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PubMed2000

Disturbed bile secretion and cytochrome P450 function during the acute state of experimental colitis in rats.

BACKGROUND/AIMS: A variety of hepatobiliary abnormalities has been described in patients with inflammatory bowel diseases. However, the pathophysiological mechanisms leading to these liver alterations are poorly understood. The aim of the present study was to investigate parameters of liver function in a trinitrobenzenesulfonic acid (TNB)-induced rat colitis model. METHODS: Glucose output, bile acid secretion, bile acid uptake, and the cytochrome P-450 metabolic capacity during TNB-colitis were studied in the perfused liver model. Furthermore, hepatic bile acid- and glycogen content was measured. To evaluate the inflammatory response in the colon and liver, NF-kappaB/Rel was quantified by electrophoretic mobility shift assays. As an NF-kappaB/Rel regulated gene the inducible NO-synthase (NOS2) was evaluated by Western blot analysis. As possible mediators released from the inflamed colon into the portal vein, endotoxin and the stable metabolite of prostaglandin I2 (6-keto-prostaglandin-F1alpha) were determined. RESULTS: Glucose output, bile acid secretion, bile acid uptake, and cytochrome P-450 metabolic capacity decreased on the first and second day of TNB-colitis. Hepatic bile acid content increased at day 14 of colitis. Glycogen content was reduced, most likely due to an inadequate chow intake of these animals. A low level of portal endotoxin was detectable during the first 2 days of colitis. In addition, 6-keto-prostaglandin-F1alpha was clearly increased in portal blood. NF-kappaB/Rel binding activity and inducible NOS2 were strongly positive in the colon during colitis. Although low levels of portal endotoxin were measured during the first 2 days of colitis, no significant NF-kappaB/Rel activity and NOS2 induction were detected in the liver. CONCLUSION: Our results indicate that during the acute state of the TNB-colitis, bile acid secretion and cytochrome P-450 function are disturbed in the absence of distinct inflammatory changes in the liver.

Animals↗
PubMed1999

Concanavalin A-binding cholesterol crystallization inhibiting and promoting activity in bile from patients with Crohn's disease compared to patients with ulcerative colitis.

BACKGROUND/AIMS: Crohn's disease is a risk factor for gallstone formation. In contrast, patients with ulcerative colitis have an incidence of gallstone formation comparable to the general population. The reason for this difference is not known. The aim of this study was to elucidate the factors controlling cholesterol crystallization in gallbladder bile of Crohn's disease and ulcerative colitis patients. METHODS: Gallbladder bile was obtained by aspiration during bowel resections (26 Crohn's disease patients, 20 ulcerative colitis patients). Biliary lipid composition, crystal detection time and the effect of extraction of the concanavalin A-binding fraction on crystal formation were determined. RESULTS: Cholesterol crystals were present in seven of the 26 bile samples of Crohn's disease-patients and one of the 20 ulcerative colitis patients. Four of the bile samples of Crohn's disease patients were fast nucleating. None of the 20 ulcerative colitis patients had fast nucleating bile. Lipid composition, total lipid concentration and CSI were not significantly different between the two groups. In Crohn's disease patients extraction of concanavalin A-binding fraction decreased crystallization in 10 bile samples but accelerated crystallization in one bile sample. In eight bile samples from ulcerative colitis patients crystallization increased after concanavalin A-binding fraction extraction. CONCLUSIONS: Compared to ulcerative colitis patients, gallbladder bile of Crohn's disease patients showed increased cholesterol crystallization despite comparable lipid composition and cholesterol saturation index. This difference is caused by increased cholesterol crystallization-promoting activity. Bile from ulcerative colitis patients contains a Con A-binding factor which inhibits cholesterol crystallization.

Adult↗
PubMed2006

Intestinal disease in Hermansky-Pudlak syndrome: occurrence of colitis and relation to genotype.

BACKGROUND & AIMS: Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction, results from mutations in 1 of at least 7 different genes. Some patients develop a fatal pulmonary fibrosis and others a disabling colitis. This study aimed to document the occurrence of colitis among HPS patients, characterize gastrointestinal tract involvement in HPS, and analyze the distribution of colitis among HPS genotypes. METHODS: Of the 122 HPS patients followed at the National Institutes of Health Clinical Center between 1993 and 2005, 24 were evaluated by endoscopy for gastrointestinal complaints. The histology of gastrointestinal biopsies was retrospectively examined to assess for inflammatory changes, granulomata, and pigmented macrophages. These data were compared with symptoms and HPS genetic subtypes. RESULTS: At colonoscopy, 7 of 23 patients (30%) had endoscopic mucosal abnormalities, including nodularity, erythema, petechiae, or erosions. Six of these 7 patients (86%) had findings of colitis on biopsy. Of the 16 patients with normal-appearing colonic mucosa, 2 patients (12%) had colitis on biopsy. Pigmented macrophages were also observed in the colonic lamina propria in 16 of the 23 patients (70%). Of the 8 patients with confirmed colitis, 7 had the HPS-1 subtype, and 1 had the HPS-4 subtype. CONCLUSIONS: There is an increased frequency of colitis in our population of 122 HPS patients (8/122, 7%) and in HPS patients referred specifically for symptom evaluation (8/24, 33%). Colitis was found in patients with HPS-1 and HPS-4 genotypes.

Adolescent↗
PubMed2003

Colorectal cancer and high grade dysplasia complicating ulcerative colitis in Italy. A retrospective co-operative IG-IBD study.

BACKGROUND: Ulcerative colitis is a well-known risk factor for colorectal cancer. AIM: To take a census of the cases of colorectal cancer in ulcerative colitis patients observed in Italy and to evaluate the clinical presentation of neoplastic complication. PATIENTS AND METHODS: Experts from 28 Italian centres specialised in the management of inflammatory bowel disease or malignancies participated to the study. They were invited to send clinical data of patients with ulcerative colitis complicated by colorectal cancer or high-grade dysplasia consecutively observed between 1985 and 2000. One hundred and twelve patients (92 with cancer and 20 with high-grade dysplasia) were collected. Fourteen of them had undergone colectomy and ileo-rectal anastomosis for ulcerative colitis. Data of surgical patients were analysed separately. RESULTS: The mean age at diagnosis of ulcerative colitis and colorectal cancer patients was 39.3 and 53.2 years, respectively, and the mean duration between diagnosis of ulcerative colitis and cancer was 13.9 years (range 0-53). Inflammation was proximal to the splenic flexure in 71 cases (76.3%). One hundred and three colorectal cancers were registered (93 patients with single lesion and five patients with two synchronous cancers), with 76.7% of cancers being located in the left colon. As to the surgical patients, the mean age at diagnosis of ulcerative colitis and cancer was 28.9 and 47.0 years, respectively, and the mean diagnostic interval for ulcerative colitis and cancer was 18.1 years. Only 51 out of 112 patients were in follow-up. An early diagnosis of neoplasia (high grade dysplasia, stage A or B sec. Dukes) occurred in 72.5% of patients who were subjected to endoscopic surveillance and in 48.0% of patients who did not undergo endoscopic surveillance (p=0.02). CONCLUSIONS: These data show an earlier diagnosis of cancer in patients who had undergone endoscopic surveillance. The poor compliance to the follow-up program, however, reduces its effectiveness. Moreover, total colectomy allows an easier follow-up, with only the rectum being controlled. Colectomy with ileo-rectal anastomosis or proctocolectomy with ileo-anal anastomosis, could represent a valid alternative in patients at high risk of cancer who refuse endoscopic surveillance.

Adolescent↗
PubMed1998

Effects of local budesonide treatment on the cell-mediated immune response in acute and relapsing colitis in rats.

Glucocorticosteroids (GCS) are effective in treatment of inflammatory bowel disease (IBD), but also have unwanted systemic side effects. Here, we describe the effects of budesonide and dexamethasone on acute experimental colitis and on T cells in thymus and spleen, as well as the effect of budesonide treatment on relapsing colitis. Acute colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in ethanol, and a relapse was induced by an intraperitoneal booster of TNBS. GCS were administered intrarectally on days 1, 4, and 6 after induction of acute colitis or a relapse. Inflammatory cells in the colon were studied on day 7, and in acute colitis also on days 13 and 16. Budesonide treatment in acute and relapsing colitis resulted in reduction of macroscopic damage and decreased the numbers of macrophages and neutrophils in the colon. Dexamethasone was less effective. Dexamethasone, but not budesonide, reduced the number of T cells in the thymus. It is concluded that local budesonide is more effective in treatment of acute experimental colitis than dexamethasone and, in contrast to dexamethasone, did not cause a general suppression of T cells. Although budesonide was very effective in the treatment of relapsing colitis, this effect was not accomplished by affecting the number of T cells in the colon.

Acute Disease↗
PubMed2004

Modulation of the effect of dextran sulfate sodium-induced acute colitis by the administration of different probiotic strains of Lactobacillus and Bifidobacterium.

The pathogenic mechanism of inflammatory bowel diseases is not fully understood but colonic microflora including Lactobacillus and Bifidobacterium species may affect the induction of colonic inflammation. In this study the relative efficacy of different probiotic organisms in the prevention of colitis was compared in an induced rat colitis model. Three Lactobacillus strains and two Bifidobacterium strains were fed to Sprague-Dawley rats for 7 days prior to offering the rats 5% dextran sulfate sodium (DSS) in their drinking water to induce colitis and the administration of the probiotics continued for 7 days with the DSS. Colitis severity was assessed daily using a disease activity index (DAI). Samples were collected 7 days after colitis induction for intestinal bacterial flora and bacterial translocation. The DAI decreased significantly on days 4, 5, 6, and 7 in the Lactobacillus plantarum DSM 9843, Bifidobacterium sp. 3B1, and Bifidobacterium infantis DSM 15158 groups compared to the colitis control. It decreased significantly on days 5, 6, and 7 in the Bifidobacterium infantis DSM 15158 group compared to the Lactobacillus paracaesi DSM 13434 and Lactobacillus gasseri 5B3 groups. It also decreased significantly on day 7 in the L. plantarum DSM 9843 group compared to the L. gasseri 5B3 group. Bacterial translocation to the mesenteric lymph nodes decreased significantly in all treatment groups compared to the colitis control. Enterobacteriaceae bacterial translocation to the liver decreased in all treatment groups compared to the colitis control. Administration of certain strains of Lactobacillus and Bifidobacterium significantly improves the DAI and reduces bacterial translocation, and L. plantarum DSM 9843, Bifidobacterium sp. 3B1, and Bifidobacterium infantis DSM 15158 seem to have the best effect.

Acute Disease↗
PubMed2001

Lycopene supplementation attenuates the inflammatory status of colitis in a rat model.

The aim of this study was to examine the influence of lycopene and beta-carotene on the inflammatory status in a rat model of induced-colitis. Using the 2,4,6-trinitrobenzenesulfonic acid (TNBS) model, colitis was induced in thirty-two male Wistar rats divided into four groups. Each group received a different diet regime in parallel with the induction of colitis and was sacrificed after seven days. The groups were divided as follows: Group A: without colitis and fed a normal chow diet; Group B: induced with colitis and fed a diet supplemented with lycopene (300 micrograms/rat/day); Group C: induced with colitis and fed a diet supplemented with beta-carotene (300 micrograms/rat/day); Group D: induced with colitis and fed a normal chow diet. Colonic inflammation following TNBS induction was characterized by hemorrhagic necrosis and fibrosis of the mucosa, increased colonic wall thickness, infiltration of inflammatory cells, and increased myeloperoxidase (MPO) activity. Supplementation of lycopene in the diet had a beneficial effect on the various macroscopic parameters examined including: colonic thickness, colon weight, and total area of inflammation. Furthermore, the level of myeloperoxidase (MPO) was significantly lower in the lycopene-treated group compared to the control group. In terms of microscopic changes, a more attenuated inflammatory reaction was observed in the group fed a diet supplemented with lycopene. No significant effect was noted in the beta-carotene-supplemented group. Therefore, we propose that the dietary supplementation of lycopene may be an effective approach for reducing the level of oxidative stress and improving the inflammatory status of colitis.

Analysis of Variance↗
PubMed1994

Intraluminal colonic release of immunoreactive tumour necrosis factor in chronic ulcerative colitis.

1. Tumour necrosis factor is a proinflammatory macrophage-derived polypeptide cytokine. Its participation in disease processes has been usually inferred from data obtained from experiments in vitro or from measurements of its plasma circulating levels. To investigate its role in chronic ulcerative colitis, we have quantified in vivo the steady-state release of tumour necrosis factor into the colonic lumen. 2. We studied 19 patients with untreated active ulcerative colitis and seven patients with irritable bowel syndrome as controls. A group of seven patients with active ulcerative colitis were studied before and after 4 weeks on treatment with oral 5-aminosalicylic acid. By means of an intracolonic double-lumen perfusion tube, an isotonic solution was continuously infused 50 cm from the anal verge at a rate of 5 ml/min, and was recovered 30 cm distally by siphonage. Effluents were assayed for tumour necrosis factor by a specific e.l.i.s.a. and for prostaglandin E2 and leukotriene B4 by specific r.i.a.s. 3. The intracolonic release of tumour necrosis factor was undetectable in patients with irritable bowel syndrome, whereas measurable release occurred in 15 out of 19 patients with active ulcerative colitis (P < 0.01). Prostaglandin E2 and leukotriene B4 release were also increased in active ulcerative colitis by comparison with irritable bowel syndrome (P < 0.01). Five out of seven patients with colitis improved with 5-aminosalicylic acid treatment, and tumour necrosis factor release became undetectable or decreased markedly (P < 0.05 compared with before treatment). However, tumour necrosis factor release remained high in the non-responder patients. 4. These findings indicate that intracolonic immunoreactive tumour necrosis factor release is enhanced in active chronic ulcerative colitis, becoming undetectable when mucosal lesions are healed. These results suggest that the luminal release of tumour necrosis factor may serve as an objective index of inflammatory activity in patients with chronic ulcerative colitis.

Adolescent↗
PubMed2000

Abnormal contractile properties of rectal smooth muscle in chronic ulcerative colitis.

BACKGROUND: Patients with ulcerative colitis have abnormal rectal motility. AIM: To compare the contractile properties of rectal smooth muscle from patients with ulcerative colitis and controls. METHODS: Rectal smooth muscle strips from patients undergoing resection for ulcerative colitis or cancer (control) were mounted in an organ bath. The effects of carbachol (receptor-mediated) and potassium (causes membrane depolarization) were studied. Acetylcholinesterase histochemistry was performed and nerve counts compared. RESULTS: Ulcerative colitis (n=41) and control (n=34) strips contracted in response to potassium and carbachol. Mean (S.E. M.) maximum response to potassium in the control and ulcerative colitis groups was 1.07 (0.06) g/mg and 1.02 (0.09) g/mg tissue, respectively (P=N.S.). EC50s (concentrations required to give 50% of maximal response) were 75 (1) mM and 73 (1) mM, respectively (P=N.S. ). Although maximum responses to carbachol were similar, 2.12 (0.12) g/mg and 1.95 (0.12) g/mg tissue (P=N.S.), ulcerative colitis strips exhibited an increased sensitivity to carbachol, EC50s: 5.05 x 10-6 (0.55 x 10-6) M vs. 8.36 x 10-6 (0.88 x 10-6) M, P=0.002). There was no significant difference in nerve counts between the tissues, as assessed by staining for acetylcholinesterase. CONCLUSIONS: Ulcerative colitis tissue has an increased sensitivity to carbachol and this is not due to denervation; it may result from increased calcium release from intracellular stores since contraction due to membrane depolarization is not altered. Modulation of this pathway could potentially be used to alter rectal motility in patients with ulcerative colitis.

Acetylcholinesterase↗
PubMed2002

Depletion of non specific esterase activity in the colonic mucosa of patients with ulcerative colitis.

BACKGROUND: Non specific esterases (NSE) are a group of cellular carboxylesterases, enzyme markers of monocytes/macrophages, whose tissue distribution in the human body and changes in various disease states have not been adequately studied. We investigate the presence and localization of NSE, in the normal and inflamed human colonic mucosa. DESIGN: NSE were studied histochemically and biochemically using alpha-naphthyl acetate as the substrate, in the colonic mucosa from 67 patients with colitis of various aetiologies and 10 normal controls. In addition, esterase activity was studied biochemically in serum from colitic patients and normal controls. RESULTS: Histochemical study of the colonic tissue demonstrated that NSE were localised in the epithelial brush border, the goblet cells of the glands and a macrophage population of the lamina propria in the colonic mucosa of normal controls and patients with non specific colitis. In active ulcerative colitis, esterase depletion and esterase negative macrophages were identified in parallel with goblet cell disappearance. Gradual reappearance of esterase activity was found after successful treatment. Biochemical study of NSE activity showed that serum and colonic tissue esterase levels were greatly (P < 0.001) reduced in active ulcerative colitis compared to the normal controls or non specific colitis patients and they were increased after successful treatment. Despite this increase, the esterase activity in the colonic tissue from ulcerative colitis patients after treatment was significantly reduced compared to the normal controls. Interestingly, the enzyme levels from non-inflamed areas of the bowel of patients with ulcerative colitis were also significantly (P < 0.01) decreased compared to the normal controls. CONCLUSIONS: These data suggest that esterase reduction in ulcerative colitis is not a simple result of the inflammatory process but rather it precedes its development. This enzyme depletion might have an important pathogenetic implication in the inflammatory process.

Adult↗
PubMed1998

Appendiceal inflammation in ulcerative colitis.

AIMS: Previous uncontrolled reports have suggested that appendiceal inflammation may occur as a discontinuous lesion in ulcerative colitis. This study aims semiquantitatively to compare the prevalence and histological features of appendiceal inflammation in patients with ulcerative colitis and Crohn's disease, using colonic carcinoma and acute appendicitis specimens as controls. METHODS AND RESULTS: Surgical pathology records and original histological slides for the period 1980-1994 were examined. The prevalence of appendiceal inflammation in ulcerative colitis (24/50, 48%), was higher than in colonic carcinoma (5/65, 8%, P < 0.001), but was similar to that in Crohn's disease (14/27, 52%). Appendiceal inflammation with caecal sparing was seen in nine out of 24 specimens with ulcerative colitis (37%), two out of nine (22%) with Crohn's disease and five out of 65 (8%) with colonic carcinoma. Inflamed appendixes from patients with inflammatory bowel disease showed histological features typical of ulcerative colitis and Crohn's disease rather than acute appendicitis and were significantly less likely to have transmural inflammation. There had been a previous appendicectomy in 3% of ulcerative colitis patients compared with 8% of colonic carcinoma specimens and 21% (P < 0.01) Crohn's disease controls. CONCLUSION: In ulcerative colitis, as in Crohn's disease, appendiceal inflammation commonly occurs as a skip lesion and histologically resembles the colonic disease rather than acute appendicitis. The low prevalence of appendicectomy supports the hypothesis that the appendix itself may have a central role in the pathogenesis of ulcerative colitis.

Adolescent↗
PubMed2003

Subepithelial myofibroblasts and tenascin expression in microscopic colitis.

AIMS: To assess differences in the pattern of subepithelial myofibroblasts and the expression of tenascin as a marker of extracellular matrix production in collagenous and lymphocytic colitis. METHODS AND RESULTS: Colorectal biopsies were studied from 122 patients with chronic diarrhoea and normal colonoscopy. The pathological diagnoses were collagenous colitis (n = 35), lymphocytic colitis (n = 37), mild non-specific chronic inflammation (n = 28) and normal mucosa (n = 18). Four cases showed features of collagenous colitis but with collagen bands <10 micro m thick. Normal mucosa from 14 patients without diarrhoea served as healthy control tissue. Immunohistochemical expression of alpha-smooth muscle actin (myofibroblast marker) and tenascin was evaluated in well-orientated sections. The expression of alpha-smooth muscle actin was significantly increased in collagenous colitis compared with all the other groups. Strong tenascin subepithelial expression was seen in all cases of collagenous colitis, including the four without full-blown features. The mean thickness of tenascin bands was greater than that obtained by conventional stains. CONCLUSIONS: There are clear differences, with respect to extracellular matrix remodelling, between collagenous and lymphocytic colitis. These results support the theory of matrix overproduction in the genesis of collagenous colitis.

Actins↗
PubMed2000

Immune activation in the intestinal mucosa before the onset of colitis in Galphai2-deficient mice.

G-protein subunit Galphai2-deficient mice spontaneously develop an inflammatory bowel disease that clinically and histopathologically resembles ulcerative colitis in humans. The aim of this study was to determine whether immunological changes precede the development of colitis in Galphai2-deficient mice. Therefore, Galphai2-deficient mice with no clinical or histopathological signs of colitis were compared with Galphai2-deficient mice with established colitis and wild-type animals, concerning immunological parameters. Healthy Galphai2-deficient mice displayed an increased frequency of CD4+ T cells and a decreased frequency of CD19+ B lymphocytes in the intestinal mucosa compared with control mice. The CD4+ population was characterized by a memory phenotype, i.e. increased expression of CD44 and decreased expression of CD45RB and CD62L, as well as increased expression of the mucosal homing receptors integrins alpha4beta7 and alphaEbeta7. Production of pro-inflammatory cytokines, interleukin (IL)-1beta and interferon (IFN)-gamma, were increased in Galphai2-deficient mice before clinical signs of disease were evident. In addition, total immunoglobulin (Ig)G and IgA levels in large intestinal secretions were increased significantly compared with wild-type mice, and antibodies specific for the normal intestinal flora in large intestinal secretions were present in Galphai2-deficient mice several weeks before the onset of colitis. In contrast, antibodies against tropomyosin, a putative autoantigen in human ulcerative colitis, were not found in Galphai2-deficient mice before the onset of colitis, although they were present in animals with established disease. In conclusion, activation of the intestinal immune system precedes histopathological and clinical signs of inflammation in Galphai2-deficient mice, suggesting that immune abnormalities play an important role in the induction of colitis.

Animals↗
PubMed2003

Idiopathic colitis following cardiac transplantation: three pediatric cases.

Colitis can cause significant morbidity in pediatric solid organ transplant recipients. In many cases, despite intensive evaluation, a specific infectious, inflammatory, or immunologic etiology is not identified, and idiopathic colitis may be the ultimate diagnosis. We defined idiopathic colitis as the presence of gastrointestinal symptoms (vomiting, diarrhea, abdominal pain) with inflammatory changes seen on intestinal biopsy in the absence of identifiable bowel disease. We describe three cases of idiopathic colitis following cardiac transplantation. In each case, the post-transplant course was complicated by persistent abdominal pain, diarrhea, and in two cases, vomiting. All three patients' post-transplant courses were marked by multiple graft rejection episodes, and all received intensified immune therapy in addition to usual maintenance immunosuppression. Differential diagnosis of the patients' gastrointestinal symptoms included drug side effect, indolent opportunistic infections, inflammatory bowel disease, post-transplant lymphoproliferative disease, and microvascular ischemic colitis. Continued symptoms led these patients to extensive evaluation including imaging studies, endoscopy and tissue biopsy, and stool, blood and tissue cultures for viral, bacterial and parasitic pathogens. Definitive differentiation presented significant diagnostic challenge, and once identifiable etiologies were excluded, the diagnosis of idiopathic colitis was assigned. We conclude that idiopathic colitis following pediatric cardiac transplantation can be a cause of significant morbidity. Endoscopic evaluation of patients who present with gastrointestinal symptoms after transplant is warranted to identify the presence of idiopathic colitis once common causes are ruled out. Further study is needed to identify its incidence, etiology, therapeutic options and prognosis.

Adolescent↗
PubMed2001

Dietary fiber fraction of germinated barley foodstuff attenuated mucosal damage and diarrhea, and accelerated the repair of the colonic mucosa in an experimental colitis.

BACKGROUND AND AIMS: Germinated barley foodstuff (GBF) contains protein and insoluble dietary fiber. We have previously shown in ulcerative colitis patients and a colitis model that GBF feeding attenuates mucosal damage by increasing luminal butyrate levels. However, the detailed mechanism remains unclear because of its heterogeneous nature. The present study was carried out to: (i) evaluate the active ingredient in GBF; and (ii) examine its effect on the repair process in colonic inflammation by using a dextran sulfate sodium (DSS) colitis model. METHODS: Colitis was induced by feeding a diet containing 0.5-3.5% DSS to male Sprague-Dawley rats. (i) Active ingredient: GBF was fractionated enzymatically into fiber- and protein-rich fractions. Each fraction was administered to DSS-colitis rats. Clinical signs, cecal short chain fatty acid concentrations and serum alpha1-acid glycoprotein (AAG) levels were determined. (ii) Effect on mucosal repair: GBF with or without salazosulfapyridine (SASP), or SASP alone was administered to rats after the onset of colitis. Seven days after initial treatment, the number of epithelial cells in HE sections was evaluated morphologically in a blind fashion and serum AAG was determined. RESULTS: (i) Germinate barley foodstuff and GBF-fiber significantly attenuated the clinical signs of colitis and decreased serum AAG levels, with a significant increase in cecal butyrate production, while GBF-protein did not. (ii) Treatment with GBF alone and GBF plus SASP significantly accelerated colonic epithelial repair and improved clinical signs. CONCLUSIONS: These findings suggest that the fiber fraction of GBF may effectively enhance luminal butyrate production, and thereby accelerate colonic epithelial repair in colitis.

Animals↗
PubMed2002

Dysplasia and carcinoma development in a repeated dextran sulfate sodium-induced colitis model.

BACKGROUND: As an important mechanism underlying the increased risk of colorectal carcinoma development in patients with long-standing ulcerative colitis, promotion as a result of the regenerative process has been proposed. In the present study, a dysplasia-carcinoma sequence in a novel repeated colitis model in mice is documented. METHODS: Repeated colitis was induced by nine administration cycles of 3% dextran sulfate sodium (DSS; molecular weight, 54 000): each administration cycle comprised 3% DSS for 7 days followed by distilled water for the subsequent 14 days, to give conditions similar to the clinically observed active and remission phases in humans. RESULTS: Multiple colorectal tumors (nine low- and four high-grade dysplasias and two carcinomas) developed in 25 mice. These neoplastic lesions consisted of tubular structures, presenting as various types of elevated, flat and depressed tumor, similar to those in ulcerative colitis patients. A time-course study with assessment of the severity of colitis and in vivo bromodeoxyuridine uptake during a single 3% DSS administration cycle revealed a high level of regenerative activity in the colitis-affected mucosal epithelia. CONCLUSION: Thus, with the present repeated colitis model, regeneration and neoplastic lesions were apparent, the biological features of which provide evidence of a colorectal dysplasia-invasive carcinoma sequence in ulcerative colitis.

Adenocarcinoma↗
PubMed2002

Experimental murine colitis is regulated by two genetic loci, including one on chromosome 11 that regulates IL-12 responses.

BACKGROUND & AIMS: Immunogenetic analysis of experimental colitis may contribute to the further unraveling of the complex genetic basis of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis. METHODS: Genetic regions associated with susceptibility to trinitrobenzene sulfonic acid (TNBS)-induced colitis were identified in a genome-wide linkage analysis in F2 progeny of colitis-susceptible SJL/J and -resistant C57BL/6 mice. An immunogenetic approach was then used to further study the pathophysiologic role of one of the identified loci. RESULTS: We identified susceptibility loci on chromosomes 9 (Tnbs1) and 11 (Tnbs2). Tnbs2 harbors the interleukin (IL)-12 p40 gene, a likely candidate gene because IL-12 is a known central mediator for both experimental colitis and human Crohn's disease. We therefore tested the ability of colitis-susceptible and -resistant strains to mount IL-12 responses to lipopolysaccharide (LPS), a strong inducer of IL-12 that is abundantly present in the intestine. We observed a remarkably higher serum IL-12 response to LPS in susceptible SJL/J mice. Subsequently, we showed that the genetic region regulating the IL-12 response to LPS colocalizes with Tnbs2. CONCLUSIONS: These data strongly suggest that the tendency to mount a high LPS-induced IL-12 response and susceptibility to TNBS-induced colitis are related and that in fact a genetically determined high IL-12 response is involved in the immunologic basis of susceptibility to colitis.

Animals↗
PubMed2003

Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis.

BACKGROUND & AIMS: The human multidrug resistance 1 (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics. The finding that mdr1a knockout mice develop a form of colitis that is similar to ulcerative colitis, which can be prevented by antibiotics, indicates a barrier function for P-glycoprotein against the invasion of bacteria or toxins. Because the MDR1 single nucleotide polymorphism C3435T is associated with lower intestinal P-glycoprotein expression, we tested whether this polymorphism predisposes to development of ulcerative colitis. METHODS: Allele frequencies and genotype distributions of the C3435T single nucleotide polymorphism were investigated in 149 patients with ulcerative colitis, 126 patients with Crohn's disease, and sex-matched healthy controls. RESULTS: Significantly increased frequencies of the 3435T allele and the 3435TT genotype were observed in patients with ulcerative colitis compared with controls (3435T: P = 0.049; odds ratio, 1.4; 95% confidence interval, 1.02-1.94; 3435TT: P = 0.045; odds ratio, 2.03; 95% confidence interval, 1.04-3.95). In contrast, frequencies of the T allele and the TT genotype were the same in patients with Crohn's disease as in controls (P = 0.66 and P = 0.59, respectively). In comparison to 998 non-sex-matched controls, the effect for the TT genotype in ulcerative colitis patients was more pronounced (P = 0.0055; odds ratio, 2.1). CONCLUSIONS: The higher frequency of the 3435TT genotype in patients with ulcerative colitis corroborates the findings from the mdr1a knockout mice. The results support the notion that P-glycoprotein plays a major role in the defense against intestinal bacteria or toxins. Impairment of barrier function in 3435TT subjects could render this genotype more susceptible to the development of ulcerative colitis.

Adolescent↗