Ferenc Izbéki

Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity

Objectives: Diarrhoea-predominant irritable bowel syndrome (IBS-D) is characterised by elevated colonic lumenal serine protease activity. The aims of this study were (1) to investigate the origin of this elevated serine protease activity, (2) to evaluate if it may be sufficient to trigger alterations in colonic paracellular permeability (CPP) and sensitivity, and (3) to examine the role of the proteinase-activated receptor-2 (PAR-2) activation and signalling cascade in this process. Patients and methods: Faecal enzymatic activities were assayed in healthy subjects and patients with IBS, ulcerative colitis and acute infectious diarrhoea. Following mucosal exposure to supernatants from control subjects and IBS-D patients, electromyographic response to colorectal balloon distension was recorded in wild-type and PAR-2–/– mice, and CPP was evaluated on colonic strips in Ussing chambers. Zonula occludens-1 (ZO-1) and phosphorylated myosin light chain were detected by immunohistochemistry. Results: The threefold increase in faecal serine protease activity seen in IBS-D patients compared with constipation-predominant IBS (IBS-C) or infectious diarrhoea is of neither epithelial nor inflammatory cell origin, nor is it coupled with antiprotease activity of endogenous origin. Mucosal application of faecal supernatants from IBS-D patients in mice evoked allodynia and increased CPP by 92%, both of which effects were prevented by serine protease inhibitors and dependent on PAR-2 expression. In mice, colonic exposure to supernatants from IBS-D patients resulted in a rapid increase in the phosphorylation of myosin light chain and delayed redistribution of ZO-1 in colonocytes. Conclusions: Elevated colonic lumenal serine protease activity of IBS-D patients evokes a PAR-2-mediated colonic epithelial barrier dysfunction and subsequent allodynia in mice, suggesting a novel organic background in the pathogenesis of IBS.

Fecal MMP-9: A new noninvasive differential diagnostic and activity marker in ulcerative colitis

Background:Ulcerative colitis (UC) is characterized by frequent relapses, with the presence of colorectal inflammation and mucosal lesions. Matrix-metalloprotease 9 (MMP-9) is elevated in colonic biopsies, urine, and blood plasma of UC patients. MMP-9 has been suggested as a predictor of UC in the urine of children; however, 20% of the controls tested positive. So far, fecal MMP-9 levels have never been measured. Our aims were: 1) to compare fecal MMP-9 levels in UC patients to control subjects and a functional gastrointestinal disorder characterized by diarrhea (IBS-D); 2) to test the correlation between UC disease activity and fecal levels of MMP-9; and 3) to correlate fecal MMP-9 levels with a known fecal marker of UC activity, calprotectin. Methods:UC (n = 47), IBS-D (n = 23) patients, and control subjects (n = 24) provided fecal samples for MMP-9 analysis. In UC patients, disease severity was evaluated by the Mayo score. Fecal MMP-9 and calprotectin levels were measured by enzyme-linked immunosorbent assay and lateral flow assay, respectively. Results:MMP-9 was undetectable or ⩽0.22 ng/mL in the feces of all controls and IBS-D patients. In UC patients, fecal MMP-9 levels significantly correlated with the overall Mayo score (P < 0.001), the endoscopic score (P < 0.001), and the serum C-reactive protein levels (P = 0.002). Additionally, in UC patients fecal MMP-9 levels showed a significant correlation with a known disease activity marker, fecal calprotectin (P = 0.014). Conclusions:These results highlight fecal MMP-9 as a useful tool in the differential diagnosis of diarrheic disorders and in the noninvasive evaluation of disease activity and mucosal healing in UC.

Leaky Gut in Patients with Diarrhea-Predominant Irritable Bowel Syndrome and Inactive Ulcerative Colitis

Background/Aims: Defective epithelial barrier has been implicated in the pathogenesis of irritable bowel syndrome (IBS) and inflammatory bowel diseases. The aim of this study was to investigate gut permeability in patients with inactive ulcerative colitis (UC) and in patients with IBS. Methods: IBS patients of the diarrhea-predominant (IBS-D) and of the constipation-predominant subgroup (IBS-C), patients with inactive UC and healthy subjects were enrolled. Gut permeability was evaluated by measuring 24-hour urine excretion of orally administered 51Cr-EDTA. Clinical symptoms were evaluated in IBS-D patients and correlated to colonic permeability. Results: There was a significant decrease in the proximal small intestinal permeability in IBS-C patients compared to controls (0.26 ± 0.05 vs. 0.63 ± 0.1%; p < 0.05). Distal small intestinal permeability showed no significant difference in the studied group of patients compared to controls. Colonic permeability of IBS-D and inactive UC patients was significantly increased compared to controls (2.68 ± 0.35 and 3.74 ± 0.49 vs. 1.04 ± 0.18%; p < 0.05, p < 0.001). Colonic permeability of IBS-D patients correlated with stool frequency. Conclusions: Elevated gut permeability is localized to the colon both in IBS-D and in inactive UC patients.

Immediate insulin treatment prevents gut motility alterations and loss of nitrergic neurons in the ileum and colon of rats with streptozotocin-induced diabetes

The streptozotocin-induced diabetic rat model was used to investigate the relation between the deranged gut motility and the segment-specific quantitative changes in the nitrergic myenteric neurons. Additionally, we studied the effectiveness of early insulin replacement to prevent the diabetes-induced changes. Rats were divided into three groups: controls, diabetics and insulin-treated diabetics. Ten weeks after the onset of diabetes, animals were chosen from each group for intestinal transit measurements. The remainder were killed and gut segments were processed for NADPH-diaphorase histochemistry and HuC/HuD immunohistochemistry. The diabetic rats displayed faster transit than that for the controls. In the insulin-treated group, the transit time was the same as that in the controls. In the duodenum of the diabetic rats, the number of nitrergic neurons was decreased, while the total neuronal number was not altered. In the jejunum, ileum and colon, both the total and the nitrergic neuronal cell number decreased significantly. Insulin treatment did not prevent the nitrergic cell loss significantly in the duodenum and jejunum, but it did prevent it significantly in the ileum and colon. These findings comprise the first evidence that the nitrergic neurons located in different intestinal segments exhibit different susceptibilities to a diabetic state and to insulin treatment.

Is rectal indomethacin effective in preventing of post-endoscopic retrograde cholangiopancreatography pancreatitis?

AIM To investigate the effectiveness of rectally administered indomethacin in the prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis and hyperamylasaemia in a multicentre study. METHODS A prospective, randomised, placebo-controlled multicentre study in five endoscopic units was conducted on 686 patients randomised to receive a suppository containing 100 mg indomethacin, or an inert placebo, 10-15 min before ERCP. Post-ERCP pancreatitis and hyperamylasaemia were evaluated 24 h following the procedure on the basis of clinical signs and laboratory parameters, and computed tomography/magnetic resonance imaging findings if required. RESULTS Twenty-one patients were excluded because of incompleteness of their data or because of protocol violation. The results of 665 investigations were evaluated: 347 in the indomethacin group and 318 in the placebo group. The distributions of the risk factors in the two groups did not differ significantly. Pancreatitis developed in 42 patients (6.3%): it was mild in 34 (5.1%) and severe in eight (1.2%) cases. Hyperamylaesemia occurred in 160 patients (24.1%). There was no significant difference between the indomethacin and placebo groups in the incidence of either post-ERCP pancreatitis (5.8% vs 6.9%) or hyperamylasaemia (23.3% vs 24.8%). Similarly, subgroup analysis did not reveal any significant differences between the two groups. CONCLUSION 100 mg rectal indomethacin administered before ERCP did not prove effective in preventing post-ERCP pancreatitis.

Impaired Accommodation of Proximal Stomach in Patients with Alcoholic Liver Cirrhosis

Background: Impaired gastric emptying has previously been detected by ultrasonography in cirrhotic patients, and the role of the type of meal has also been discussed. While these earlier studies dealt with the distal part of the stomach, the aim of our study was to examine the effects of three different types of meal on the proximal stomach in cirrhotic patients. Methods: The proximal stomach was examined by ultrasonography in 15 healthy volunteers and in 21 alcoholic cirrhotic patients. The subjects received a liquid meal with a low calorie content and two different semisolid test meals with a low calorie content or high calorie and fat contents. The proximal gastric size was assessed by ultrasonography in a sagittal area and a frontal diameter. On the basis of assessment of the autonomic nervous function, the cirrhotic patients were divided into two groups: autonomic neuropathy positive and autonomic neuropathy negative. Results: The postcibal gastric size immediately after ingestion of the liquid test meal was significantly lower in the cirrhotic patients than in the healthy controls. In the healthy volunteers, the measures of the proximal gastric size were significantly higher than in either group of cirrhotic patients at t 0 , and at 10, 20 or 30 min after ingestion of a semisolid test meal with low calorie and fat contents. The proximal gastric sizes in the three groups of investigated subjects did not differ when the meal with high fat and calorie contents was tested. When the liquid meal was administered, the proximal gastric size was significantly lower in the cirrhotic patients with autonomic neuropathy. A significant intragroup difference was not observed when the semisolid meals were tested. Conclusions: This study reveals an impairment of the proximal stomach in alcoholic cirrhotic patients. The low calorie liquid meal distinguishes between the two groups of cirrhotic patients and healthy controls.

Prevalence of Respiratory Symptoms and Diseases Associated with Gastroesophageal Reflux Disease

Aim: Investigation of the prevalence of respiratory symptoms and diseases associated with gastroesophageal reflux disease (GERD). Patients and Methods: 299 subjects with GERD were submitted to upper gastrointestinal endoscopy and 24-hour esophageal pH monitoring and a symptom analysis. Results: Chronic respiratory symptoms or diseases were present in 18% (56/299). Chronic cough was observed in 42/56 patients, while typical reflux symptoms such as heartburn and acid regurgitation were observed in 30/56 and 24/56 cases, respectively. The prevalence of airway diseases was chronic bronchitis 12/56, asthma 10/56, recurrent pneumonia 10/56, chronic sinusitis 7/56 and chronic laryngitis 1/56. In patients with respiratory complications pathologic acid reflux was established in 29/51 cases on the basis of the DeMeester score, while 17/51 had pathologic postprandial, nocturnal or diurnal reflux events. Upper gastrointestinal endoscopy revealed a normal esophageal mucosa in 6/56, Savary-Miller stage I esophagitis in 23/56, stage II in 15/56, stage III in 5/56 and stage IV in 6/56 patients. Conclusions: These investigations have demonstrated an abnormal 24-hour pH score in about half of the patients with GERD-associated respiratory complications, and indicated that short reflux events are characteristic of the reflux activity in one third of this population.

Diabetic Gastroparesis: Functional/Morphologic Background, Diagnosis, and Treatment Options

The regulation of gastrointestinal motility mainly involves the smooth muscle, neural (extrinsic and intrinsic), and hormonal elements, the glial cells, and the interstitial cells of Cajal. An orchestrated function of all these components is required for the appropriate propulsive movement of the food in the gastrointestinal tract. Gastroparesis, a pathological slowing-down of gastric emptying, is a result of the damage to the tissue elements involved in the regulation of motility. Gastroparesis is one of the well-known complications of long-standing diabetes mellitus. Although it is rarely a life-threatening complication, it has a deteriorating effect on the quality of life, leads to unpredictable oscillation of the blood glucose level, and increases the time required for the absorption of food and medicines. This review describes the clinical characteristics of diabetic gastroparesis and summarizes the organic and functional motility abnormalities caused by this complication. Finally, the currently available and potential future therapeutic approaches are summarized.

Gut Region‐Specific Diabetic Damage to the Capillary Endothelium Adjacent to the Myenteric Plexus

Please cite this paper as: Bódi N, Talapka P, Poles MZ, Hermesz E, Jancsó Z, Katarova Z, Izbéki F, Wittmann T, Fekete É, Bagyánszki M. Gut region‐specific diabetic damage to the capillary endothelium adjacent to the myenteric plexus. Microcirculation 19: 316–326, 2012.

Asthma and Gastroesophageal Reflux: Clinical Evaluation of Esophago-Bronchial Reflex and Proximal Reflux

Aims: To evaluate the prevalence of proximal reflux and esophago-bronchial reflex (EBR) in patients with asthma, and to compare the symptom spectrum, esophageal acid sensitivity, pH monitoring, and the endoscopic and manometric parameters of EBR-positive and -negative patients with asthma. Patients and Methods: Forty-three consecutive patients with recent diagnoses of asthma and 20 patients with chronic cough but without asthma were prospectively submitted to detailed reflux and respiratory symptom analysis, upper gastrointestinal endoscopy, esophageal manometry, Bernstein test and double-channel intra-esophageal pH monitoring. The presence of EBR was studied by combined esophageal acid (0.1 N HCl) perfusion and methacholine test. Results: Patients with asthma had significantly more proximal acid reflux than controls. Patients with EBR positivity were more likely to have an acid-sensitive esophagus and had more acid reflux especially in the supine period at the distal measurement point. Other parameters were similar. Conclusions: Patients with asthma had significantly more proximal acid reflux than those with chronic cough. The combination of the methacholine test with esophageal acid perfusion is able to establish the presence of EBR, however prospective therapeutic trials are needed to confirm its clinical value. The increased amount of acid reflux during the supine period in patients with EBR may indicate a role for appropriate nighttime acid suppressive therapy.