Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor α (TNF-α). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-α expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-α, Bcl-2, and Bax expression. TNF-α mRNA was significantly lower with ACE-I treatment compared to placebo at every time point, as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.     

Mechanisms of acupuncture and moxibustion in regulation of epithelial cell apoptosis in rat ulcerative colitis

AIM: To investigate the effect of acupuncture and moxibustion on epithelial cell apoptosis and expression of Bcl-2, Bax, fas and FasL proteins in rat ulcerative colitis. METHODS: A rat model of ulcerative colitis was established by immunological methods and local stimulation. All rats were randomly divided into model control group (MC), electro-acupuncture group (EA), herbs-partition moxibustion group (HPM). Normal rats were used as normal control group (NC). Epithelial cell apoptosis and expression of Bcl-2, Bax, fas and FasL proteins were detected by TUNEL and immunohistochemical method respectively. RESULTS: The number of epithelial cell apoptosis in MC was significantly higher than that in NC, and was markedly decreased after the treatment with herbs-partition moxibustion or electro-acupuncture. The expression of Bcl-2, Bax, fas and FasL in colonic epithelial cells in MC was higher than that in NC, and was markedly down- regulated by herbs-partition moxibustion or electro-acupuncture treatment. CONCLUSION: The pathogenesis of ulcerative colitis in rats involves abnormality of apoptosis. Acupuncture and moxibustion can regulate the expression of Bcl-2, Bax, fas and FasL proteins and inhibit the apoptosis of epithelial cells of ulcerative colitis in rats by Bcl-2/Bax, fas/FasL pathways.     

Effect of Scutellariae Radix extract on experimental dextran-sulfate sodium-induced colitis in rats

AIM： To investigate the effect of Scutellariae Radix extract （SRE） on ulcerative colitis （UC） in rats induced by dextran-sulfate sodium （DSS）. METHODS： Colitis was induced in male Sprague-Dawley （SD） rats （170-180 g） by 4% dextran sulfate sodium （DSS, wt/v, MW 54000） in drinking water for 8 d. The treated rats received 4% DSS and SRE orally （100 mg/kg per day）. Control rats received either tap water or SRE only. Macroscopic assessment which included body weight changes, fecal occult blood and stool consistency were determined daily. At the appointed time, the rats were sacrificed and the entire colons were removed. The colon length and the myeloperoxidase （MPO） activity were measured. The severity of colitis was graded by morphological and histological assessments. The ion transport activity of the colonic mucosa was assessed by electrophysiological technique. RESULTS： Rats treated with oral administration of 4% DSS regularly developed clinical and macroscopic signs of colitis. Treatment with SRE relieved the symptoms, including the reduction in body weight, shortening 2nd ulceration of the colon. Administration of SRE also significantly reduced the histological damage induced by DSS. Moreover, the Isc responses of the colonic mucosa to forskolin, were suppressed after the induction of colitis. The stimulated ion transport activity of DSS-rats treated with SRE displayed significant improvement in the secretory responsiveness. CONCLUSION： SRE was effective in treating acute DSS- induced ulcerative colitis, as gauged by reduced clinical disease, improved macroscopic and histological damage scores, and enhanced recovery of normal colonic secretory function.     

Protective action of NADPH oxidase inhibitors and role of NADPH oxidase in pathogenesis of colon inflammation in mice

AIM: To investigate the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in colon epithelial cells in the pathogenesis of acute and chronic colon inflammation in a mouse model of dextran sulphate sodium (DSS)-induced colitis.METHODS: Balb/c mice were divided into three groups: 8 mice with acute DSS-induced colitis (3.5% DSS solution; 7 d), 8 mice with chronic DSS-induced colitis (3.5% DSS solution for 5 d + water for 6 d; 4 cycles; total: 44 d) and 12 mice without DSS supplementation as a control group. Primary colonic epithelial cells were isolated using chelation method. The cells were cultivated in the presence of mediators (lipopolysaccharide (LPS), apocynin or diphenyleneiodonium). Viability of cells was assessed by fluorescent microscopy. Production of reactive oxygen species (ROS) by the cells was measured fluorometrically using Amplex Red. Production of tumour necrosis factor-alpha (TNF-α) by the colonic epithelial cells was analysed by ELISA. Nox1 gene expression was assessed by real-time PCR.RESULTS: Our study showed that TNF-α level was increased in unstimulated primary colonic cells both in the acute and chronic colitis groups, whereas decreased viability, increased ROS production, and expression of Nox1 was characteristic only for chronic DSS colitis mice when compared to the controls. The stimulation by LPS increased ROS generation via NADPH oxidase and decreased cell viability in mice with acute colitis. Treatment with NADPH oxidase inhibitors increased cell viability and decreased the levels of ROS and TNF-α in the LPS-treated cells isolated from mice of both acute and chronic colitis groups.CONCLUSION: Our study revealed the importance of NADPH oxidase in the pathogenesis of both acute and chronic inflammation of the colon.     

Changes in the Expression and Distribution of Claudins,Increased Epithelial Apoptosis,and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis

Background/Aims

This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction.

Methods

Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay.

Results

The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%±1.2% in controls and was significantly increased to 7.2%±1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis.

Conclusions

There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability.     

Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis

Background Neutrophil elastase (NE) is a major secretory product from activated neutrophils and a major contributor to tissue destruction. However, little is known about the pathogenic contribution of NE to ulcerative colitis (UC). This study was designed to investigate the contribution of NE by measuring NE activity in plasma and colonic mucosal tissue from UC patients and a murine acute colitis model, and to elucidate the therapeutic effect of the NE-specific inhibitor ONO-5046. Methods The NE enzyme activities in plasma and colonic mucosal tissue from UC patients were directly measured using an enzyme–substrate reaction. Acute colitis was induced in mice by administration of 1.5% dextran sulfate sodium (DSS) for 5 days. DSS-induced colitis mice were then treated with ONO-5046 (50 mg/kg body weight) intraperitoneally twice a day. Results In UC patients, the NE enzyme activity was significantly elevated in both the plasma and colonic mucosal tissue compared with healthy controls. In DSS-induced colitis mice, the NE enzyme activity increased in parallel with the disease development. ONO-5046 showed therapeutic effects in DSS-treated mice by significantly reducing weight loss and histological score. ONO-5046 suppressed the NE enzyme activities in both plasma and culture supernatant of colonic mucosa from DSS-induced colitis mice. Conclusions ONO-5046, a specific NE inhibitor, prevented the development of DSS-induced colitis in mice. NE therefore represents a promising target for the treatment of UC patients.     

Antibody to eosinophil cationic protein suppresses dextran sulfate sodium-induced colitis in rats

AIM: To produce an antibody against rat eosinophil cationic protein (ECP) and to examine the effects of the antibody in rats with dextran sulfate sodium (DSS)-induced colitis. METHODS: An antibody was raised against rat ECP. Rats were treated with 3% DSS in drinking water for 7 d and received the antibody or normal serum. The colons were examined histologically and correlated with clinical symptoms. Immunohistochemistry and Western blot analysis were estimated as a grade of inflammation. RESULTS: The ECP antibody stained the activated eosinophils around the injured crypts in the colonic mucosa. Antibody treatment reduced the severity of colonic ulceration and acute clinical symptoms (diarrhea and/or bloodstained stool). Body weight gain was significantly greater and the colon length was significantly longer in anti-ECP-treated rats than in normal serum-treated rats. Expression of ECP in activated eosinophils was associated with the presence of erosions and inflammation. The number of Ki-67-positive cells in the regenerated surface epithelium increased in anti-ECP-treated rats compared with normal serum-treated rats. Western blot analysis revealed reduced expression of macrophage migration inhibitory factor (MIF) in anti-ECP-treated rats. CONCLUSION: Our results indicate that treatment with ECP antibody, improved DSS-induced colitis in rats, possibly by increasing the regenerative activity of the colonic epithelium and downregulation of the immune response, and suggest that anti-ECP may promote intestinal wound healing in patients with ulcerative colitis (UC).     

Dextran Sulfate Sodium-Induced Colitis Is Associated with Enhanced Low Molecular Mass Polypeptide 2 (LMP2) Expression and Is Attenuated in LMP2 Knockout Mice

Low molecular mass polypeptide 2 (LMP2) is an inducible proteasome subunit. Our goals were to examine LMP2 expression in mice with dextran sulfate sodium (DSS)-induced colitis and to evaluate colitis in LMP2 knockout (LMP2-/-) mice. Mice were given 2.5% DSS in the drinking water. On day 0, 2, 4, or 6 after DSS treatment, LMP2 expression was determined in the distal colon by western blot and immunohistochemistry. Parameters of colitis were measured in LMP2-/- mice or wild-type mice. LMP2 expression was enhanced in the colon of DSS-treated mice at all time points. Symptoms of DSS-induced colitis were always lower in LMP2-/- mice. Normalized histology scores and colonic IL-1ss levels increased over the 6-day study period in wild-type mice. These parameters were significantly reduced in LMP2-/- mice that consumed DSS for 6 days. Enhanced LMP2 expression contributes to the pathogenesis of DSS-induced colitis in mice.     

Protective Effect of Lafutidine, a Novel Histamine H2-Receptor Antagonist, on Dextran Sulfate Sodium-Induced Colonic Inflammation Through Capsaicin-Sensitive Afferent Neurons in Rats

Lafutidine, a histamine H2-receptor antagonist, exhibits gastric mucosal protective action mediated by capsaicin-sensitive afferent neurons, in addition to a potent antisecretory effect. In this study we examined the effect of lafutidine on dextran sulfate Na (DSS)-induced ulcerative colitis in rats, in relation to capsaicin-sensitive afferent neurons. Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Lafutidine, capsaicin, and cimetidine were administered per os twice daily for 6 days. The ulceration area, colon length, and myeloperoxidase (MPO) activity were measured on day 7 after the onset of DSS treatment. DSS caused severe mucosal lesions in the colon, accompanied by an increase in MPO activity as well as a decrease in body weight gain and colon length. Daily administration of lafutidine dose-dependently reduced the severity of DSS-induced colitis and significantly mitigated changes in the colon length and MPO activity. The effects of lafutidine were mimicked by daily administration of capsaicin but not cimetidine and were totally abolished by chemical ablation of capsaicin-sensitive afferent neurons. In contrast, desensitization of afferent neurons significantly worsened the colonic inflammation induced by DSS. It was also found that both lafutidine and capsaicin increased the secretion of mucus in the colonic mucosa. These results suggest that lafutidine is effective against the ulcerative colitis induced by DSS through capsaicin-sensitive afferent neurons. This action might be attributable at least partly to the enhancement of colonic mucus secretion.     

Hemodynamics in the colonic mucosa of rats with dextran sulfate-induced colitis in the early phase

We investigated hemodynamics in the colonic mucosa of rats with experimental colitis induced by the administration of dextran sulfate sodium (DSS). As parameters of hemodynamics, we determined the indices of mucosal hemoglobin concentration (IHb) and mucosal oxygen saturation (ISO₂), measured by reflectance spectrophotometry, and an index of colonic mucosal blood flow (Flow), measured by laser-Doppler flowmetry. In the ascending colon, each parameter was measured by a combination of these methods after 1, 3, 5, 7, and 10 days of DSS administration. Histopathological examination was also performed. IHb in the DSS group increased with time; on the 7th day, the value was 126.9±8.32, while that in the control group was 85.0±4.14, IHb in the DSS group being significantly increased (P<0.02). ISO₂ in the DSS group was lower than that in the control group, and on the 7th day, was significantly lower in the DSS group (25.7±1.34) than in the control group (33.4±1.77) (P<0.01). No changes in Flow were observed in either the DSS or the control group during the administration period, and no significant difference in Flow was found between the two groups. On histopathological examination, we observed a time-dependent increase in the infiltration of inflammatory cells in the ascending colon of rats treated with DSS, but changes such as erosion and ulceration were not found in the superficial layer of the mucosa. No histopathological changes were found in the control animals. In the early phase of the experimental colitis, hemodynamic alterations in the colonic mucosa were already present at the time the slight histopathological changes developed. These observations seemed to indicate the involvement of hemodynamic alterations in the subsequent tissue injury.     

Expression of apoptosis-related proteins in rat with induced colitis

Background and aims Inflammatory bowel diseases (IBD) evoke a damage-repair process accompanied by the activation of apoptotic genes. Data on transglutaminase (TG) expression in apoptotic cells in inflamed colonic epithelium has not been reported, although TG cross-links proteins within typical apoptotic bodies in various cell lines. In an experimental model of colitis we investigated the expression of different markers of apoptosis related to the degree and development of colonic inflammation.Methods Two studies were performed: (a) Colitis was induced by the administration of 2,4,6-trinitrobenzen sulfonic acid (TNBS) at a dose of 10 or 20 mg per rat in 50% ethanol, and the rats were killed 1 week later; (b) Colitis was induced by 20 mg TNBS and the rats were killed 3 days, 1, 2, and 4 weeks thereafter. The colon of rats was macroscopically assessed, and biopsies were histologically assessed and immunoprobed for FasL, FasR, p53 and tTG. Cell death was detected by TUNEL, and TG activity was assayed on colon homogenates.Results Study A: According to enhanced TUNEL positivity, FasR/FasL and p53 expression increased depending on the severity of the colitis. Study B showed increased p53 expression at day 3 while FasR/FasL coexpression peaked at 1 week. In both studies tTG was mainly expressed in the extracellular matrix of damaged tissue and in the submucosa.Conclusions Our findings suggest that expression of apoptosis markers is related to the degree of colitis and show that apoptosis is sustained by both p53 and FasR/FasL pathways, depending on the phase of colitis development. Moreover, the lack of TG staining in typical apoptotic bodies may account for a perturbation of the cross-linked apoptotic envelope that may be an important determinant in the development of immune response in ulcerative colitis.     

Fas/Fas ligand expression and characteristics of primed CD45RO+ T cells in the inflamed mucosa of ulcerative colitis

BACKGROUND: Chronic immune activation in the colon is characteristic of ulcerative colitis (UC). Fas/Fas ligand (FasL) system is a mechanism responsible for activation-induced cell death (AICD), which maintains homeostasis within the immune system. Thus, Fas/FasL expression on activated colonic T cells of UC patients, as well as the susceptibility of such T cells to AICD was investigated in order to determine the role of activated colonic T cells in the long lasting inflammation in UC. METHODS: Fas, FasL, and CD45RO expression on peripheral blood and colonic T cells of UC patients were assayed by flow cytometry. Apoptosis of colonic T cells induced by anti Fas antibody was assessed using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay. RESULTS: The majority of colonic T cells expressed both CD45RO and Fas in the colonic mucosa, a situation that was quite different from that in the peripheral blood. The number of CD45RO+CD8+ and Fas+CD8+ T cells was significantly lower in UC patients than the controls, unlike the number of Fas+CD4+ T cells. In contrast, the number of both CD45RO+CD4+ and CD45RO+CD8+ T cells in UC mucosa expressing FasL was significantly higher than in the controls. While Fas mediated apoptosis of CD45RO+CD8+ T cells was higher in UC patients than the controls, the number of apoptotic CD45RO+CD4+ T cells from UC mucosa was not. CONCLUSIONS: In UC patients, CD45RO+CD4+ T cells are less sensitive to apoptotic signals mediated by Fas. These phenomena may contribute to the pathogenesis of UC.     

Systemic and local evidence of increased Fas-mediated apoptosis in ulcerative colitis

BACKGROUND AND AIMS: Recent studies suggest that Fas-mediated apoptosis is involved in the pathogenesis of inflammatory bowel disease (IBD). This study was conducted to clarify whether soluble forms of Fas (sFas) and Fas ligand (sFasL) are concerned with inflammation in IBD. METHODS AND PATIENTS: Concentration of serum sFas and sFasL was measured by enzyme-linked immunosorbent assay in 10 patients with ulcerative colitis (UC), 10 with Crohn's disease (CD) in both active and remission stages, and 20 controls. Expression of Fas and sFas in colonic mucosa was examined by western blot. Distribution of Fas and FasL in colonic mucosa was examined by immunohistochemistry in 20 UC, 20 CD, and 10 non-IBD colitis patients and in 10 controls. Apoptotic cells were examined by TUNEL. RESULTS: Concentration of systemic sFas was significantly lower in active UC than controls. The number of FasL-containing cells was significantly higher in active UC than in remission UC, non-IBD colitis, and controls. Apoptotic cells were increased in active UC. CONCLUSIONS: Our results demonstrate that systemic and local Fas-mediated apoptosis is promoted in UC, which might be involved in the pathogenesis in UC.     

Systemic Iron Supplementation Replenishes Iron Stores Without Enhancing Colon Carcinogenesis in Murine Models of Ulcerative Colitis: Comparison with Iron-Enriched Diet

Ulcerative colitis (UC) patients frequently require iron supplementation to remedy anemia. The impact of systemic iron supplementation (intraperitoneal injection) on UC-associated carcinogenesis was assessed in mice subjected to cyclic dextran sulfate sodium (DSS) treatment and compared with dietary iron enrichment. Systemic iron supplementation, but not a twofold iron diet, remedied iron deficiency as indicated by the histochemical detection of splenic iron stores. A twofold iron diet, but not systemic iron, increased iron accumulation in colonic luminal contents, at the colonic mucosal surface, and in superficial epithelial cells. Colitis-associated colorectal tumor incidence after 15 DSS cycles was not affected by systemic iron (2/28; 7.1%) compared to nonsupplemented controls (4/28; 14.1%) but was significantly increased by the twofold iron diet (24/33; 72.7%) (P < 0.001). Mechanistic study revealed that systemic iron had no effect on DSS-induced inflammation, or colonic iNOS and COX-2 protein levels, compared to controls. Systemic iron supplementation for 16 weeks replenished splenic iron in a spontaneous colitis model (interleukin-2-deficient mice) and significantly reduced colonic inflammation compared to interleukin-2 (–/–) controls without increasing hyperplastic lesions. These results suggest that iron supplemented systemically could be used to remedy anemia in UC patients without exacerbating inflammation or enhancing colon cancer risk. These findings need to be verified in clinical studies.This work was supported by Research Project Grant RPG-00-034-01-CNE from the American Cancer Society and NIH Grant RO1CA104741-01A1 (G.-Y.Y.).     

溃疡性结肠炎肠黏膜组织CD8、Fas/FasL和Bcl-2/Bax的表达及关系

目的:研究溃疡性结肠炎(UC)肠黏膜CD8 T细胞Fas／FasL、Bcl-2／Bax蛋白表达以及相互关系,探讨细胞凋亡机制在UC发病中的作用．方法:采用免疫组化SP法检测60例UC肠黏膜组织以及60例正常肠黏膜组织CD8,Fas／FasL, Bcl-2／Bax蛋白表达．结果:CD8阳性细胞在上皮间的浸润在UC 组为52％,正常组为78％,两组相比差异显著 (P<0．01);急性期较缓解期也显著减少(20％ vs 74％,P<0．01)．CD8在UC患者急性期黏膜固有层的表达为80％,高于缓解期的34％(P= 0．0006)．Fas在UC上皮中表达62％,正常组织 30％,两组相比差异显著(P<0．01);急性期高于缓解期(84％ vs 45％,P<0．01)．FasL在固有膜炎性细胞中的表达UC组为62％,正常组7％, 两组相比差异显著(P<0．00;急性期(88％)高于缓解期(43％),而且CD8与FasL在黏膜固有层炎性细胞的表达呈正相关(X2=7．3,P<0．01)． Bcl-2／Bax在UC肠黏膜上皮的表达率与正常组相近,差异无显著性．结论:UC肠黏膜组织Fas／FasL表达增强, Bcl-2／Bax表达无明显变化,CD8细胞与UC急性期Fas／FasL表达相关．     

肠内营养对DSS诱导的溃疡性结肠炎大鼠血浆内毒素水平的影响

目的探讨给予肠内营养后溃疡性结肠炎（UC）大鼠血浆内毒素水平的变化,以及内毒素对黏膜修复的影响。方法将40只大鼠随机分为4组：正常对照组,模型对照组,甲泼尼龙组,谷氨酰胺组。后3组大鼠自由饮用5%葡聚糖硫酸钠（DSS）溶液7 d,建立UC模型,后2组同时分别给予甲泼尼龙及谷氨酰胺干预治疗。采用鲎试剂基质偶氮显色定量测定各组大鼠血浆内毒素的含量,并观察大鼠结肠的形态和组织病理学改变。结果 DSS诱导UC大鼠血浆内毒素水平明显高于正常对照大鼠（P〈0.01）,甲泼尼龙及谷氨酰胺干预治疗后血浆内毒素水平较模型对照组降低（P〈0.01）。结论肠内营养可以降低UC大鼠血浆内毒素水平,促进肠道黏膜屏障的修复。     

The Role of Zinc and Metallothionein in the Dextran Sulfate Sodium-Induced Colitis Mouse Model

Zinc (Zn) and its binding protein metallothionien (MT) have been proposed to suppress the disease activity in ulcerative colitis. To determine the role of Zn and MT in the dextran sulfate sodium (DSS)-induced model of colitis in mice, a DSS dose-response study was conducted in male C57BL/6 wild-type (MT+/+) and MT-null (MT−/−) mice by supplementing 2%, 3%, and 4% DSS in the drinking water for 6 days. In the intervention study, colitis was induced with 2% DSS, Zn (24 mg/ml as ZnO) was gavaged (0.1 ml) daily, concurrent with DSS administration, and the disease activity index (DAI) was scored daily. Histology, MT levels, and myeloperoxidase (MPO) activity were determined. DAI was increased (P<0.05) by 16% and 21% with 3% and 4% concentrations of DSS, respectively, compared to 2%, evident after 5 days of DSS administration. MPO activity was increased in MT+/+ compared to MT−/− mice and those receiving DSS. Zn administration had a 50% (P<0.05) lower DAI compared to DSS alone. Zn partially prevented the distal colon of MT+/+ by 47% from DSS-induced damage compared to MT−/− mice. MT did not prevent DSS-induced colitis and Zn was partially effective in amelioration of DSS-induced colitis.