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PubMed1997

Gene expression of group II phospholipase A2 in intestine in ulcerative colitis.

BACKGROUND: It has been suggested that phospholipase A2 (PLA2) has an essential role in the pathogenesis of inflammatory bowel diseases. AIMS: This study aimed at identifying cells in intestinal and mesenteric tissue samples that might express group II phospholipase A2 (PLA2-II) at the mRNA and enzyme protein levels in patients with ulcerative colitis. PATIENTS AND TISSUE SAMPLES: Tissue samples were obtained from the intestine, mesentery, skeletal muscle, and subcutaneous fat of six patients who underwent panproctocolectomy for severe ulcerative colitis. Mucosal biopsy specimens were obtained from the colon of another group of six patients with ulcerative colitis during routine diagnostic colonoscopies. Tissues from six patients without intestinal inflammatory diseases served as controls. METHODS: Tissue samples were studied by light microscopy, immunohistochemistry for PLA2-II enzyme protein, and in situ hybridisation and northern hybridisation for PLA2-II mRNA. RESULTS: PLA2-II mRNA and PLA2-II protein were detected in metaplastic Paneth cells in six patients and in the columnar epithelial cells of colonic mucosa in four out of six patients with active ulcerative colitis. Positive findings were less numerous in patients with mild ulcerative colitis. Only two out of six control patients had a weak positive signal for PLA2-II mRNA and one of these two patients had a weak positive immunoreaction for PLA2-II in columnar epithelial cells in the colonic mucosa. None of the control patients had metaplastic Paneth cells. CONCLUSIONS: Metaplastic Paneth cells and colonic epithelial cells synthesise PLA2-II in ulcerative colitis. The activity of the PLA2-II synthesis seems to be related to the degree of inflammation in the diseased bowel.

Adult↗
PubMed1997

Bone mineral density is reduced in patients with Crohn's disease but not in patients with ulcerative colitis: a population based study.

BACKGROUND: Patients with inflammatory bowel disease are at risk of developing metabolic bone disease. AIMS: To compare bone mineral density in patients with Crohn's disease with patients with ulcerative colitis and healthy subjects, and to evaluate possible risk factors for bone loss in inflammatory bowel disease. PATIENTS: 60 patients with Crohn's disease, 60 with ulcerative colitis, and 60 healthy subjects were investigated. Each group consisted of 24 men and 36 women. METHODS: Lumbar spine, femoral neck, and total body bone mineral density were measured by dual x ray absorptiometry (DXA), and Z scores were obtained by comparison with age and sex matched normal values. RESULTS: Mean Z scores were significantly lower in patients with Crohn's disease compared with patients with ulcerative colitis and healthy subjects. Patients with ulcerative colitis had bone mineral densities similar to healthy subjects. Use of corticosteroids, body mass index (BMI), and sex were significant predictor variables for bone mineral density in Crohn's disease. In ulcerative colitis only body mass index and sex were of significant importance. Disease localisation and small bowel resections had no influence on bone mineral density in patients with Crohn's disease. CONCLUSIONS: Patients with Crohn's disease have reduced bone mineral density. Several factors are probably involved, but the reduction is associated with corticosteroid therapy. When studying skeletal effects of inflammatory bowel disease, patients with Crohn's disease and those with ulcerative colitis should be evaluated separately.

Absorptiometry, Photon↗
PubMed1997

Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial.

BACKGROUND: Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. AIMS: To assess the efficacy of topical SCFA treatment in ulcerative colitis. PATIENTS AND METHODS: 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. RESULTS: Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (< 6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p < 0.02) in their clinical and histological activity scores. CONCLUSIONS: Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit.

Acute Disease↗
PubMed1997

Lack of association between an interleukin-1 receptor antagonist gene polymorphism and ulcerative colitis.

BACKGROUND: Recently, the association of a polymorphism in the gene coding for the anti-inflammatory cytokine interleukin-1 receptor antagonist with ulcerative colitis has been reported. This was interpreted as a possible genetic predisposition for severity of the inflammatory response. AIMS: To examine this polymorphism in a southern German population. SUBJECTS: The study included 234 healthy controls, 57 patients with ulcerative colitis, including 31 patients with pancolitis, 44 first degree healthy relatives of patients with ulcerative colitis, and 65 patients with Crohn's disease. METHODS: Genotypes were determined by a polymerase chain reaction amplification of the intron 2 fragment harbouring a variable number of tandem repeat nucleotide sequences. Amplification products were separated on a 2% agarose gel. RESULTS: The allele frequency for allele 2 was 27% in healthy controls, 28% in Crohn's disease, and 21% in patients with ulcerative colitis. The same allele frequency (21%) was found in a subgroup of patients with ulcerative colitis affecting the whole colon. Thus for allele 2 as well as for all other alleles, genotypes, or carriage rates no significant differences were found compared with controls. All allele frequencies in the control population were similar to those in earlier studies. CONCLUSIONS: No association of a polymorphism in the interleukin-1 receptor antagonist gene with ulcerative colitis could be identified in this southern German population. The findings of an earlier study reporting an increased frequency of allele 2, particularly in patients with pancolitis, could not be confirmed.

Adult↗
PubMed1999

Biased JH usage in plasma cell immunoglobulin gene sequences from colonic mucosa in ulcerative colitis but not in Crohn's disease.

BACKGROUND: Ulcerative colitis is an inflammatory disease of the colonic and rectal mucosa. Autoantibodies have been observed in ulcerative colitis which may have a role in the pathogenesis of the disease. Evidence also suggests that there is an hereditary predisposition towards the disease, although no individual genes have been identified. AIMS: This is a pilot study of immunoglobulin heavy chain genes (IgH) in ulcerative colitis to determine whether they have any particular genetic characteristics which may lead to a better understanding of the disease aetiology. SUBJECTS: Colonic or rectal tissue was obtained from five children with ulcerative colitis. Tissue was also obtained from five children with Crohn's disease and five children who did not have inflammatory bowel disease as controls. METHODS: B cells and IgD+ B cells were identified by immunohistochemistry on frozen sections. Areas of lamina propria containing plasma cells, and areas of IgD+ B cells were microdissected. The immunoglobulin genes were PCR amplified, cloned, and sequenced. Sequences were analysed for content of somatic mutations and composition of heavy chain. RESULTS: An increase in the use of JH6 and DXP'1, and a decrease in the use of JH4, gene segments in immunoglobulin genes from lamina propria plasma cells, and from virgin IgD+ B cells, was found in patients with ulcerative colitis. These biases were not present in the control groups. CONCLUSIONS: There is a fundamental difference in the immunoglobulin genes from patients with ulcerative colitis. Whether this is caused by a difference in content of immunoglobulin gene segments in the germline or a difference in the recombination mechanism is not known.

Adolescent↗
PubMed1999

Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis.

BACKGROUND: Decreased synthesis of the predominant secretory human colonic mucin (MUC2) occurs during active ulcerative colitis. AIMS: To study possible alterations in mucin sulphation and mucin secretion, which could be the cause of decreased mucosal protection in ulcerative colitis. METHODS: Colonic biopsy specimens from patients with active ulcerative colitis, ulcerative colitis in remission, and controls were metabolically labelled with [35S]-amino acids or [35S]-sulphate, chase incubated and analysed by SDS-PAGE, followed by quantitation of mature [35S]-labelled MUC2. For quantitation of total MUC2, which includes non-radiolabelled and radiolabelled MUC2, dot blotting was performed, using a MUC2 monoclonal antibody. RESULTS: Between patient groups, no significant differences were found in [35S]-sulphate content of secreted MUC2 or in the secreted percentage of either [35S]-amino acid labelled MUC2 or total MUC2. During active ulcerative colitis, secretion of [35S]-sulphate labelled MUC2 was significantly increased twofold, whereas [35S]-sulphate incorporation into MUC2 was significantly reduced to half. CONCLUSIONS: During active ulcerative colitis, less MUC2 is secreted, because MUC2 synthesis is decreased while the secreted percentage of MUC2 is unaltered. Furthermore, sulphate content of secreted MUC2 is unaltered by a specific compensatory mechanism, because sulphated MUC2 is preferentially secreted while sulphate incorporation into MUC2 is reduced.

Adolescent↗
PubMed1999

Molecular screening of patients with long standing extensive ulcerative colitis: detection of p53 and Ki-ras mutations by single strand conformation polymorphism analysis and differential hybridisation in colonic lavage fluid.

BACKGROUND: In patients with long standing ulcerative colitis at risk of developing malignancy, mutations of the p53 and Ki-ras gene were investigated in lavage solution obtained at surveillance colonoscopy. METHODS: DNA was isolated from 31 consecutive patients with total or subtotal ulcerative colitis and a disease duration of between seven and 26 years. Twenty seven control patients showed no macroscopic or microscopic inflammation on colonoscopy. Exons 5-8 of the p53 gene and exon 1 of the Ki-ras gene were amplified by polymerase chain reaction. Mutations of the p53 gene were detected by single strand conformation polymorphism analysis. Point mutations of the Ki-ras gene were hybridised on dot blots with oligonucleotides marked with digoxigenin. RESULTS: In all cases of ulcerative colitis and in all of the 27 control patients, wild type p53 and wild type Ki-ras could be detected. In four patients with ulcerative colitis, a mutation in exon 5 to 7 of the p53 gene was found, and two patients had a mutation of the Ki-ras gene (Gly to Asp-12, Gly to Val-12). None of these patients had dysplasia in serial biopsy specimens, and all but one had had the disease for more than 10 years. One control patient had a mutation. CONCLUSIONS: Mutations were more frequent in patients with long standing ulcerative colitis (19%) than in control patients (3%, p = 0.07). The technique may be useful for screening for early malignancy in ulcerative colitis.

Adult↗
PubMed1999

Restorative proctocolectomy for distal ulcerative colitis.

BACKGROUND: Chronic distal colitis may cause troublesome symptoms and alter quality of life. When medical treatment fails to control symptoms, patients and doctors are often reluctant to consider surgical resection because of the relatively small portion of the large bowel affected by the disease. AIM: To assess the outcome of restorative proctocolectomy (RP) in patients with distal colitis who required surgery for chronic debilitating symptoms and failed medical management. PATIENTS/METHODS: From 1986 to 1996, of 263 patients receiving RP for ulcerative colitis, 27 (16 men) were operated on for distal ulcerative colitis limited to the rectum and sigmoid colon. Bowel function and quality of life were compared before and one year after RP. RESULTS: The mean (SD) duration of ulcerative colitis was 11 (6) years. RP was performed at a mean age of 46 (10) years. All the pouches were J-shaped, and a diverting loop ileostomy was always performed. Mean (SD) hospital stay was 25 (10) days. Seven complications occurred in six patients. Previously unknown severe dysplasia was discovered on the colectomy specimen in two patients. After RP there was a significant decrease in mean (SD) daytime stool frequency (8.2 (4) v 4.7 (2), p<0.05), night-time stool frequency (2 (2) v 1 (1), p = 0.05), and the number of patients with urgency to defecate (26/27 v 1/27, p<0.001). Sex life was improved in eight patients, social life in 26, and professional life in eight. Twenty six patients were satisfied with the results, and 25 wished that they had received surgery earlier in the course of their disease. CONCLUSION: RP can improve bowel function and quality of life in patients with disabling chronic symptoms of distal ulcerative colitis.

Adult↗
PubMed2000

Fracture risk is increased in Crohn's disease, but not in ulcerative colitis.

AIMS: To study fracture rates and risk factors for fractures in patients with Crohn's disease and ulcerative colitis. METHODS: 998 self administered questionnaires were issued to members of the Danish Colitis/Crohn Association, and 1000 questionnaires were issued to randomly selected control subjects. 845 patients (84.5%) and 645 controls (65.4%) returned the questionnaire (p<0.01). 817 patients and 635 controls could be analysed. RESULTS: Analysis was performed on 383 patients with Crohn's disease (median age 39, range 8-82 years; median age at diagnosis 26, range 1-75 years), 434 patients with ulcerative colitis (median age 39, range 11-86 years; median age at diagnosis 29, range 10-78 years), and 635 controls (median age 43, range 19-93 years, p<0.01). The fracture risk was increased in female patients with Crohn's disease (relative risk (RR) = 2.5, 95% confidence interval (CI) 1.7-3.6), but not in male patients with Crohn's disease (RR = 0.6, 95% CI 0.3-1.3) or in patients with ulcerative colitis (RR = 1.1, 95% CI 0.8-1.6). An increased proportion of low energy fractures was observed in patients with Crohn's disease (15.7% versus 1.4 % in controls, 2p<0. 01), but not in patients with ulcerative colitis (5.4%, 2p=0.30). The increased fracture frequency in Crohn's disease was present for fractures of the spine, feet, and toes and fractures of the ribs and pelvis. Fracture risk increased with increasing duration of systemic corticosteroid use in Crohn's disease (2p=0.028), but not in ulcerative colitis (2p=0.50). CONCLUSIONS: An increased risk of low energy fractures was observed in female patients with Crohn's disease, but not in male patients with Crohn's disease or in patients with ulcerative colitis.

Adolescent↗
PubMed2000

Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival.

BACKGROUND: There is significant geographic variation in the reported incidence of ulcerative colitis. AIMS: To update the incidence and prevalence of ulcerative colitis in Olmsted County, Minnesota, examine temporal trends, and determine overall survival. PATIENTS: All Olmsted County residents diagnosed with ulcerative colitis between 1940 and 1993 (incidence cases), and all residents with ulcerative colitis alive on 1 January 1991 (prevalence cases). METHODS: Incidence and prevalence rates were adjusted using 1990 US census figures for whites. The effects of age, sex, and calendar year on incidence rates were evaluated using Poisson regression. Survival from diagnosis was compared with that expected for US north-central whites. RESULTS: Between 1940 and 1993, 278 incidence cases were identified, for an adjusted incidence rate of 7.6 cases per 100 000 person years (95% confidence interval (CI), 6.7 to 8.5). On 1 January 1991, there were 218 residents with definite or probable ulcerative colitis, for an adjusted prevalence rate of 229 cases per 100 000 (95% CI, 198 to 260). Increased incidence rates were associated with later calendar years (p<0.002), younger age (p<0.0001), urban residence (p<0.0001), and male sex (p<0.003). Overall survival was similar to that expected (p>0.2). CONCLUSIONS: The overall incidence rate of ulcerative colitis in Olmsted County increased until the 1970s, and remained stable thereafter. Incidence rates among men and urban residents were significantly higher. The prevalence rate in Rochester in 1991 was 19% higher than that in 1980. Overall survival was similar to that of the general population.

Adolescent↗
PubMed2000

Interleukin 10 gene transfer prevents experimental colitis in rats.

BACKGROUND: The development of colitis in interleukin 10 (IL-10) deficient mice, together with the known anti-inflammatory and immunomodulatory properties of this cytokine have prompted consideration of IL-10 as a treatment for inflammatory bowel disease (IBD). However, studies using hrIL-10 in IBD models have yielded inconsistent results. AIMS: To examine the therapeutic potential of overexpressing the IL-10 gene before and after the induction of experimental colitis in rats. METHODS: Gene transfer was achieved by intraperitoneal injection of non-replicating human type 5 adenovirus bearing the IL-10 gene, either 24 hours before or one hour after intrarectal administration of dinitrobenzene sulphonic acid in rats. Colonic damage and inflammation was assessed macroscopically and by measuring myeloperoxidase activity and leukotriene B4 concentrations. RESULTS: Gene transfer increased IL-10 protein in serum for up to six days. IL-10 gene transfer prior to colitis improved colitis macroscopically and histologically, and significantly reduced colonic myeloperoxidase activity and leukotriene B4 concentrations. In contrast, IL-10 gene transfer after the onset of colitis had no beneficial effect. CONCLUSIONS: Gene therapy using an adenovirus-IL-10 construct was successful in preventing but not in reversing experimental colitis in the rat.

Adenoviridae↗
PubMed2006

Comparison of RANTES expression in Crohn's disease and ulcerative colitis: an aid in the differential diagnosis?

BACKGROUND: RANTES (regulated on activation, normal T cell expressed and secreted) expression is increased in inflammatory bowel disease (IBD). RANTES is produced at higher levels in granulomatous conditions, so increased RANTES expression can be expected in Crohn's disease compared with ulcerative colitis. AIM: To compare RANTES expression between intestinal biopsy specimens of patients with Crohn's disease and those with ulcerative colitis. MATERIALS AND METHODS: A prospective study of patients presenting with lower gastrointestinal symptoms at the Bahrain Specialist Hospital from July 2004 to April 2005 was carried out. Endoscopic colonic biopsy specimens were taken from every patient and subjected to (a) routine haematoxylin and eosin staining examination by light microscopy, (b) immunohistochemistry for examination of RANTES protein expression by light microscopy and (c) in situ hybridisation for examination of RANTES mRNA expression by light microscopy. RANTES expression was assessed and quantified. RESULTS: 58 patients were enrolled to the study. Of them, 40 had IBD (21 had Crohn's disease and 19 had ulcerative colitis), 15 were controls with normal colonic biopsy results or non-inflammatory lesions and 3 had colonic inflammatory lesions other than IBD. RANTES expression in lymphocytes or histiocytes was significantly higher (p = 0.04) in new patients with ulcerative colitis than in those with Crohn's disease analysed by immunohistochemistry (IHC). CONCLUSION: RANTES expression in lymphocytes or histiocytes is significantly higher in patients with ulcerative colitis than in those with Crohn's disease. Hence, RANTES IHC can be an effective method for distinguishing between biopsy specimens of patients with ulcerative colitis from those of patients with Crohn's disease, where routine histological features are indeterminate. RANTES IHC may prove to be a useful technique for identifying early or equivocal granulomas.

Biomarkers↗
PubMed2002

Does patient knowledge affect the colorectal cancer risk in ulcerative colitis?

OBJECTIVES: Formal efforts to improve patient education are associated with fewer disease complications in a number of conditions. The possible relationship between knowledge about ulcerative colitis and its cancer risk, and the development of colorectal cancer using a previously developed and validated instrument-the Crohn's and colitis knowledge (CCKNOW) score-were investigated. METHODS: The 24 item CCKNOW questionnaire was mailed to patients known to have developed colorectal cancer as a complication of ulcerative colitis (cases) and to colitics from the Leicestershire inflammatory bowel disease patient database who had not developed cancer (controls). RESULTS: The mean (SD) CCKNOW scores for cases was 8.21 (3.02) and for controls was 8.27 (4.3). These scores did not differ significantly between cases and controls (difference 0.06, 95% confidence interval (CI) -1.7 to 1.5, p=0.9). There were four times as many members of the National Association of Crohn's and Colitis (NACC) in the control group compared with the cancer group and patients who are members of NACC achieve statistically significantly higher scores than non-members (11.6 v 7.8, p=0.05, 95% CI -0.1 to 7.6). However, after adjusting for NACC membership, the CCKNOW score did not appear to be associated with having developed cancer (odds ratio 1.04, 95% CI 0.92 to 1.18, p=0.5). CONCLUSIONS: The CCKNOW scores were comparable in cases and controls. Thus, in a retrospective study, no evidence has been demonstrated of an association between patient knowledge and the risk of developing colorectal cancer in patients with ulcerative colitis. However, knowledge may have been increased in cases as a direct result of having had colorectal cancer as a complication of ulcerative colitis.

Colitis, Ulcerative↗
PubMed1992

Indomethacin worsens and a leukotriene biosynthesis inhibitor accelerates mucosal healing in rat colitis.

The implication of leukotrienes as mediators of inflammation and recent evidence that prostaglandin analogues provide a beneficial effect during experimental colitis led to the speculation that (i) leukotrienes may be injurious and (ii) prostaglandins may be protective to colonic mucosa. Using a 2% acetic acid induced rat colitis model, we administered specific cyclooxygenase (indomethacin) and leukotriene biosynthesis inhibitors (MK-886) to examine the effect of endogenous prostaglandins and leukotrienes on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, net in vivo intestinal fluid absorption, and colonic PGE2 and LTB4 levels as measured by in vivo rectal dialysis. Indomethacin treatment prior to induction of colitis reduced endogenous mucosal PGE2 levels and exacerbated macroscopic ulceration and net fluid absorption. Addition of the exogenous PGE1 analogue misoprostol to the indomethacin-exacerbated colitis completely healed colonic macroscopic ulceration and inflammation but only partially improved fluid absorptive injury. The specific leukotriene biosynthesis inhibitor MK-886 administered prior to induction of colitis healed macroscopic ulceration and inflammation but not fluid absorptive injury. This mucosal reparative effect of MK-886 occurred at a dose that reduced colonic LTB4 synthesis while concomitantly enhancing PGE2 levels. Combining MK-886 with misoprostol treatment improved not only macroscopic ulceration and inflammation but also provided a synergistic effect that maintained net colonic fluid absorption at noncolitic control levels. These studies suggest that, during the induction of experimental colitis, endogenous prostaglandins play a pivotal role in providing a mucosal healing effect, and that leukotriene biosynthesis inhibitor may manifest part of its beneficial effect by shifting arachidonic acid metabolism towards production of prostaglandins.

Acetates↗
PubMed2003

Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-kappaB.

Butyrate enemas have been demonstrated to ameliorate inflammation in ulcerative colitis. The mechanism of this protective effect of butyrate is not known, and this study examines the effect of butyrate on epithelial function, inducible heat shock protein 70 (HSP70) expression, and NF-kappaB activation in experimental colitis. Colitis was induced in rats by oral dextran sulfate sodium (DSS) and by butyrate or saline enemas. Mucosal barrier function was assessed by electrical resistance and [14C]mannitol permeability. HSP70 production was determined by [35S]methionine labeling, Western blot analysis, and immunohistochemistry. Activation of heat shock factors (HSFs) and NF-kappaB was evaluated by EMSA. Butyrate showed a significant protection against the decrease in cell viability, increase in mucosal permeability, and polymorphonuclear neutrophil infiltration seen in DSS colitis. Butyrate inhibited HSP70 expression in DSS colitis and also inhibited the activation of HSF and NF-kappaB. Thus butyrate enema was found to be cytoprotective in DSS colitis, an effect partly mediated by suppressing activation of HSP70 and NF-kappaB.

Animals↗
PubMed2004

Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis.

The interleukin-2-deficient (IL-2(-/-)) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2(-/-) mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2(-/-) mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-kappaB (p65) activation with the inhibitory p50 form of NF-kappaB predominating in CEC in both the healthy and inflamed colon. Development of colitis was, however, associated with the activation of MAPK family members and upregulation of MyD88-independent signaling pathways characterized by increased caspase-1 activity and IL-18 production. These findings identify changes in TLR expression and signaling during the development of colitis that may contribute to changes in the host response to bacterial antigens seen in colitis.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a-/- mice.

P-glycoprotein, the product of the multidrug resistance protein 1 (MDR1) gene, is a xenobiotic transporter that may contribute to the physiology of the intestinal barrier. Twenty-five percent of mdr1a-deficient (mdr1a(-/-)) mice spontaneously develop colitis at variable ages when maintained under specific pathogen-free conditions. We hypothesized that this disease would result from epithelial dysfunction and that conventional housing would increase incidence and severity of the colitis phenotype. Wild-type congenic FVB (+/+) mice were maintained under the same conditions as controls. Knockout and wild-type mice were matched for age and gender and observed for signs of colitis. Colonic tissues from both groups of mice were examined for macroscopic and microscopic injury and for basal ion transport and transepithelial resistance (TER). Translocation of bacteria across the intestine was assessed by culturing the spleen and mesenteric lymph nodes. Protein analysis was performed by Western blot analysis. All mdr1a(-/-) mice developed weight loss and signs of colitis, whereas wild-type mice never showed such signs. Within the mdr1a(-/-) group, males consistently developed severe colitis earlier than females. Knockout mice showed increased basal colonic ion transport (females, 162.7 +/- 4.6 vs. 49.7 +/- 3.8 muA/cm(2); males, 172.6 +/- 5.6 vs. 54.2 +/- 3.1 muA/cm(2); P < 0.01) and decreased TER (females, 25.4 +/- 0.3 vs. 36.4 +/- 0.8 Omega.cm(2); males, 23.1 +/- 1.0 vs. 38.3 +/- 0.2 Omega.cm(2); P < 0.01) compared with wild-type mice. Barrier dysfunction was accompanied by decreased phosphorylation of tight junction proteins. Expression of cyclooxygenase-2 and inducible nitric oxide synthase in intestinal tissues was increased in the mdr1a(-/-) group (P < 0.01) and correlated with disease severity. Bacterial translocation was greater both in incidence (P < 0.01) and severity (P < 0.001) for the knockout group. With respect to all indexes studied, mdr1a(-/-) males performed worse than females. Our data support the hypothesis that alterations in the intestinal barrier alone, in the absence of immune dysfunction, may rapidly lead to colitis in the setting of a normal colonic flora.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Lactobacillus casei prevents the upregulation of ICAM-1 expression and leukocyte recruitment in experimental colitis.

Lactobacillus casei has been shown to attenuate the severity of experimental colitis. The objective of the present study was to determine whether the effects of L. casei on colitis are related to modulation of leukocyte recruitment into the inflamed intestine. Rats with a colonic segment excluded from fecal transit were surgically prepared. The segment was decontaminated with antibiotics and recolonized with normal flora isolated from the inflamed rat colon, associated or not to L. casei. Control and colitic [2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced] animals were studied. Leukocyte-endothelial cell interactions were characterized in the colonic microcirculation by intravital microscopy, and ICAM-1 and VCAM-1 expression was measured by the radiolabeled antibody technique. Compared with the noninflamed colonic segment, induction of colitis by TNBS provoked a marked increase in the number of leukocytes firmly adherent to the venular wall (0.5 +/- 0.1 vs. 2.1 +/- 0.6 leukocytes/100 mum, P < 0.01). Colonization with L. casei significantly reduced the number of adherent leukocytes (1.3 +/- 0.4 leukocytes/100 mum; P < 0.05) but did not affect the increased rolling interactions associated with the induction of colitis. Compared with the noncolitic group, induction of colitis was associated with a marked increase in ICAM-1 expression (117 +/- 4 vs. 180 +/- 3 ng antibody/g tissue) that was abrogated when the colitic segment was colonized by L. casei (117 +/- 3 ng antibody/g tissue, P < 0.05). However, L. casei administration did not modify VCAM-1 upregulation in colitic animals. L. casei attenuates leukocyte recruitment observed in experimental colitis induced by TNBS. This effect is possibly related to abrogation of ICAM-1 upregulation.

Animals↗