
Soc Trans 29(Pt 2):337–341
10. Dalle-Donne I, et al. (2003) Protein carbonylation in human dis-
eases. Trends Mol Med 9(4):169–176
11. Hoffmann JC, et al. (2002) Animal models of inflammatory bowel
disease: an overview. Pathobiology 70(3):121–130
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):G848–855
13. Forrest CM, et al. (2003) Levels of purine, kynurenine and lipid
peroxidation products in patients with inflammatory bowel disease.
Adv Exp Med Biol 527:395–400
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–
1116
Springer
2020
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):675–679
16. Koutroubakis IE, et al. (2004) Decreased total and corrected an-
tioxidant capacity in patients with inflammatory bowel disease.
Dig Dis Sci 49(9):1433–1437
17. Wendland BE, et al. (2001) Lipid peroxidation and plasma antioxi-
dant micronutrients in Crohn’s disease. Am J Clin Nutr 74(2):259–
264
18. Erichsen K, et al. (2003) Ferrous fumarate deteriorated plasma
antioxidant status in patients with Crohn’s disease. Scand J Gas-
troenterol 38(5):543–548
19. Holmes EW, et al. (1998) Glutathione content of colonic mucosa:
evidence for oxidative damage in active ulcerative colitis. Dig Dis
Sci 43(5):1088–1095
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)
21. Miles AM, Grisham MB (1994) Antioxidant properties of aminos-
alicylates. Methods Enzymol 234:555–572
22. Aghdassi E, et al. (2003) Antioxidant vitamin supplementation
in Crohn’s disease decreases oxidative stress: a randomized con-
trolled trial. Am J Gastroenterol 98(2):348–353
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): 253–261
24. Trebble TM, et al. (2004) Fish oil and antioxidants alter the com-
position and function of circulating mononuclear cells in Crohn
disease. Am J Clin Nutr 80(5):1137–1144
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):77–84
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):358–369
27. Hendrickson BA, Gokhale R, Cho JH (2002) Clinical aspects and
pathophysiology of inflammatory bowel disease. Clin Microbiol
Rev 15(1):79–94
28. Meyer CT, et al. (1981) Hydrogen peroxide colitis: a report of three
patients. J Clin Gastroenterol 3(1):31–35
29. Bilotta JJ, Waye JD (1989) Hydrogen peroxide enteritis: the “snow
white” sign. Gastrointest Endosc 35(5):428–430
30. Riedle B, Kerjaschki D (1997) Reactive oxygen species cause
direct damage of Engelbreth-Holm-Swarm matrix. Am J Pathol
151(1):215–231
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–G823
32. Fries W, et al. (2005) Intestinal permeability and genetic deter-
minants in patients, first-degree relatives, and controls in a high-
incidence area of Crohn’s disease in Southern Italy. Am J Gas-
troenterol 100(12):2730–2736
33. Buhner S, et al. (2006) Genetic basis for increased intestinal perme-
ability in families with Crohn’s disease: role of CARD15 3020insC
mutation? Gut 55(3):342–347
34. Ding X, et al. (2005) Inducible nitric oxide synthase-dependent
DNA damage in mouse model of inflammatory bowel disease.
Cancer Sci 96(3):157–163
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–
646
Springer
Dig Dis Sci (2007) 52:2015–2021
36. Ardite E, et al. (2000) Replenishment of glutathione levels im-
proves mucosal function in experimental acute colitis. Lab Invest
80(5):735–744
37. Nieto N, et al. (2000) Experimental ulcerative colitis impairs an-
tioxidant defense system in rat intestine. Dig Dis Sci 45(9):1820–
1827
38. Ghazanfari GMB, Yasa N, Ashtaral-Nakhai L, Mohammadi-
rad 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 inflamma-
tory bowel diseases. Toxicology Mechanisms Methods 16(7):365–
372
39. Ghafari HYN, Mohammadirad A, Dehghan G, Zamani MJ,
Nikfar S, Khorasani S, Minaie B, Abdollahi M (2006 Jun) Protec-
tion by Ziziphora clinopoides of acetic acid-induced toxic bowel
inflammation through reduction of cellular lipid peroxidation and
myeloperoxidase activity. Human Experimental Toxicol 25:325–
332
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):1752–1757
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):837–842
42. Kruidenier L, et al. (2003) Intestinal oxidative damage in inflam-
matory bowel disease: semi-quantification, localization, and asso-
ciation with mucosal antioxidants. J Pathol 201(1):28–36
43. Tuzun A, et al. (2002) Oxidative stress and antioxidant capac-
ity in patients with inflammatory bowel disease. Clin Biochem
35(7):569–572
44. Sampietro GM, et al. (2002) Oxidative stress, vitamin A and vita-
min E behaviour in patients submitted to conservative surgery for
complicated Crohn’s disease. Dig Liver Dis 34(10):696–701
45. D’Odorico A, et al. (2001) Reduced plasma antioxidant concentra-
tions and increased oxidative DNA damage in inflammatory bowel
disease. Scand J Gastroenterol 36(12):1289–1294
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):807–815
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):889–894
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):2078–2086
49. Cao W, et al. (2004) Hydrogen peroxide contributes to motor dys-
function in ulcerative colitis. Am J Physiol Gastrointest Liver Phys-
iol 286(5):G833–G843
50. Pelli MA, et al. (1999) Breath alkanes determination in ulcerative
colitis and Crohn’s disease. Dis Colon Rectum 42(1):71–76
51. Hatoum OA, et al. (2003) Acquired microvascular dysfunction in
inflammatory bowel disease: loss of nitric oxide-mediated vasodi-
lation. Gastroenterology 125(1):58–69
52. Koch TR, et al. (2000) Total antioxidant capacity of colon in
patients with chronic ulcerative colitis. Dig Dis Sci 45(9):1814–
1819
53. Tsunada S, et al. (2003) Redox imbalance in the colonic mucosa
of ulcerative colitis. Scand J Gastroenterol 38(9):1002–1003
54. Kruidenier L, et al. (2003) Imbalanced secondary mucosal antiox-
idant response in inflammatory bowel disease. J Pathol 201(1):17–
27
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):164–176
Dig Dis Sci (2007) 52:2015–2021
56. Buffinton GD, Doe WF (1995) Depleted mucosal antioxidant
defenses in inflammatory bowel disease. Free Radic Biol Med
19(6):911–918
57. Reimund JM, et al. (2000) Antioxidant and immune status in active
Crohn’s disease: a possible relationship. Clin Nutr 19(1):43–48
58. Hoffenberg EJ, et al. (1997) Circulating antioxidant concentra-
tions in children with inflammatory bowel disease. Am J Clin Nutr
65(5):1482–1488
2021
59. Fernandez-Banares F, et al. (1989) Vitamin status in patients
with inflammatory bowel disease. Am J Gastroenterol 84(7):744–
748
60. Kuroki F, et al. (1993) Multiple vitamin status in Crohn’s dis-
ease. Correlation with disease activity. Dig Dis Sci 38(9):1614–
1618
61. Hinks LJ, et al. (1988) Reduced concentrations of selenium in mild
Crohn’s disease. J Clin Pathol 41(2):198–201
Springer