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PubMed1991

Lymphoid follicular hyperplasia--a distinctive feature of diversion colitis.

Diversion colitis refers to the inflammatory changes that occur in the defunctioned segment of the large intestine following diversion of the faecal stream. We report the histological features in the defunctioned rectums from seven patients: one each with severe constipation and Behçet's disease, two with Crohn's disease with rectal sparing and three with ulcerative colitis. The appearances of diversion colitis in a previously normal rectum are compared with diversion colitis with superimposed inflammatory bowel disease. Lymphoid follicular hyperplasia was found in all cases. This was marked in patients with inflammatory bowel disease, with or without initial rectal involvement. Other changes comprised surface epithelial degeneration and ulceration, mucosal inflammation including crypt abscesses, and crypt branching. Inflammatory and crypt changes were mild, except in ulcerative colitis where changes were marked and resembled those of the proximal colon. Lymphoid hyperplasia is a distinctive feature in diversion colitis. The term follicular proctitis, previously used to indicate chronic ulcerative colitis exclusively, should be re-examined.

Adult↗
PubMed2005

Disruption of the blood-brain barrier during TNBS colitis.

Well-documented central nervous system changes during colitis suggest possible alterations of blood-brain barrier (BBB) permeability, yet the integrity of the BBB has not been fully evaluated in experimental colitis. Our aim was to investigate whether trinitrobenzene sulphonic acid (TNBS) colitis was associated with an increase in the permeability of the BBB. Sprague-Dawley rats were given an intracolonic injection of saline or TNBS and studied 1, 2, 3, 7 and 21 days after treatment. The extravasation of endogenous immunoglobulin G, a large molecule, was not altered at any time after TNBS treatment. In contrast, significant increases in the BBB leakage of sodium fluorescein, a much smaller molecule, were observed 1 and 2 days after the induction of colitis, in and around the circumventricular organs; the organum vasculosum of the lamina terminalis, subfornical organ and median eminence of the hypothalamus. TNBS-treated rats also exhibited sodium fluorescein leakage in focal areas in the brain parenchyma. The expression of endothelial barrier antigen, a protein associated with the BBB, was reduced about 60% 48 h after the induction of colitis. This returned to control values by 3 weeks, when colitis had largely subsided. In conclusion, experimental colitis transiently increased permeability of the brain to small molecules through a mild disruption of the BBB.

Animals↗
PubMed1999

Increased intraluminal release of eosinophil granule proteins EPO, ECP, EPX, and cytokines in ulcerative colitis and proctitis in segmental perfusion.

OBJECTIVE: The role of the eosinophil granulocyte in bowel mucosa in inflammatory bowel disease still remains obscure. The present study was performed in order to elucidate the local eosinophil activity and activating cytokines in the inflamed lesions of colon and rectum in patients with ulcerative colitis and proctitis. METHODS: The activity of intestinal eosinophils with respect to the release of granule proteins was studied in 18 patients (10 with colitis and 8 with isolated proctitis) and 18 healthy controls, using intraluminal segmental perfusion of the sigmoid colon and rectum. The released amounts of eosinophil granule proteins: eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil protein X (EPX) to perfusion fluid were determined by radioimmunoassays. The intraluminal release of possible eosinophil priming cytokines granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 8 (IL-8), were analyzed by immunoassays. RESULTS: The mucosal release of ECP, EPO, and EPX was increased 10- to 20-fold in patients with colitis and proctitis compared with controls. The intraluminal release of GM-CSF and IL-8, was several-fold enhanced in patients with colitis and proctitis. We also found a correlation between all three eosinophil granule proteins and the levels of IL-8/GM-CSF in the sigmoidal segments of patients with colitis. CONCLUSIONS: We conclude that the increased release of ECP, EPO, and EPX to colorectal perfusion fluid indicate eosinophil involvement in the local disease in patients with colitis and proctitis. IL-8 and GM-CSF may play a role in eosinophil accumulation and priming in colitis.

Adult↗
PubMed2000

The SIBDQ: further validation in ulcerative colitis patients.

OBJECTIVE: The Inflammatory Bowel Disease Questionnaire (IBDQ) is an instrument that assesses quality of life in patients with inflammatory bowel disease. It has 32 items in four domains. The short form of the IBDQ (SIBDQ) was developed in Canadian Crohn's disease patients for use in clinical practice. Patients with ulcerative colitis might require a different form of the SIBDQ. Our aim was to design and validate a SIBDQ for patients with ulcerative colitis and to compare this to the Crohn's SIBDQ. METHODS: We recruited 122 patients with colitis as an initial sample. Using linear regression modeling, the 10 items that best predicted the total IBDQ score were identified. The colitis and Crohn's versions of the SIBDQ were compared by univariate linear regression with the total IBDQ score in two other cohorts of colitis patients. RESULTS: Ten items explained 97% of the variance of the total IBDQ score in our first cohort. These were items 1 and 9 (bowel); 7, 11, 21, 30 (emotional); 2 and 10 (systemic); and 12 and 28 (social). Only three items were shared with the Crohn's SIBDQ. The R2 for both SIBDQs with the total IBDQ score in the other cohorts were very high (> or =0.95), although the Colitis SIBDQ showed better internal consistency. CONCLUSIONS: The development of a SIBDQ for patients with ulcerative colitis did not reveal any clear advantage over the original version of the SIBDQ. Further studies are required to determine the role of the SIBDQ in routine clinical practice.

Attitude to Health↗
PubMed2000

Identification of a prodromal period in Crohn's disease but not ulcerative colitis.

OBJECTIVES: Irritable bowel syndrome, a common gastrointestinal diagnosis, has not been clearly studied in inflammatory bowel disease. Some of the residual symptoms in subjects treated with Crohn's disease and ulcerative colitis are thought to be related to irritable bowel syndrome. The aims of this study were 1) to describe the duration and nature of complaints before the diagnosis of Crohn's disease and ulcerative colitis (prodromal period), and 2) to determine the role of IBS in this prodromal period. METHODS: A total of 66 patients with confirmed inflammatory bowel disease were enrolled in the study. The subjects received a questionnaire to ascertain the nature and duration of symptoms preceding the diagnosis of Crohn's disease or ulcerative colitis, including features described under the Rome criteria for irritable bowel syndrome. RESULTS: Of the 66 subjects analyzed, 45 had Crohn's disease and 21 had ulcerative colitis. The prodromal period was 7.7 +/- 10.7 yr for Crohn's disease and 1.2 +/- 1.8 yr for ulcerative colitis (p < 0.05). Once patients meeting the Rome criteria for irritable bowel syndrome during the prodrome were excluded, the duration of the prodromal period (non-IBS) for ulcerative colitis dropped to 0.8 +/- 1.3 yr compared to 6.9 +/- 9.8 yr in the Crohn's disease group (p < 0.05). The symptoms of the non-IBS prodrome in subjects with Crohn's disease were bloating, diarrhea, stomach pain, heartburn, fever, weight loss, and fatigue. Further analysis demonstrated that subjects whose Crohn's disease initially began as colonic disease had a longer prodrome than with small bowel. In the non-IBS Crohn's group, there was also a correlation between the age at the time of diagnosis and the duration of prodrome (r = 0.67, p < 0.0001). CONCLUSIONS: There is a significant prodromal period before the time of diagnosis of Crohn's disease that is not found in ulcerative colitis even after exclusion of subjects with IBS.

Adult↗
PubMed2001

Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis.

OBJECTIVES: Cytomegalovirus infection has been reported as a cause of refractory inflammatory bowel disease, but no data are available on its prevalence in severe colitis. The aim of this study was to evaluate the prevalence and outcome of cytomegalovirus infection in a consecutive series of patients with severe steroid refractory colitis admitted to our department from 1997 to 1999. METHODS: Among 62 patients with severe colitis, 55 with ulcerative colitis and seven with Crohn's disease, 19 (30%) were resistant to intravenous steroids and bowel rest. In all of them, rectal biopsies were examined for cytomegalovirus (the flexible proctoscopy being performed without air insufflation and limited to the first 10 cm). Buffy coat preparation on leukocytes was also performed to detect systemic infection. If cytomegalovirus was not detected, cyclosporine was started. RESULTS: In seven (five with ulcerative colitis and two with Crohn's disease) out of 19 (36%) patients with refractory disease, cytomegalovirus was diagnosed in the rectal specimens as well as by buffy coat preparation. Five patients went into remission after antiviral treatment (three with ganciclovir and two with foscarnet). One patient did not respond and was operated on. In one patient, cytomegalovirus was found in the surgical specimen. CONCLUSIONS: Cytomegalovirus infection is a frequent cause of severe refractory colitis. Rectal biopsy should always be performed in severe steroid-resistant colitis.

Adult↗
PubMed2002

Lymphocytic colitis: clinical features, treatment, and outcomes.

OBJECTIVE: There are no reports of the clinical features or treatment outcomes in large series of patients with lymphocytic colitis, and it is not known whether treatments that appear to be beneficial in patients with collagenous colitis are also beneficial in lymphocytic colitis. We sought to analyze these issues in our patients with lymphocytic colitis. METHODS: All patients with biopsy-proven lymphocytic colitis evaluated at our institution between January 1, 1997, and December 31, 1999, were identified. Clinical features on presentation and treatment outcomes were abstracted from the medical records. RESULTS: A total of 170 patients with lymphocytic colitis were identified (median age 67 yr, 61% female). Diarrhea, bloating, rectal urgency, fecal incontinence, weight loss, concomitant autoimmune disorders, and aspirin or nonsteroidal anti-inflammatory drug use were common. Loperamide, diphenoxylate/atropine, and bismuth subsalicylate were effective therapies and were well tolerated. However, no therapy produced a complete response in more than 40% of patients. CONCLUSIONS: Lymphocytic colitis typically presents in elderly patients as chronic diarrhea. Nocturnal stools, urgency, and abdominal pain occur frequently, as do weight loss, fecal incontinence, and concomitant autoimmune disorders. Many empiric treatment options are used, but overall response rates are disappointing. Randomized controlled trials are needed to determine the optimum therapeutic approach to these patients.

Adolescent↗
PubMed2005

Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial.

BACKGROUND AND AIMS: Preliminary data have shown that delayed release oral mesalamine (Asacol) dosed at 4.8 g/day provided additional efficacy benefit compared to 1.6 g/day in patients with mildly to moderately active ulcerative colitis. Additionally, Asacol dosed at 2.4 g/day has been proved to be more effective than 1.6 g/day. Whether 4.8 g/day of mesalamine (dosed with an investigational 800 mg tablet) is more effective than Asacol 2.4 g/day (dosed with a 400 mg tablet) in patients with moderately active ulcerative colitis is unknown. METHODS: A randomized, double-blind, controlled trial (ASCEND II) was conducted to evaluate the efficacy of 4.8 g/day of mesalamine in adults with active ulcerative colitis. Three hundred eighty-six patients with mild to moderate ulcerative colitis were randomized for treatment with mesalamine 2.4 g/day (400 mg tablet) or 4.8 g/day (800 mg tablet) for 6 wk. The primary efficacy population was 268 patients with moderately active ulcerative colitis treated with 2.4 g/day (n = 139) or 4.8 g/day (n = 129). The primary endpoint was the proportion of patients in each treatment group that achieved overall improvement ("treatment success," defined as either complete remission or a clinical response to therapy) from baseline at week 6. RESULTS: Seventy-two percent of patients receiving 4.8 g/day of mesalamine for moderate ulcerative colitis (89/124 patients) achieved treatment success at week 6, compared with 59% of those who received 2.4 g/day (77/130 patients) (p= 0.036). Both regimens were well tolerated. Adverse events and clinically significant changes in laboratory results were similar in both treatment groups. CONCLUSIONS: Patients with moderately active ulcerative colitis treated with 4.8 g/day of mesalamine (800 mg tablet) are significantly more likely to achieve overall improvement at 6 wk compared to patients treated with 2.4 g/day.

Administration, Oral↗
PubMed2006

Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data.

BACKGROUND: Ischemic colitis and serious complications of constipation have been reported in association with the use of alosetron, which is approved for women with severe diarrhea-predominant IBS who have failed conventional therapies. This systematic review calculated the incidence of these adverse events in alosetron-using patients in clinical trials and post-marketing surveillance. METHODS: A panel of experts in epidemiology and functional bowel disorders reviewed clinical trial report forms and FDA MedWatch forms of each reported case of ischemic colitis or serious complications of constipation. Experts were blinded about whether patients used alosetron or placebo. Using pre-specified criteria, experts rated the likelihood of an accurate diagnosis and an association between medication use and adverse events. Cases that were not consistent with the reported diagnosis or not possibly associated with medication use were eliminated from calculation of incidence rates of adverse events. RESULTS: Pooled data from clinical trials indicate an increased rate of ischemic colitis among alosetron-using patients compared to placebo-using patients (0.15%vs 0.0%, respectively, p = 0.03), but there was no significant difference in the rate of serious complications of constipation. All (19/19) alosetron-using patients with ischemic colitis had reversible colitis without long-term sequelae. Based on post-marketing surveillance data, the post-adjudication rate of ischemic colitis is 1.1 per 1,000 patient-years of alosetron use and the rate of serious complications of constipation is 0.66 per 1,000 patient-years of alosetron use. CONCLUSION: The incidence of ischemic colitis and serious complications of constipation is very low and is rarely associated with long-term sequelae or serious morbidity.

Carbolines↗
PubMedDate not supplied

Expression profiling of apoptosis-related genes in enterocytes isolated from patients with ulcerative colitis.

Apoptosis regulation has been implicated as a main cause of epithelial dysfunction in patients with ulcerative colitis. Apoptosis can be divided into distinct pathways, which depend on the expression of a large number of apoptosis-related genes. The aim was to elucidate which pathways are dominant in normal and inflamed colonic epithelial cells. An apoptosis-specific gene array expression profiling system of 96 genes was used to determine the expression profile of apoptosis-related genes. Epithelial cells isolated from three patients with active ulcerative colitis were pooled and compared to pooled epithelial cells isolated from three control subjects. Genes found to be three-fold or more overexpressed in ulcerative colitis were subsequently analysed by PCR in a larger population (10 patients with ulcerative colitis, 8 control subjects). Selected genes found not to be regulated were additionally tested by PCR in the same population. Six genes were found to be highly expressed in epithelial cells from both controls and ulcerative colitis patients. These included Bcl-2 antagonist/killer, B lymphoid tyrosine kinase, caspase 14, Harakiri, tumour necrosis factor (TNF) receptor 2, and TNF receptor-associated factor 1 (TRAF1). Three genes were found to be upregulated in ulcerative colitis (p<0.01): caspase 1 and 5, and inhibitor of apoptosis protein 2 (c-IAP2). Both receptor- and mitochondrion-dependent apoptosis pathways are well expressed in enterocytes. Mainly activation-dependent and cytoprotective genes were upregulated in ulcerative colitis.

Adolescent↗
PubMed1999

Colitis in transgenic and knockout animals as models of human inflammatory bowel disease.

Spontaneous colitis in knockout (KO) and transgenic rodents provides experimental models to study the development of mucosal inflammation and inflammatory bowel disease (Crohn's disease and ulcerative colitis). Genetic and environmental factors, particularly the normal enteric flora, are important factors in the development of mucosal inflammation. The normal mucosal homeostasis is disrupted when there is either cytokine imbalance, abrogation of oral tolerance, alteration of epithelial barrier and function or loss of immunoregulatory cells. Some but not all immunodeficiencies, in the appropriate setting, lead to colitis. CD4+ T cells have been identified as the pathogenic T cells in colitis, which mediate inflammation by either the Th1 or the Th2 pathway. The Th1 pathway dominates most colitis models and in Crohn's disease. In contrast, the colitis in TCR alpha KO mice shares many features of ulcerative colitis including the dominance of Th2 pathway in colonic inflammation. A major benefit of these models is in the development of therapeutic strategies for the treatment of inflammatory bowel disease.

Animals↗
PubMed2003

Compromised neuroimmune status in rats with experimental colitis.

In colitis, chronic and recurrent inflammation is associated with a breakdown in host defence mechanisms that leads to local and systemic infection. Whether this is due to a compromised neuroimmune response has not been studied. Our aim was to determine if colitis altered the host neuroimmune response as reflected in either body temperature rhythm or the febrile responses to lipopolysaccharide (LPS). Body temperature was monitored by telemetry from conscious, unrestrained male rats treated with trinitrobenzene sulphonic acid or saline. Twenty-six days after initial induction, colitis was reactivated. Animals were given LPS (50 microg kg-1 Escherichia coli LPS) during colitis and after reactivation. At the peak of colitis, treated rats showed a disruption of circadian body temperature rhythm, manifested as day-time fever followed by night-time hypothermia. In response to LPS, controls displayed a characteristic fever, whereas treated animals had a significantly reduced fever and low plasma levels of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha). During reactivation of colitis, treated animals did not mount a fever or exhibit increased plasma levels of IL-6 and TNF-alpha after LPS. We conclude that experimental colitis is associated with a compromised neuroimmune status.

Animals↗
PubMed2004

Endotoxin-mediated disturbance of hepatic cytochrome P450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis.

Hepatobiliary abnormalities have been described in patients with chronic inflammatory bowel diseases. Hepatic cytochrome P450 (P450)-dependent drug-metabolizing enzyme activities and susceptibility to a hepatotoxin, d-galactosamine, were determined in rats with dextran sulfate sodium (DSS)-induced colitis to assess whether liver function is affected in the model of inflammatory bowel disease. Colitis was induced by treatment of rats with 3% DSS in drinking water for 7 days. Liver microsomes for enzyme activities and serum for biological analysis were prepared from the rats with colitis, along with untreated and lipopolysaccharide (LPS)-treated rats. Other rats received intraperitoneal injection of d-galactosamine to assess their susceptibility to the toxin-induced liver injury. Treatment of rats with DSS resulted in not only colitis but also decreases in hepatic P450-dependent drug-metabolizing enzyme activities. Elevated endotoxin was found in portal blood, which was not associated with liver injury. The potency and the isoform selectivity in the suppression of the P450 enzymes by DSS treatment were similar to those of LPS-treated rats. Coadministration of antibiotics, polymyxin B or metronidazole, with DSS protected rats from decreases in some but not all P450 enzyme activities, indicating partial involvement of bacterial endotoxin in the P450 decreases. The rats with colitis were less susceptible than untreated rats to d-galactosamine-induced liver injury and TNF-alpha production, suggesting development of endotoxin tolerance in DSS-colitis. In conclusion, these results suggest that the DSS-colitis leads to endotoxin-mediated down-regulation of hepatic P450 enzymes and protection against d-galactosamine-induced liver injury, probably due to endotoxin tolerance.

Administration, Oral↗
PubMed1969

Cellular hypersensitivity to components of intestinal mucosa in ulcerative colitis and Crohn's disease.

The migration of peripheral leucocytes in vitro is examined in 36 patients with ulcerative colitis, in 34 patients with Crohn's disease, in 12 patients with ulcerative colitis or Crohn's disease, and in 31 patients with other gastrointestinal disorders. In a majority of the patients with ulcerative colitis extracts of foetal, colonic, and jejunoileal mucosa inhibit migration of leucocytes. A similar reactivity is seldom seen in Crohn's disease. Extracts of liver, kidney, and adrenal gland do not inhibit the migration. The reactivity of the ulcerative colitis group was found to be significantly different from that in controls and in the Crohn group, whereas the Crohn group did not differ significantly from the controls. The examination thus reveals a biological difference between ulcerative colitis and Crohn's disease, which are otherwise separable mainly on nosological criteria. The finding of a similar inhibition of leucocyte migration in five out of 31 patients with miscellaneous gastrointestinal disorders unrelated to ulcerative colitis and Crohn's disease was inconclusive. An antigen-induced inhibition of leucocyte migration has been shown in vitro to be a correlate of cellular hypersensitivity. The immunological mechanisms behind the present system are discussed, and it is concluded that the reactivity observed probably indicates the existence in ulcerative colitis of a state of cellular hypersensitivity to components of normal foetal, colonic, and jejunoileal mucosa.

Adolescent↗
PubMed1970

Incidence and clinical significance of lactose malabsorption in ulcerative colitis and Crohn's disease.

The incidence of lactose malabsorption was investigated in 85 patients with ulcerative colitis and 71 patients with Crohn's disease by means of lactose tolerance tests and disaccharidase determinations in small intestinal mucosa. Eight patients with ulcerative colitis (9%) and four with Crohn's disease (6%) had lactose malabsorption. A control group displayed a similar incidence. It is concluded that lactose malabsorption is not particularly common in ulcerative colitis and Crohn's disease. If it is present, its aetiology seems to be unrelated to the intestinal disease. Transitional lactose malabsorption was detected in two cases during a relapse of ulcerative colitis. Institution of a lactose-free (or lactose-poor) diet was an important supporting measure in seven patients who were unaware of their milk intolerance, in particular in two with ileostomy. Therefore, it is recommended that a lactose tolerance test should always be performed in patients with ulcerative colitis or Crohn's disease.Twenty-one patients with ulcerative colitis and nine with Crohn's disease, none of whom had lactose malabsorption, were placed on milk-free diets. A beneficial effect was noticed in five of the patients with ulcerative colitis, and in three of those with Crohn's disease. The mechanism is unknown. Evidence is presented that milk allergy is not responsible for the beneficial effect of a lactosefree diet in patients with associated lactose malabsorption.

Adolescent↗
PubMed2004

Epidemiology of appendicectomy in primary sclerosing cholangitis and ulcerative colitis: its influence on the clinical behaviour of these diseases.

BACKGROUND AND AIMS: Appendicectomy and smoking are environmental factors that are known to influence ulcerative colitis (UC). The phenotype of UC is different in patients with coexistent primary sclerosing cholangitis (PSC). This study investigates the interaction of appendicectomy and PSC on the epidemiology and clinical behaviour of colitis. METHODS: Patients were from the Brisbane IBD Research Group database. Controls were from the Australian twin registry. Seventy eight PSC-inflammatory bowel disease (PSC-IBD) patients, 12 pure PSC, and 294 UC patients were matched with 1466 controls by sex and birth cohort that comprised randomly selected twins from each twin pair. The effects of appendicectomy, smoking, or PSC on the onset of disease, disease extent, disease severity (as identified by immunosuppression-colectomy or liver transplant), and disease related complications (high grade dysplasia, colorectal cancer, or cholangiocarcinoma) were investigated using univariate and multiple logistic regression analyses. RESULTS: PSC-IBD patients had a more extensive colitis than UC patients (p<0.0001) but required less immunosuppression (p = 0.007), which was independent of disease extent. They were more likely to have high grade dysplasia or colorectal cancer (p = 0.029) than UC patients. Appendicectomy rates in the PSC groups were not different from the control groups (p = 0.72, 0.76), which was in sharp contrast with UC where the rate was four times less (p = 0.0001). Prior appendicectomy appeared to be associated with an approximate five year delay in the onset of intestinal (PSC-IBD or UC) or hepatic (PSC) disease, which was independent of smoking. Appendicectomy did not independently alter the extent or severity of disease in PSC. In contrast, prior appendicectomy in UC was associated with more extensive disease but with a lesser requirement for immunosuppression or colectomy for the treatment of colitis (p = 0.004). There were trends for high grade dysplasia or colorectal cancer with appendicectomy in both PSC-IBD and UC. Although these trends were not statistically significant, colorectal cancer appeared more frequent with appendicectomy in a meta-analysis of the available UC data from this and another Australian study. CONCLUSIONS: In contradistinction to UC, appendicectomy did not significantly influence the prevalence of the PSC groups, or the extent of colitis in PSC-IBD, but as with UC, did appear to delay their onset. The extensive milder colitis, which is characteristic of PSC-IBD, relates to other poorly understood factors. Further prospective studies are required to determine any influence of appendicectomy on the extent of colitis in IBD and an associated dysplasia or colorectal cancer.

Adult↗
PubMed2006

Acute distal colitis impairs gastric emptying in rats via an extrinsic neuronal reflex pathway involving the pelvic nerve.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease often present with abnormal gut motility away from the inflammatory site. We studied remote motility disturbances and their pathophysiology in a rat model of colitis. METHODS: Colitis was induced 72 h prior to experiments using trinitrobenzene sulphate (TNBS) instillation. Inflammation was verified using histology and myeloperoxidase (MPO) measurements. To assess gut motility, we determined gastric emptying, distal front and geometric centre (GC) of intestinal transit 30 min after intragastric administration of a semiliquid Evans blue solution. The effects of hexamethonium (20 mg/kg), capsaicin (125 mg/kg) and pelvic nerve section on colitis induced motility changes were evaluated. c-Fos expression was studied in the pelvic nerve dorsal root ganglion (DRG) S1. RESULTS: Colitis reduced gastric emptying from 38.4 (3.6)% in controls to 22.7 (4.4)% in TNBS treated rats in the absence of local gastric inflammation. Colitis had no effect on the distal front or on the geometric centre of small intestinal transit. Hexamethonium reduced gastric emptying in controls to 26.3 (4.1)% but restored it to 35.8 (4.4)% in TNBS treated rats. Capsaicin significantly impaired gastric emptying in controls from 33.1 (5.2)% to 9.5 (3.3)% while this effect was less pronounced in TNBS treated rats (from 19.2 (2.3)% to 11.5 (3.8)%; NS). In TNBS treated rats, pelvic nerve section completely restored gastric emptying from 19.8 (5.3)% to 52.5 (6.3)% without any effect on gastric emptying in control rats. TNBS colitis induced de novo c-Fos expression in the DRG S1. CONCLUSIONS: Experimental colitis in rats delays gastric emptying via a neuronal pathway involving pelvic afferent nerve hyperactivity.

Acute Disease↗
PubMed2007

G protein-coupled receptor kinase 6 controls chronicity and severity of dextran sodium sulphate-induced colitis in mice.

BACKGROUND: Infiltration of inflammatory cells into the colon plays an important role in the onset and course of inflammatory bowel disease. G-protein-coupled receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G-protein-coupled receptors, including those involved in the migration of inflammatory cells. Therefore, it is hypothesised that GRK6 plays a role in determining the course of inflammation. AIM: To analyse the role of GRK6 in the course of dextran sodium sulphate (DSS)-induced colitis. METHODS: Colitis was induced by administering 1% DSS in drinking water to GRK6(-/-), GRK6(+/-) and wild-type (WT) mice for 6 days. The severity of colitis was assessed on the basis of clinical signs, colon length and histology. Moreover, keratinocyte-derived chemokine (KC) levels, granulocyte infiltration, interleukin 1beta (IL1beta), CD4, CD8 and forkhead box protein P3 (FoxP3) expression in the colon were determined. In addition, regulatory T cell function in WT and GRK6(-/-) mice was analysed. The chemotactic response of granulocytes to colon culture supernatants was assessed using a transendothelial migration assay. RESULTS: The severity of colitis was increased in GRK6(-/-) and GRK6(+/-) mice and was accompanied by increased KC levels and increased granulocyte infiltration. Moreover, the chemotactic response of GRK6(-/-) granulocytes to supernatants of colon cultures was enhanced. Interestingly, the WT mice completely recovered from colitis, whereas the GRK6(-/-) and GRK6(+/-) mice developed chronic colitis, which was accompanied by increased IL1beta and CD4 expression and decreased FoxP3 expression. Moreover, regulatory T cell function was impaired in the GRK6(-/-) mice. CONCLUSIONS: The intracellular level of GRK6 is an important factor in determining the onset, severity and chronicity of DSS-induced colitis.

Acute Disease↗