Philippe Ducrotté

Modulating effect of glutamine on IL-1β-induced cytokine production by human gut

BACKGROUND & AIMS Balance between pro-and anti-inflammatory mediators plays a key role in the pathogenesis and treatment of inflammatory bowel disease. Glutamine can modulate cytokine production by intestinal mucosa in healthy subjects, but studies in inflammatory states are still limited. The aim of this work was to evaluate the effects of glutamine on IL-1beta-induced cytokine production by human gut. METHODS Duodenal biopsies from healthy volunteers were stimulated in vitro by IL-1beta in the presence of increasing glutamine concentrations. Cytokine production was assessed in culture media by ELISA and cytokine mRNA expression in biopsies by RT-PCR. Results, in pg/mg of tissue, (median [range]), were compared by non-parametric paired tests. RESULTS IL-1beta stimulation increased IL-6 and IL-8, but did not affect IL-4 and IL-10 production. IL-8 and IL-6 production from stimulated biopsies significantly decreased with increasing glutamine concentration from 0.5 to 10mM, (2543 [828-3634] to 1499 [282-2617] for IL-8, 62 [22-117] to 24 [12-99] for IL-6, both P<0.05), whereas IL-10 production was increased (0.7 [0.2-1.6] to 1.2 [2.6-0.5],P<0.05). Glutamine also increased IL-10 mRNA level in biopsies (P<0.05). IL-4 production was not affected by glutamine. CONCLUSIONS Glutamine was shown in human intestinal mucosa to reduce the production of the pro-inflammatory cytokines IL-6 and IL-8, and enhance the production of the anti-inflammatory cytokine, IL-10.

Yield and impact of emergency capsule enteroscopy in severe obscure-overt gastrointestinal bleeding.

BACKGROUND AND STUDY AIMS Patients with obscure-overt gastrointestinal bleeding (OOGIB) are defined by overt hemorrhage and negative upper and lower endoscopy findings. At present, the place of emergency capsule enteroscopy in patients with severe OOGIB is unknown. The aim of this study was to assess the diagnostic yield and the impact of emergency capsule enteroscopy on further management in patients with severe OOGIB. PATIENTS AND METHODS Between 2003 and 2010, we retrospectively included all patients with severe OOGIB who underwent emergency capsule enteroscopy in the 24-48 h following negative urgent upper and lower endoscopy. Severe OOGIB was defined by ongoing bleeding with hemodynamic instability and/or the need for significant red blood cell transfusion. RESULTS Out of 5744 patients hospitalized in our Gastrointestinal Bleeding Unit, 55 (1%) presented with severe OOGIB and underwent emergency capsule enteroscopy. Capsule enteroscopy showed blood in 41 patients (75%) and lesions in 37 patients (67%). Findings included small bowel angiodysplasia in 19 patients (35%), ulcers in 7 (13%), tumors in 5 (9%), small-bowel varices in 2 (3%), cecum angiodysplasia in 4 (7%), fresh blood in small bowel without identified lesion in 12 (22%). Specific diagnostic and therapeutic procedures were undertaken in 78 % of patients. Further management included endoscopy (54%), surgery (22%), and radiology (2%). CONCLUSIONS Emergency capsule enteroscopy identified bleeding lesions in 67 % of patients with severe OOGIB. Emergency capsule enteroscopy seems to be a promising diagnostic tool with a subsequent impact on clinical management in patients with severe OOGIB.

Factors Associated With Diagnosis of Obscure Gastrointestinal Bleeding by Video Capsule Enteroscopy

BACKGROUND & AIMS Capsule enteroscopy (CE) is the best noninvasive tool to explore the entire small bowel of patients with obscure gastrointestinal bleeding (OGIB); it has a diagnostic yield of 40%-80%. However, little is known about the factors associated with a diagnosis of OGIB by CE. METHODS We analyzed data from 911 consecutive patients who underwent CE for OGIB from January 2004 to January 2010. Results from upper and lower gastrointestinal endoscopy examinations were negative in all patients. CE findings were recorded. Features of patients that were associated with diagnosis of OGIB by CE were identified by using logistic regression. RESULTS Based on CE, 509 patients (56%) had a confirmed lesion responsible for the OGIB: 203 had disease of the small bowel (22%), 88 had ulcerations (10%), 70 had tumors (8%), 24 had varices (2%), 6 had diverticula (0.5%), and 118 had what appeared to be bleeding lesions of the esophagus or stomach (10.6%) or colon (2%). Factors independently associated with a diagnosis of OGIB by CE were age >60 years (odds ratio [OR], 1.2), male sex, history of overt bleeding (OR, 3.8), and current hospitalization (OR, 1.4). Women were less likely to be diagnosed with OGIB by CE (OR, 0.7). CONCLUSIONS A history of overt bleeding is the factor most strongly associated with a diagnosis of OGIB by CE. Male sex, age >60 years, and inpatient status were also independent predictors of positive diagnosis by CE.

Cytokine-stimulated nitric oxide production and inducible NO-synthase mRNA level in human intestinal cells: lack of modulation by glutamine

BACKGROUND & AIMS Excess NO production has been reported during intestinal inflammation. Modulation of the inflammatory response with nutrients in critically ill patients has gained increasing interest. Glutamine has beneficial effects on gut mucosa but its effects on human intestinal NO production during an inflammatory response are not known. METHODS Caco-2/TC7 and HCT-8 cells were stimulated with a cytokine mixture (IL-1 beta, TNF alpha, IFN gamma) and duodenal biopsies from human healthy volunteers in organ culture were stimulated with IL-1 beta. All cultures were performed in the presence of 2-10 mmol/l glutamine. NO release in culture supernatant and iNOS mRNA level in cultured cells or biopsies were assessed by nitrate reduction and Griess assay and RT-PCR, respectively. RESULTS In Caco-2, HCT-8 cells and duodenal biopsies, cytokine stimulation increased iNOS mRNA level 1.2-fold (ns), 3.8-fold (P=0.02), 4.7-fold (P=0.03) and NO production 1.4-fold (ns), 9.1 (P=0.01) and 1.7-fold (P=0.01), respectively. Increasing glutamine concentration had no significant effect on NO production and iNOS mRNA in any type of culture, stimulated or not by cytokines. In various models of human intestinal cells, glutamine does not further increase NO production induced by pro-inflammatory cytokines.

Do endoflip assessments of anal sphincter distensibility provide more information on patients with fecal incontinence than high-resolution anal manometry?

Anal manometry is the standard technique for evaluating anal sphincter function. However, the functional lumen imaging probe (EndoFLIP®) can be used to measure sphincter distensibility during volume‐controlled distensions. Our aims were (i) to assess anal distensibility in patients with fecal incontinence (FI) and in healthy subjects using the EndoFLIP® and (ii) to compare the results with anal pressures measured by 3D high‐resolution manometry (3D‐HRM) to determine whether the EndoFLIP® was more sensitive and specific for diagnosing FI than 3D‐HRM.

Symptomatic fructose malabsorption in irritable bowel syndrome: A prospective study

Introduction Fructose can trigger or worsen symptoms in irritable bowel syndrome (IBS) patients. The aim of this study was to determine the prevalence of symptomatic fructose malabsorption in IBS patients and to test whether the patients characteristics can help to detect a fructose malabsorption. Materials and methods Ninety Rome III IBS patients (predominant diarrhoea (IBS-D): 31%, predominant constipation (IBS-C): 18%, mixed type (IBS-M): 51%) were included prospectively. After exclusion of a small intestinal bacterial overgrowth by a glucose breath test, fructose malabsorption was assessed by a five-hour breath test, with symptom monitoring, after a 25 g load of fructose. An increase of more than 20 ppm of hydrogen (H2) or methane (CH4) levels in the exhaled air led to the diagnosis of malabsorption. Results Fructose test was abnormal in 20/90 patients among whom only 35% were intolerant, with a simultaneous rise of H2/CH4 levels and the onset of abdominal discomfort or diarrhoea. IBS characteristics were not predictive even if young (p = 0.031) and male IBS patients (p = 0.029) were at higher risk of malabsorption. At variance, 18 additional patients experienced intestinal symptoms during the test despite normal fructose absorption. Discussion After a 25 g fructose load, symptomatic fructose malabsorption and intolerance without malabsorption were detected in 22% and 28% of IBS patients respectively.

Effect of transcranial magnetic stimulation on rectal sensitivity in irritable bowel syndrome: a randomized, placebo‐controlled pilot study

Repetitive transcranial magnetic stimulation (rTMS) applied to the motor cortex can induce analgesic effects in patients with chronic pain syndromes through its effect on central pain‐modulatory systems. Our aim was to evaluate the effect of rTMS on rectal sensitivity in irritable bowel syndrome (IBS) patients.

The diagnostic value of the functional lumen imaging probe versus high-resolution anorectal manometry in patients with fecal incontinence

The functional lumen imaging probe (EndoFLIP®) is a new technology that measures the distensibility of the anal canal represented by the anal distensibility index. The aims of this study were (i) to compare the anal distensibility index to anal pressure in a cohort of patients with fecal incontinence (FI) and (ii) to compare the diagnostic value of the EndoFLIP® to that of high‐resolution anorectal manometry (HRAM) in the same cohort of patients.

Proteasome inhibitors exacerbate interleukin-8 production induced by protease-activated receptor 2 in intestinal epithelial cells.

Protease activated receptors (PARs) and the ubiquitin-proteasome system (UPS) regulate inflammatory response in intestinal cells. We aimed to elucidate putative connections between PARs and UPS pathways in intestinal epithelial cells. Caco-2 cells were treated by agonist peptides of PARs and/or IL-1β and/or proteasome inhibitors, bortezomib or MG132. Inflammatory response was evaluated by measuring IL-8 production. Proteasome activities were also evaluated. We showed that PAR-1 and -2 activation increased release of IL-8 compared with vehicle and independently of IL-1β. In contrast, PAR-4 agonist peptide had no effect. Caspase-like and chymotrypsin-like proteasomal activities were increased by PAR-2 activation only in the presence of IL-1β. Interestingly, in polarized Caco-2 cells, the release of IL-8 was predominantly upregulated in the side where PAR-2 agonist peptide was added, apical or basalolateral. In contrast, proteasome activities were only affected when PAR-2 agonist peptide was added in the apical side. Proteasome inhibitors, bortezomib and MG132, enhanced IL-8 production in both sides, apical and basolateral. In conclusion, PAR-2 activation alone did not affect proteasome but needed inflammatory stimulus IL-1β to synergistically increase chymotrypsin-like activity in intestinal epithelial cells. However, proteasome inhibition led to exacerbate inflammatory response induced by PAR-2 activation.

Efficacy of a CO2-releasing suppository in dyschezia: A double-blind, randomized, placebo-controlled clinical trial

BACKGROUND Constipation has a significant impact on quality of life. Aim of this study was to evaluate the safety and the efficacy for relieving dyschezia symptoms of a CO2-releasing suppository in a randomized, placebo-controlled, clinical trial. METHODS Fifty-three office-based primary care physicians and 24 gastroenterologists conducted the study in France, between November 2010 and January 2012. Patients (aged 18-75 years) with dyschezia were eligible. Patients were randomly allocated a once-a-day suppository (CO2-releasing suppository or placebo) for 21 days. Primary endpoint was the change, from Day 0 to Day 21, in the intensity of discomfort related to dyschezia based on a self-assessed 0-100 visual analogue scale. RESULTS A total of 323 patients were randomized, i.e. 166 into the intervention group and 157 into the placebo group. Co-variance analysis showed a greater reduction in discomfort visual analogue scale score in the intervention group (-34.5mm; standard error of the mean: 1.8mm) than in the placebo group (-26.2mm; standard error of the mean: 1.9 mm; p<0.001). The greater efficacy of the CO2-releasing suppository was confirmed for all secondary efficacy parameters. No significant side effects for either treatment were observed. CONCLUSION A CO2-releasing suppository is more effective than a placebo for the relief of symptoms of dyschezia. This efficacy is associated with a good safety profile.