To assess the symptomatic efficacy of Lactobacillus plantarum 299v (L. plantarum 299v) (DSM 9843) for the relief of abdominal symptoms in a large subset of irritable bowel syndrome (IBS) patients ...fulfilling the Rome III criteria.
In this double blind, placebo-controlled, parallel-designed study, subjects were randomized to daily receive either one capsule of L. plantarum 299v (DSM 9843) or placebo for 4 wk. Frequency and intensity of abdominal pain, bloating and feeling of incomplete rectal emptying were assessed weekly on a visual analogue scale while stool frequency was calculated.
Two hundred and fourteen IBS patients were recruited. After 4 wk, both pain severity (0.68 + 0.53 vs 0.92 + 0.57, P < 0.05) and daily frequency (1.01 + 0.77 vs 1.71 + 0.93, P < 0.05) were lower with L. plantarum 299v (DSM 9843) than with placebo. Similar results were obtained for bloating. At week 4, 78.1 % of the patients scored the L. plantarum 299v (DSM 9843) symptomatic effect as excellent or good vs only 8.1 % for placebo (P < 0.01).
A 4-wk treatment with L. plantarum 299v (DSM 9843) provided effective symptom relief, particularly of abdominal pain and bloating, in IBS patients fulfilling the Rome III criteria.
Introduction
Chronic constipation is a common disorder with a reported prevalence ranging from 3% to 27% in the general population. Several management strategies, including diagnostic tests, empiric ...treatments, and specific treatments, have been developed. Our aim was to develop European guidelines for the clinical management of constipation.
Design
After a thorough review of the literature by experts in relevant fields, including gastroenterologists, surgeons, general practitioners, radiologists, and experts in gastrointestinal motility testing from various European countries, a Delphi consensus process was used to produce statements and practical algorithms for the management of chronic constipation.
Key Results
Seventy‐three final statements were agreed upon after the Delphi process. The level of evidence for most statements was low or very low. A high level of evidence was agreed only for anorectal manometry as a comprehensive evaluation of anorectal function and for treatment with osmotic laxatives, especially polyethylene glycol, the prokinetic drug prucalopride, secretagogues, such as linaclotide and lubiprostone and PAMORAs for the treatment of opioid‐induced constipation. However, the level of agreement between the authors was good for most statements (80% or more of the authors). The greatest disagreement was related to the surgical management of constipation.
Conclusions and Inferences
European guidelines on chronic constipation, with recommendations and algorithms, were developed by experts. Despite the high level of agreement between the different experts, the level of scientific evidence for most recommendations was low, highlighting the need for future research to increase the evidence and improve treatment outcomes in these patients.
We produced a guideline for management of functional constipation that provides evidence‐based practical algorithms for diagnosis and stepwise treatment of constipation in adults. Implementation of the guideline should improve and harmonize management of constipation across different countries.
The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose pathogenesis is not completely understood. Its high prevalence and the considerable effects on quality of life make ...IBS a disease with high social cost. Recent studies suggest that low grade mucosal immune activation, increased intestinal permeability and the altered host-microbiota interactions that modulate innate immune response, contribute to the pathophysiology of IBS. However, the understanding of the precise molecular pathophysiology remains largely unknown.
In this study our objective was to evaluate the TLR expression as a key player in the innate immune response, in the colonic mucosa of IBS patients classified into the three main subtypes (with constipation, with diarrhea or mixed). TLR2 and TLR4 mRNA expression was assessed by real time RT-PCR while TLRs protein expression in intestinal epithelial cells was specifically assessed by flow cytometry and immunofluorescence. Mucosal inflammatory cytokine production was investigated by the multiplex technology. Here we report that the IBS-Mixed subgroup displayed a significant up-regulation of TLR2 and TLR4 in the colonic mucosa. Furthermore, these expressions were localized in the epithelial cells, opening new perspectives for a potential role of epithelial cells in host-immune interactions in IBS. In addition, the increased TLR expression in IBS-M patients elicited intracellular signaling pathways resulting in increased expression of the mucosal proinflammatory cytokines IL-8 and IL1β.
Our results provide the first evidence of differential expression of TLR in IBS patients according to the disease subtype. These results offer further support that microflora plays a central role in the complex pathophysiology of IBS providing novel pharmacological targets for this chronic gastrointestinal disorder according to bowel habits.
There have been conflicting results from trials of gastric electrical stimulation (GES) for treatment of refractory vomiting, associated or not with gastroparesis. We performed a large, multicenter, ...randomized, double-blind trial with crossover to study the efficacy of GES in patients with refractory vomiting, with or without gastroparesis.
For 4 months, we assessed symptoms in 172 patients (66% women; mean age ± standard deviation, 45 ± 12 years; 133 with gastroparesis) with chronic (>12 months) of refractory vomiting (idiopathic, associated with a type 1 or 2 diabetes, or postsurgical). A GES device was implanted and left unactivated until patients were randomly assigned, in a double-blind manner, to groups that received 4 months of stimulation parameters (14 Hz, 5 mA, pulses of 330 μs) or no stimulation (control); 149 patients then crossed over to the other group for 4 months. Patients were examined at the end of each 4-month period (at 5 and 9 months after implantation). Primary endpoints were vomiting score, ranging from 0 (daily vomiting) to 4 (no vomiting), and the quality of life, assessed by the Gastrointestinal Quality of Life Index scoring system. Secondary endpoints were changes in other digestive symptoms, nutritional status, gastric emptying, and control of diabetes.
During both phases of the crossover study, vomiting scores were higher in the group with the device on (median score, 2) than the control group (median score, 1; P < .001), in diabetic and nondiabetic patients. Vomiting scores increased significantly when the device was ON in patients with delayed (P < .01) or normal gastric emptying (P = .05). Gastric emptying was not accelerated during the ON period compared with the OFF period. Having the GES turned on was not associated with increased quality of life.
In a randomized crossover study, we found that GES reduced the frequency of refractory vomiting in patients with and without diabetes, although it did not accelerate gastric emptying or increase of quality of life. Clinicaltrials.gov, Number: NCT00903799
Abstract Objective Peptide hormones synthesized in gastrointestinal and adipose tissues in addition to neuropeptides regulate appetite and body weight. Previously, autoantibodies directed against ...melanocortin peptides were found in patients with eating disorders; however, it remains unknown whether autoantibodies directed against other appetite-regulating peptides are present in human sera and whether their levels are influenced by gut-related antigens. Methods Healthy women were studied for the presence of immunoglobulin (Ig) G and IgA autoantibodies directed against 14 key appetite-regulating peptides. The concept of molecular mimicry was applied to search in silico whether bacteria, viruses, or fungi contain proteins with amino acid sequences identical to appetite-regulating peptides. In addition, autoantibodies serum levels were studied in germ-free and specific pathogen-free rats. Results We found these IgG and IgA autoantibodies directed against leptin, ghrelin, peptide YY, neuropeptide Y, and other appetite-regulating peptides are present in human sera at levels of 100–900 ng/mL. Numerous cases of sequence homology with these peptides were identified among commensal and pathogenic micro-organisms including Lactobacilli , bacteroides, Helicobacter pylori , Escherichia coli , and Candida species. Decreased levels of IgA autoantibodies directed against several appetite-regulating peptides and increased levels of antighrelin IgG were found in germ-free rats compared with specific pathogen-free rats. Conclusion Healthy humans and rats display autoantibodies directed against appetite-regulating peptide hormones and neuropeptides, suggesting that these autoantibodies may have physiologic implications in hunger and satiety pathways. Gut-related antigens including the intestinal microflora may influence production of theses autoantibodies, suggesting a new link between the gut and appetite control.
Proteasome-mediated protein degradation may contribute to the regulation of intestinal inflammation. At the same time, low-grade inflammation and increased intestinal permeability seem to be involved ...in the pathophysiology of irritable bowel syndrome (IBS). Thus, we aimed to evaluate proteasome composition and activities in colonic mucosa of IBS patients and its putative pathogenic role.
Proteasome activities and proteasome subunit expression were measured in colonic mucosa of IBS, Crohn's disease (CD), and control patients by fluorometric assays and western blot, respectively. Expression of inhibitor of kappa B factor (IkappaB alpha) and occludin, a tight junction protein, was also evaluated in colonic biopsies. The degradation of recombinant occludin incubated with protein extracts from colonic mucosa was evaluated in the presence or absence of proteasome inhibitor, MG132.
Proteasome trypsin-like activity was increased in IBS patients compared with CD and controls, whereas chymotrypsin-like activity was upregulated in CD patients only. Caspase-like activity was reduced both in IBS and CD patients. IkappaB alpha expression was similar between IBS and controls. In contrast, occludin expression was lower in IBS than in controls, but occludin mRNA level was similar. Protein extracts from IBS patients but not from controls degraded recombinant occludin (20% over 160 min), which was blocked by MG132. Although mast cell number was increased in IBS patients, no correlation was found between this number and proteasome alterations.
Our study shows that proteasome alterations are present in the colonic mucosa of IBS patients and may contribute to the pathophysiology of IBS by increasing occludin degradation.
Luminal serine-proteases lead to increased colonic paracellular permeability and visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Other proteases, ...namely cysteine-proteases (CPs), increase airway permeability by digesting epithelial tight junction proteins. In this study, we focused on constipation-predominant IBS (IBS-C) and we aimed to (i) evaluate CP levels in two cohorts of IBS patients, (ii) test if IBS-C fecal supernatant (FSN) affects permeability, and visceral sensitivity after repeated administrations in mice, and (iii) evaluate occludin expression in IBS-C colonic biopsies.
Fecal CP activity was determined using selective substrate and inhibitor (E64). The effect of papain, as positive control, and IBS-C FSN administrations were evaluated on colonic paracellular permeability and mucosal occludin levels in mice and T84 monolayers. Occludin protein levels were evaluated in IBS-C colonic biopsies. Sensitivity to colorectal distension (CRD) was measured after repeated administrations of IBS-C FSN.
We found in a subset of IBS-C patients an enhanced fecal CP activity, in comparison with healthy controls and IBS-D patients. CP activity levels positively correlated with disease severity and abdominal pain scoring. This association was confirmed by receiver operating characteristic curve analysis. In mice, repeated application of IBS-C FSN into colon triggered increased permeability, linked to the enzymatic degradation of occludin, and was associated with enhanced visceral sensitivity to CRD. Finally, occludin levels were found decreased in colonic biopsies from IBS-C patients, and IBS-C FSNs were able to degrade recombinant human occludin in vitro. All these effects were abolished by preincubation of IBS-C FSN with a CP inhibitor, E64.
These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS.
A role for immunoproteasome in the regulation of intestinal permeability has been previously suggested both in mice during water avoidance stress (WAS) and in patients with irritable bowel syndrome ...(IBS). Here, we provide evidence that the ubiquitin–proteasome system (UPS) contributes to the pathophysiology of IBS. Indeed, we report that colonic proteome is altered in WAS mice and that β2i subunit deficiency modifies the proteome response that is associated with a limitation of colonic hyperpermeability. Interestingly, we show specific alterations of proteins involved in UPS, mitochondrial, and energy metabolism. We also report changes in the pattern of colonic ubiquitome in diarrhea-predominant IBS (IBS-D) patients and particularly a reduced expression of ubiquitinated proteins involved in the nuclear factor-kappa B (NF-κB) inflammatory signaling pathway. All these data suggest that immunoproteasome targeting may represent a new therapeutic strategy for the treatment of IBS patients with increased intestinal permeability.
To compare the prevalence of anxiety and depression states and eating disorders (EDs) between patients with irritable bowel syndrome (IBS) and healthy volunteers without IBS.
IBS patients according ...to Rome III criteria referred to our tertiary care center for therapeutic management and matched volunteers without IBS were prospectively included. EDs were screened by Sick, Control, One stone, Fat, Food-French version (SCOFF-F) questionnaire. IBS symptom severity (IBS symptom severity score), stool consistency (Bristol stool scale), anxiety and depression levels (Hospital Anxiety and Depression scale), and quality of life (validated Gastrointestinal Quality of Life Index) were assessed by validated self-questionnaires.
IBS (228) patients and healthy volunteers (228) were included. Mean age was 42.5 ± 13.9 years with mainly women (76.7%). Among IBS patients, 25.4% had positive SCOFF-F compared to 21.1% of volunteers. IBS patients more frequently had a lower body mass index (BMI) than volunteers (p < 0.0001). IBS patients with ED had poorer quality of life and more stressful life events (p = 0.02) than IBS patients without ED. The prevalence of anxiety and depression was significantly higher in IBS patients with ED than in volunteers without ED, respectively (19.0% vs 1.9%, p=0.00, and 60.3% vs 19.7%, p < 0.0001).
The prevalence of ED assessed with positive SCOFF-F questionnaire was not significantly different between IBS patients and healthy volunteers. The combination of IBS and ED was associated with higher levels of anxiety or depression and poorer quality of life.
Abstract
Background:
The management of opioid-induced constipation (OIC) is often complicated by the fact that clinical measures of constipation do not always correlate with patient perception. As ...the discomfort associated with OIC can lead to poor compliance with the opioid treatment, a shift in focus towards patient assessment is often advocated.
Scope:
The Bowel Function Index* (BFI) is a new patient-assessment scale that has been developed and validated specifically for OIC. It is a physician-administered, easy-to-use scale made up of three items (ease of defecation, feeling of incomplete bowel evacuation, and personal judgement of constipation). An extensive analysis has been performed in order to validate the BFI as reliable, stable, clinically valid, and responsive to change in patients with OIC, with a 12-point change in score constituting a clinically relevant change in constipation.
Findings:
The results of the validation analysis were based on major clinical trials and have been further supported by data from a large open-label study and a pharmaco-epidemiological study, in which the BFI was used effectively to assess OIC in a large population of patients treated with opioids. Although other patient self-report scales exist, the BFI offers several unique advantages. First, by being physician-administered, the BFI minimizes reading and comprehension difficulties; second, by offering general and open-ended questions which capture patient perspective, the BFI is likely to detect most patients suffering from OIC; third, by being short and easy-to-use, it places little burden on the patient, thereby increasing the likelihood of gathering accurate information.
Conclusion:
Altogether, the available data suggest that the BFI will be useful in clinical trials and in daily practice.
PDF
