Tryggve Ljung

Increased luminal nitric oxide in inflammatory bowel disease as shown with a novel minimally invasive method

BACKGROUND The production of nitric oxide (NO) is increased in ulcerative colitis, as shown by bioassays of NO synthase activity in mucosal biopsy specimens. We wanted to develop a less invasive method for measurement of NO directly in the rectum in patients with inflammatory bowel disease (IBD). METHODS We studied 10 patients with active ulcerative colitis, 6 with active Crohns disease, 6 with non-active ulcerative colitis, and 24 controls without inflammation A tonometer balloon catheter was inserted in the rectum and inflated with 5 ml of NO-free air. After 15 min of incubation the sample was extracted, and the NO concentration was immediately analysed with a chemiluminescence technique. RESULTS Patients with active disease had greatly increased concentrations of NO in the rectum as compared with controls and patients with non-active disease. CONCLUSIONS During inflammation in the large intestine increased amounts of NO are released from the mucosa. Measurements of NO directly in the rectum could be of help in further understanding the role of this gas in IBD. Moreover, it is tempting to speculate that this minimally invasive method could be clinically useful as a diagnostic tool and in monitoring the effect of therapy.

Endotoxin actions on myoelectric activity, transit, and neuropeptides in the gut role of nitric oxide

The lipopolysaccharide (endotoxin) ofgram-negative bacteria has systemic effects in animalsand man. Our aim was to investigate the effects of E.coli lipopolysaccharide on motility and transit through the small intestine in rats and to analyzeplasma and tissue concentrations of intestinalneuropeptides. When lipopolysaccharide (20–160μg/kg) was administered intravenously, the migratingmyoelectric complex was replaced by spike burstsaccompanied by rapid transit. Tissue concentrations ofsubstance P and neurokinin A decreased, while plasmalevels of calcitonin gene-related peptide increased.Nω-Nitro-L-arginine, Nω-L-arginine methyl ester,dexamethasone, or indomethacin prevented these changesin myoelectric activity and tissue contents ofneuropeptides. All of these compounds, exceptindomethacin, prevented the increased rate of transit. Thus,lipopolysaccharide changes motility through the nitricoxide and arachidonic pathways, resulting in rapidtransit through the gut.

Rectal Mucosal Nitric Oxide in Differentiation of Inflammatory Bowel Disease and Irritable Bowel Syndrome

BACKGROUND & AIMS Differentiating patients with functional bowel disorders from those with inflammatory bowel disease (IBD) can be difficult. Rectal luminal levels of nitric oxide (NO) are greatly increased in IBD. To further evaluate this disease marker, we compared NO in patients with irritable bowel syndrome (IBS) with those found in patients with active IBD and in healthy control subjects. METHODS Rectal NO was measured with chemiluminescence technique by using a tonometric balloon method in 28 healthy volunteers, 39 patients with IBS, 86 with IBD (Crohns disease and ulcerative colitis), and 12 patients with collagenous colitis. In addition, NO was measured before and after a 4-week treatment period in patients with active ulcerative colitis and repeatedly during 2 weeks in healthy volunteers. RESULTS NO was low in healthy control subjects (median, 45; 25th-75th percentile, 34-64 parts per billion [ppb]), and variations over time were small. In IBS patients NO was slightly increased (150, 53-200 ppb; P < .001), whereas patients with active IBD or collagenous colitis had greatly increased NO levels (3475, 575-8850 ppb, and 9950, 4475-19,750 ppb, respectively; P < .001). With a cutoff level of 250 ppb, NO had a sensitivity of 95% and a specificity of 91% in discriminating between active bowel inflammation and IBS. Rectal NO correlated with disease activity in IBD and collagenous colitis and decreased markedly in IBD patients responding to anti-inflammatory treatment. CONCLUSIONS Rectal NO is a minimally invasive and rapid tool for discriminating between active bowel inflammation and IBS and a possibly useful add-on for monitoring patients with IBD.

Granulocyte, monocyte/macrophage apheresis for inflammatory bowel disease: The first 100 patients treated in Scandinavia

Objective. Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohns disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated. Material and methods. Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5–30). Results. The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohns disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohns disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7). Conclusions. Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.

Increased Nitric Oxide in Infective Gastroenteritis

Nitric oxide (NO) production is increased in several inflammatory disorders, although the role of this gas is not clear. The purpose of this study was to determine whether luminal NO in the intestine is increased in infective gastroenteritis. Rectal gas was sampled in 17 patients with gastroenteritis and 10 healthy volunteers, with balloon catheters made of 100% silicone and analyzed for NO by chemiluminescence. Plasma nitrate and nitrite levels were determined by capillary electrophoresis. Rectal NO was (mean+/-SEM) 9441+/-3126 parts per billion (ppb) in the patients and 74+/-13 ppb in controls (P<.0001). There was no individual overlap. Plasma nitrite but not nitrate was significantly increased in patients compared with controls. These data indicate that luminal NO is greatly increased in gastroenteritis. The high levels of NO are easily measurable by rectal sampling, and measurement of luminal NO seems to be useful for evaluating local NO production in the gut in health and disease.

Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease: comparison with peptide YY.

Background and aim Glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) are produced in endocrine L-cells of the intestine and secreted in response to food intake. GLP-2 has a trophic effect on the intestinal epithelium, whereas PYY has pro-absorptive effects. It can be speculated that, in inflammatory bowel disease (IBD), the production and secretion of GLP-2 and PYY could be affected as a part of a regulatory mechanism. Therefore, tissue levels and meal-stimulated secretion of GLP-2 and PYY were studied in IBD patients and compared to controls. Methods Outpatients with IBD and control patients were included. Mucosal biopsies were taken from the ileum and colon and the content of GLP-2 and PYY was measured. After colonoscopy the patients took a mixed meal and plasma was collected for 90 min for plasma measurements of GLP-2 and PYY. Results Tissue levels of GLP-2 in control patients were highest in the terminal ileum (407±82 pmol/g tissue, n=10), whereas PYY was highest in the rectum (919±249 pmol/g tissue, n=10). In IBD patients with acute inflammation, the content of GLP-2 was similar to controls, whereas PYY was decreased to 72.1±17.7% (P=0.03, n=13) of control values. Neither the fasting plasma levels nor the meal responses of GLP-2 and PYY differed between controls and IBD patients. Conclusion The similar responses of GLP-2 and PYY in patients and controls do not support the suggestion that L-cell secretion is altered in IBD. The decreased tissue PYY concentrations may contribute to the diarrhoea of some of these patients.

Rectal nitric oxide assessment in children with Crohn disease and ulcerative colitis. Indicator of ileocaecal and colorectal affection.

BACKGROUND Nitric oxide (NO) production is increased in inflammatory bowel disease (IBD). Measurements of luminal NO in Crohn disease and ulcerative colitis have revealed that levels are increased during active disease. We aim to evaluate whether rectal measurements of NO can reveal active disease of the colon as well as ileum. METHODS Sixteen children with active Crohn disease in the ileocaecal or colorectal regions of the gut and 6 children with active ulcerative colitis were compared to a group of 14 healthy children. Gaseous samples for analysis of luminal NO were collected using a Foley catheter inserted into rectum. The balloon of the catheter was filled with NO-free air and incubated for 10 min. After aspiration, samples were analysed using chemiluminescence. Values are expressed as median and range. RESULTS In healthy children, rectal NO values were 60 (0-275) ppb. In children with Crohn disease of the colorectal region, NO concentrations were 5,675 (300-49,350) ppb (P < 0.001), while those with Crohn disease of the ileocaecal region had NO levels of 2,625 (300-15,000) ppb (P < 0.01). In children with ulcerative colitis, NO values of 5,500 (950-34,000) ppb were found (P < 0.001). CONCLUSION Rectal NO levels are greatly increased in children with IBD. Highest values were found in patients with colorectal engagement, but rectal NO was increased also in ileocaecal disease. Rectal sampling of luminal NO is a simple and minimally invasive method and should be considered a diagnostic tool for intestinal inflammatory activity in children regardless of primary disease location.Background: Nitric oxide (NO) production is increased in inflammatory bowel disease (IBD). Measurements of luminal NO in Crohn disease and ulcerative colitis have revealed that levels are increased during active disease. We aim to evaluate whether rectal measurements of NO can reveal active disease of the colon as well as ileum. Methods: Sixteen children with active Crohn disease in the ileocaecal or colorectal regions of the gut and 6 children with active ulcerative colitis were compared to a group of 14 healthy children. Gaseous samples for analysis of luminal NO were collected using a Foley catheter inserted into rectum. The balloon of the catheter was filled with NO-free air and incubated for 10 min. After aspiration, samples were analysed using chemiluminescence. Values are expressed as median and range. Results: In healthy children, rectal NO values were 60 (0-275) ppb. In children with Crohn disease of the colorectal region, NO concentrations were 5,675 (300-49,350) ppb (P < 0.001), while those with Crohn disease of the ileocaecal region had NO levels of 2,625 (300-15,000) ppb (P < 0.01). In children with ulcerative colitis, NO values of 5,500 (950-34,000) ppb were found (P < 0.001). Conclusion: Rectal NO levels are greatly increased in children with IBD. Highest values were found in patients with colorectal engagement, but rectal NO was increased also in ileocaecal disease. Rectal sampling of luminal NO is a simple and minimally invasive method and should be considered a diagnostic tool for intestinal inflammatory activity in children regardless of primary disease location.

Increased rectal nitric oxide in children with active inflammatory bowel disease.

Background Luminal nitric oxide increases in ulcerative colitis and Crohn disease. The authors have previously used a minimally invasive method to demonstrate increased luminal nitric oxide in ulcerative colitis and Crohn disease of the colon. The aim of the current study was to determine whether this method could be applied to identify inflammatory activity in ulcerative colitis and Crohn disease in children. Methods Thirty-six children (18 of whom had active disease) with inflammatory bowel disease localized to the colon were studied. The control group comprised 12 healthy children. To measure nitric oxide, a silicon catheter with an inflatable balloon was inserted into the rectum and inflated with 10 mL of nitric oxide–free air. After a 10-minute incubation time, the air was withdrawn and nitric oxide concentrations were immediately analyzed using a chemiluminescence technique. Results Children with active ulcerative colitis and Crohn disease of the colon had greatly increased luminal nitric oxide concentrations in the rectum (8,840 ± 5,120 and 15,170 ± 4,757 parts per billion [ppb], respectively) compared with controls (77 ± 17 ppb) (P < 0.001). Children with nonactive ulcerative colitis or Crohn disease displayed low concentrations of rectal nitric oxide (356 ± 110 and 188 ± 55 ppb, respectively), which was not different from that of healthy controls. Conclusion Rectal nitric oxide measurement is a feasible and useful method for monitoring disease activity in inflammatory bowel disease, especially in children.

Increased rectal nitric oxide in coeliac disease after local challenge with gluten.

Background: Coeliac disease is an inflammatory disorder characterized by reversible atrophy of small intestinal villi following the ingestion of gluten. Earlier studies indicate that the inflammatory response to gluten may occur also very distally in the gastrointestinal tract. The aim of this study was to evaluate whether rectal challenge with gluten would trigger an increased local production of the gas nitric oxide (NO), a novel marker of intestinal inflammation. Methods: Rectal challenge with partially digested gluten was performed in 20 patients with treated coeliac disease and in 13 healthy controls. Luminal levels of NO were measured in the rectum at 0, 8 and 24 h using a chemiluminescence technique. Results:BACKGROUND Coeliac disease is an inflammatory disorder characterized by reversible atrophy of small intestinal villi following the ingestion of gluten. Earlier studies indicate that the inflammatory response to gluten may occur also very distally in the gastrointestinal tract. The aim of this study was to evaluate whether rectal challenge with gluten would trigger an increased local production of the gas nitric oxide (NO), a novel marker of intestinal inflammation. METHODS Rectal challenge with partially digested gluten was performed in 20 patients with treated coeliac disease and in 13 healthy controls. Luminal levels of NO were measured in the rectum at 0, 8 and 24 h using a chemiluminescence technique. RESULTS In patients with coeliac disease mean rectal NO increased from 235+/-90 parts per billion (ppb) at 0 h to 4965+/-1653 ppb at 24 h (P < 0.005). In the control group there was no significant increase. One control subject responded with high NO levels at 24 h and the same individual tested positive for anti-endomysium IgA antibodies. Subsequent duodenal biopsing showed substantial villusatrophy. CONCLUSIONS Rectal challenge with gluten results in increased luminal levels of NO in a group of patients with treated coeliac disease. Further studies are needed to evaluate the role of NO in coeliac disease and the potential usefulness of rectal NO measurements in aiding diagnosis of this intestinal disorder.

Early changes in rectal nitric oxide and mucosal inflammatory mediators in Crohn's colitis in response to infliximab treatment.

Background Treatment with tumor necrosis factor‐α monoclonal antibody (infliximab) reduces clinical activity and intestinal inflammation in Crohn’s disease.