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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:2251-2255, September 2004

Nutrient Metabolism

Dietary Iron Affects Inflammatory Status in a Rat Model of Colitis1

Ram Uritski, Iris Barshack*, Itzhak Bilkis, Kebreab Ghebremeskel{dagger} and Ram Reifen2

School of Nutritional Sciences, The Hebrew University of Jerusalem, Rehovot, Israel; * Department of Pathology, Sheba Medical Center, Tel Hashomer, Israel; and {dagger} London Metropolitan University, London, UK

2To whom correspondence should be addressed. E-mail: reifen{at}agri.huji.ac.il.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Iron deficiency anemia is a common feature in inflammatory bowel disease, and oral supplementation is one of the mainstay therapies. However, there is some concern that oral iron supplementation may lead to oxidative stress and exacerbation of inflammation. Our objective was to study the effect of severely deficient, moderately deficient, normal and high iron status on oxidative stress and the course of inflammation in a rat model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The rats were randomly assigned to receive the low-iron diet for 3 (moderately iron-deficient group, n = 16) or 5 (severely iron-deficient group, n = 16) wk, the normal iron diet for 2 wk (normal iron group, n = 16) or the high-iron diet for 2 wk (high-iron group, n = 16). Malondialdehyde concentration, electroparamagnetic resonance measurement, myeloperoxidase activity, and histological analysis were used to evaluate oxidative stress. Noncolitic rats in the high-iron group had higher oxidative stress parameters than those in the other groups. The induction of colitis resulted in severe inflammatory changes in the high-iron and severely iron-deficient groups, and produced higher histological scores in the colon of the normal and high-iron groups. Iron overload, oxidative stress, and inflammation were lower in the moderately iron-deficient group compared with the other 3 groups. In conclusion, we suggest that low rather than normal or high iron supplementation should be considered for the treatment of iron deficiency in inflammatory bowel disease.

KEY WORDS: • iron • inflammatory bowel disease • oxidative stress • rat model

Inflammatory bowel disease (IBD)3 is a chronic, remitting relapsing disorder of the gastrointestinal tract characterized by inflammation and tissue damage. The etiology of the disease, although not well understood, is thought to be multifactorial. Oxidative stress is one of the key biochemical features of the disease (1–3). The extent of oxidative stress involvement in the initiation and progress of the inflammatory process is yet to be fully elucidated. In addition, there is some doubt whether the oxidants are a major cause or a manifestation of tissue injury in IBD.

In IBD, anemia is a common problem, with a prevalence between 17 and 50% (4–7). It is characterized by a higher score of disease activity, loss of weight, impaired physical activity, and poor growth in children (5,8). The causes are thought to include chronic blood loss from the colon and intestine, reduced absorption of iron, suppression of erythropoietin production, and alteration of iron metabolism by proinflammatory cytokines, reactive oxygen metabolites, and nitric oxide (9–12).

Iron, which is one of the mainstay therapies for anemia in IBD (11), is highly reactive and has the capacity to accept and donate electrons readily (13–15). Because patients with IBD have an increased production of oxygen reactive species (1,3), there is some concern that oral iron supplementation may exacerbate inflammation and tissue damage by hydroxyl radicals formed from hydrogen peroxide via the Fenton reaction. Indeed, there is evidence that iron supplementation induces inflammation both in normal rats (16) and in rat and mouse models of colitis (11,17–19). In addition, iron chelators were shown to ameliorate oxidative stress and inflammation in colitic rats (20) and colonic biopsies from patients with ulcerative colitis (21).

In our previous study (22), we found that iron supplementation amplifies oxidative stress, the inflammatory response, and mucosal damage in a rat model of colitis. In this study, we examined different iron regimens to evaluate its effects on the course of inflammation. We hypothesized that low levels of dietary iron would be more beneficial for colitis and would not further aggravate oxidative stress and the inflammatory changes.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Animals. Specific pathogen–free male Wistar rats (weight, 150–200 g) were obtained from the Harlan Laboratory, The Weizmann Institute of Science, Rehovot, Israel. They were housed in metal cages in a room with controlled temperature (25 ± 2°C), relative humidity (65 ± 5%) and light (0800–2000 h). Ethical approval was obtained for the study, and all of the procedures were conducted in full compliance with the strict guidelines of the Hebrew University Policy on Animal Care and Use.

    Diets and treatment. Low- (7 g/kg), normal (35 g/kg), and high- (3000 g/kg) iron diets were prepared by mixing appropriate proportions of a low-iron stock diet (ICN Nutritional Biochemicals; catalog # 960183) and carbonyl iron (Sigma Chemical; catalog # C3518). The rats were randomly assigned to receive the low iron diet for 3 (moderately iron-deficient group, n = 16) or 5 (severely iron-deficient group, n = 16) wk, the normal iron diet for 2 wk (normal iron group, n = 16) or the high-iron diet for 2 wk (high-iron group, n = 16). All rats consumed the food ad libitum and had free access to distilled deionized water. At the end of the designated feeding period, colitis was induced in half of the rats from each diet group.

    Induction of colitis and sample preparation. A modification of the procedure developed by Morris et al. (23) was used to induce colitis. Rats were lightly anesthetized with ether and a rubber catheter (3 mm diameter) was inserted through the anal canal for a distance of 7 cm into the colon just proximal to the splenic flexure. Colitis was induced by the administration of 0.2 mL of 2,4,6-trinitrobenzene sulfonic acid [TNBS, 100 g/L dissolved in 50% ethanol (Sigma Chemical; catalog # P2297)]. All rats in each feeding group were killed 24 h after the induction of colitis. Specimens, colon, liver, kidney, and heparinized blood were collected for biochemistry and histology. The tissues were rinsed with buffered ice-cold saline to remove contaminating blood. Plasma and RBC were separated by cold centrifugation (4°C) at 2000 x g for 15 min. With the exception of the colon segments for histology, all of the samples were stored at –70°C until analysis.

    Iron and ferritin determination. A spectrophotometric method was used to assay liver and kidney iron concentrations (24). The tissues were digested with hydrochloric/trichloroacetic acids (TCA) at 70°C for 20 h. The resulting mixture was reacted with bathophenanthroline disulfonic acid (Sigma Chemical; catalog # B1375); the intensity of the color-complex formed was read at 535 nm. Plasma iron and ferritin concentrations were determined by a Roche automatic analyzer using diagnostic kits # 1876996 and 1661400, respectively (Roche Diagnostics GmbH).

    Myeloperoxidase activity. Myeloperoxidase (MPO) activity in colon tissue was assayed by determining the decomposition of hydrogen peroxide in the presence of o-dianisidine (25). Finely ground colon tissue (200 mg) was homogenized in 1 mL of ice-cold solublizing reagent, 0.5% hexadecyltrimethylammonium bromide (HTAB) in 50 mmol/L phosphate buffer (pH 6.0) for 30 s at 4°C. After 3 freezing/thawing cycles, the homogenate was centrifuged at 15,000 x g for 15 min at 4°C. A 100-µL aliquot of the supernatant was used for the assay.

    Quantitative determination of sulfhydryl (SH) groups. Electron paramagnetic resonance (EPR) was used for the quantitative determination of SH groups in the colon tissue extract. The method, which was originally described by Weiner (26), is based on the use of a biradical spin label carrying a disulfide bond RS-RS, where R is the nitroxyl residue. As shown in Figure 1, the symmetrical nitroxyl biradical (a) reacts with compounds containing SH groups to produce nitroxyl monoradical (b). The difference in EPR spectra between (a) and (b) and the change in concentration form the basis for the quantification of SH groups.



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  		FIGURE 1 Electron paramagnetic resonance determination of free SH groups. R is the nitroxyl residue, (a), biradical; (b), monoradical.

 
As described above, 200 mg of finely ground colon tissue was homogenized in 1 mL of ice-cold solubilizing reagent, 0.5% HTAB in 50 mmol/L phosphate buffer (pH 6.0) for 30 s at 4°C. After 3 freezing/thawing cycles, the homogenate was centrifuged at 15,000 x g for 15 min at 4°C. The increase in the concentration of the monoradical (b) was measured by EPR in a solution containing a 190-µL aliquot of the supernatant and 10 µL of 400 µmol/L nitroxyl biradical disulfide. A calibration curve (monoradical vs. thiol group) was obtained by reacting a 20-µmol/L solution of the biradical in 10 µmol/L sodium phosphate buffer (pH 7.4) with glutathione (concentration range 0–8 µmol/L).

    Determination of malondialdehyde. The malondialdehyde concentration was determined calorimetrically from the intensity of the chromogen (color complex) formed when lipid peroxides resulting from oxidative stress reacted with thiobarbituric acid (TBA). Colon tissue, 100 mg, was homogenized in 1 mL of ice-cold 1.15% KCLe. A 1-mL aliquot of the homogenate was mixed with 2 mL of a TCA-TBA-HCl reagent (5% w/V) [TCA 0.375% (w/v) TBA, 0.25 mol/L HCl]. The complete mixture was heated at 70°C for 15 h, centrifuged, and the intensity of supernatant color-complex measured at 535 nm as described by Buege and Aust (27).

    Histopathological examination. At autopsy, fresh sections of colon tissue were obtained from the same area of the large intestine from all rats in the 4 groups. The specimens were placed in PBS and fixed overnight in 4% paraformaldehyde at 4°C. Serial 5-µm sections were prepared after the samples had been dehydrated in graded ethanol solutions, cleared in chloroform, and embedded in paraplast. The sections were then stained with Prussian blue and hematoxylin/eosin and the morphological changes evaluated by an independent pathologist with the use of light microscopy.

    Statistical analysis. The data are expressed as means ± SEM. Data were analyzed by two-way ANOVA and the Newman-Keuls test. Differences with P < 0.05 were regarded as significant.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    Body weight and food consumption. Food consumption was not measured. However, the body weights of the 4 groups did not differ (P > 0.05).

    Plasma ferritin and iron concentrations of noncolitic rats. Rats that were fed the high-iron diet had higher plasma ferritin and iron concentrations than the other groups (P < 0.01, Table 1). The plasma iron concentration of the rats in the moderately iron-deficient group was less than those in the severely iron-deficient and normal iron groups (P < 0.05).


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  		TABLE 1 Iron status of noncolitic rats fed the low-iron (severely or moderately iron-deficient), normal, or high-iron diets1

 
    Liver and kidney iron concentrations of noncolitic rats. The liver iron concentration of the high-iron group was greater than those of the other 3 groups (P < 0.001) and was greater in the normal iron group than in the moderately (P < 0.001) and severely iron-deficient (P < 0.001) groups. Rats in the moderately and severely iron-deficient groups had comparable liver iron concentrations.

Rats fed the normal (P < 0.01), moderately iron-deficient (P < 0.001), and severely iron-deficient (P < 0.01) diets had a lower kidney iron concentration than those fed the high-iron diet. Both the normal iron and severely iron-deficient groups had a higher kidney iron concentration than the moderately iron-deficient rats (P < 0.05) (Table 1).

    Colon myeloperoxidase (MPO) activity. The noncolitic rats in the high-iron group had greater MPO activity in the colon than other noncolitic groups. Colitis induction resulted in higher MPO activity in all groups (P < 0.05). The activity of the enzyme in the colitic rats fed high iron was higher than in the moderately iron-deficient (P < 0.001) and normal iron (P < 0.01) colitic groups (Fig. 2).



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  		FIGURE 2 MPO activity in the colon of colitic and noncolitic rats in severely iron-deficient, moderately iron-deficient, normal, and high-iron groups. Values are means ± SEM, n = 8. Means without a common letter differ, P < 0.05.

 
    Colon malondialdehyde (MDA). Colon MDA concentration did not differ among the noncolitic groups (Fig. 3). However, the colitic rats fed high iron had a higher level of MDA than the moderately iron-deficient and normal iron groups (P < 0.05).



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  		FIGURE 3 Colon MDA concentrations of colitic and noncolitic rats in severely iron-deficient, moderately iron-deficient, normal, and high-iron groups. Values are means ± SEM, n = 8. Means without a common letter differ, P < 0.05.

 
    Colon free SH groups. Within noncolitic and colitic rats, the diet treatments did not affect the colon tissue SH concentration (P > 0.05). However, the SH level differed between the colitic (19 ± 2.1 nmol/g) and noncolitic (34 ± 3.1 nmol/g) rats fed the high-iron diet (P < 0.05).

    Colon histology. There was no difference in the structure of colon tissue among the 4 groups of noncolitic rats. Colonic sections of the normal and high iron groups but not of the severely and moderately iron-deficient groups showed clear evidence of crypt distortion and infiltration of inflammatory cells (Fig. 4). In the high-iron group, there was extensive transmural ulceration and inflammation bordered by normal mucosa. In the severely and moderately iron-deficient colitic rats, the damage was restricted to surface epithelium of the colon. Prussian blue stained samples revealed the formation of large clumps of extracellular iron in the ulcerated areas (Fig. 5).



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  		FIGURE 4 Histological analysis of colon sections from colitic and noncolitic rats in severely iron-deficient, moderately iron-deficient, normal, and high-iron groups. Sections were stained with hematoxylin and eosin. Colons of the colitic groups fed the normal and high-iron diets had crypt distortion, infiltration of inflammatory cells, and transmural necrosis. The low-iron diet prevented the inflammatory changes in colon morphology.

 


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  		FIGURE 5 Prussian blue staining of colon sections of noncolitic and colitic rats fed the high-iron diet. In addition to the inflammatory changes in the colitic rat colon, large clumps of extracellular iron can be seen in the ulcerated area.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
Iron deficiency, which is manifested in low serum iron and ferritin concentrations, low transferrin saturation, and increased total iron binding capacity, is commonly observed in patients with inflammatory bowel disease (8). The current treatment option is oral or parenteral iron (5,7,11,28,29).

Intravenous administration is the most efficacious method for the treatment of iron deficiency anemia. However, it is expensive and requires strict clinical supervision because the preparations vary considerably in their kinetics, bioavailability, and maximum dose for single administration (30). In addition, there are serious concerns about iron overload and tissue toxicity (31,32), particularly in children (33). Patients with underlying autoimmune disease, malnutrition, and indolent infection are thought to be at higher risk of iron overload syndrome (7,34).

Similarly, because >90% of dietary iron is not absorbed (35), oral supplementation may elevate the gastrointestinal iron concentration and amplify mucosal damage in patients with inflammatory bowel disease. It is thought that unabsorbed dietary iron in the colon in conjunction with intraluminal bacteria and stimulated polymorphonuclear leukocytes generates hydrogen peroxide and hydroxyl radicals at the mucosal surface via Haber-Weiss and Fenton-type reactions (35–37). Indeed, there is evidence that oral supplementation increases iron deposition in the colonic submucosa and lamina propria of noncolitic rats (17,38) and increases disease activity, inflammatory scores, crypt abscesses and oxidative stress in colitic rats (17,18,25). Moreover, it was shown that dietary iron–induced oxidative stress is ameliorated by chelators in patients with inflammatory bowel disease (21).

The primary aim of the present investigation was to search for a dietary iron management that is associated with minimal side effects in rats with and without colitis. Consistent with previous studies (17,22,38), noncolitc rats fed high dietary iron had higher concentrations of plasma, liver, and kidney iron and evidence of oxidative stress (higher MDA and lower SH concentrations) and infiltration of inflammatory cells (higher MPO activity). The combination of high dietary iron and colitis produced extensive transmural ulceration with large clumps of extracellular iron and inflammation bordered by normal mucosa. Clear evidence of crypt distortion and infiltration of inflammatory cells was also observed in colitic rats fed normal dietary iron. Similar biochemical and histological findings were reported in an iron-supplemented rat model of colitis (17,18,22).

Although the differences were not always significant, the concentrations of MDA and liver, kidney, and plasma iron and MPO activity in the severely iron-deficient group were considerably higher than the corresponding values of rats in the moderately iron-deficient group. These findings were unexpected and rather intriguing. Nevertheless, Knutson et al. (16) reported that iron deficiency precipitates lipid peroxidation in rats. It is conceivable that a breakdown of RBC and enhanced absorption of dietary iron may have led to tissue iron overload and oxidative stress in the severely iron-deficient iron rats in this study.

MDA concentration (oxidative stress) and MPO activity (infiltration of inflammatory cells) were lowest in the moderately iron-deficient colitic rats. These results suggest that a diet lower in iron or avoidance of unnecessary iron supplementation may effectively inhibit the inflammatory processes in a rat model of TNBS-induced colitis or at least not aggravate the situation without affecting most of the vital physiologic essential effects of iron. Viteri et al. (39) reported that administration of iron supplements in synchrony with gut mucosal turnover rates (every 3 d) reduces the mucosal iron overload associated with the daily supplementation of the element and was as effective as the daily supplements in correcting iron deficiency and anemia in a rat model. Similarly, Knutson et al. (16) demonstrated that intermittent iron supplementation corrects iron deficiency as well as daily iron supplementation without the associated mucosal iron overload.

On the basis of the rat model results discussed above, Viteri (40) proposed that the administration of iron supplements weekly instead of daily is a viable means of controlling iron deficiency in populations, including pregnant women. In agreement with the author, we suggest that in ulcerative colitis patients with severe iron deficiency for whom iron therapy is indicated, a diet supplemented with a low level of iron may be superior to long-term oral supplementation.


   FOOTNOTES
 
1 Supported in part by an internal grant of the Hebrew University of Jerusalem. Back

3 Abbreviations used: EPR, electron paramagnetic resonance; HTAB, hexadecyltrimethylammonium bromide; IBD, inflammatory bowel disease; MDA, malondialdehyde; MPO, myeloperoxidase; SH, sulfhydryl; TBA, thiobarbituric acid; TCA, trichloroacetic acid; TNBS, 2,4,6-trinitrobenzene sulfonic acid. Back

Manuscript received 16 January 2004. Initial review completed 4 March 2004. Revision accepted 2 June 2004.


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TOP
 ABSTRACT
 MATERIALS AND METHODS
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 DISCUSSION
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