Epidemiological characteristics of a population visiting a patient-centered informative website about irritable bowel syndrome.

Background and aims: Irritable bowel syndrome (IBS) is a chronic disorder characterized by abdominal pain and an altered bowel habit. The aim of this study was to evaluate the characteristics of a population visiting a patient-centered informative website about IBS. Methods: Five digital surveys were used to assess the Rome IV criteria, red flag symptoms, healthcare use, psychological comorbidities, quality of life, symptom severity, diet, physical activity. Patients were divided into a Rome positive and negative population with the Rome positive population being further subtyped based on dominant stool pattern. Results: Red flag symptoms (42%) and comorbid psychological disorders (65% anxiety and 39% depression) were common. Despite consulting health care professionals and therapy, most patients (96%) still experienced moderate to severe symptoms with an average impact on quality of life. 73% performed regular physical exercise and 25% of the Rome positive population followed the FODMAP diet. Almost all participants consulted a health care professional at one point in time and used some form of therapy. 54% of the patients believed there is generally sufficient information available and 57% thinks that their physician takes IBS seriously. However, only 41% thinks that their physician has sufficient knowledge about IBS. Conclusions: This study underlines the importance of a thorough characterization of IBS patients. Furthermore, patients expressed an urgent need for high quality information and education for both health care professionals and patients.

Comparison of side-viewing duodenoscope and single-balloon enteroscope to perform ERCP in patients with Billroth II gastrectomy.

Endoscopic retrograde cholangiopancreatography (ERCP) in Billroth II patients is challenging and different endoscopes can be used. We retrospectively analysed 67 ERCP procedures in 38 Billroth II patients focussing on endoscope type and respective technical success and adverse event rate. 33 (49.2 %) ERCPs were performed using a duodenoscope, 87.9 % were successful and 3 were completed with the single-balloon enteroscope. 28 (41.8 %) ERCPs were performed with the single-balloon enteroscope, 82.1 % were successful and 2 were completed with a paediatric colonoscope. For 6 (9.0 %) ERCPs a paediatric colonoscope was used but only 3 (50.0 %) were successful. Overall technical success rate was 82.1 % without difference between the success rate of the duodenoscope and the single-balloon enteroscope. Overall adverse event rate was 10.5 %: 6.1 % duodenoscope,10.7 % single-balloon enteroscope, 33.3 % paediatric colonoscope. The duodenoscope allowed all conventional ERCP procedures, whereas the singleballoon enteroscope required dedicated ERCP catheters and did not allow metallic stent placement. However, the single-balloon enteroscope facilitated access to the papilla and sphincteroplasty allowed direct cholangioscopy. ERCP indications were bile duct stones (53.7 %), cholangitis (20.9 %), chronic pancreatitis (20.9 %), pancreatic cancer (1.5 %) and liver transplantation (3%). Therapeutic ERCP success rate is high in patients with Billroth II gastrectomy using either a conventional duodenoscope or the single-balloon enteroscope, with an acceptable and comparable adverse event rate. The choice of endoscope may depend on local experience, post-operative anatomy and therapeutic indication.

Case series of Cryptogenic Multifocal Ulcerating Stenosing Enteritis (CMUSE).

BACKGROUND AND STUDY AIMS: Small bowel ulceration poses a limited, but difficult differential diagnosis. The most common causes are Crohn's disease (CD), NSAID-associated enteritis, lymphoma, cytomegaly virus infection and tuberculosis. A less known and relatively novel differential diagnosis is cryptogenic multifocal ulcerative stenosing enteritis (CMUSE). PATIENTS AND METHODS: ive patients referred for balloon-assisted enteroscopy for various reasons showed endoscopic features of CMUSE. These findings and, when available, medical imaging were reviewed in order to increase general knowledge on CMUSE. RESULTS: Five patients, 3 males and 2 females, with a mean age of 39±5 years, underwent balloon-assisted enteroscopy. Typical short, circular, ulcerative stenoses were detected in the jejunum in 2 and in the ileum in 3 patients. The number of stenoses ranged from 1 to 7 per patient. Histopathology revealed nonspecific granulocyte inflammation without specific CD findings. Stenoses were often missed on pre-enteroscopy CT or MRI enteroclysis due to their short length. Treatment consisted of endoscopic balloon dilation in 3, corticosteroids in 3, azathioprine in 1 and anti-TNFα biologicals in 3 patients. 3 patients needed additional surgery because of ongoing symptomatic small bowel stenosis or retained wireless videocapsule. CONCLUSION: In patients with short, ulcerative small intestinal stenoses CMUSE is an important but often neglected differential diagnosis. The pathophysiology and relationship to CD are subject of ongoing debate, but specific endoscopic characteristics, different histopathological findings and lack of clear abnormalities on CT or MRI enterography suggest that CMUSE is a distinct albeit rare chronic inflammatory bowel disease.

Distal esophageal spasm and the Chicago classification: is timing everything?

BACKGROUND: According to the Chicago classification of esophageal motility disorders, distal esophageal spasm (DES) is defined as premature esophageal contractions (distal latency [DL] <4.5 s) for ≥20% of swallows, in the presence of a normal mean integral relaxation pressure (IRP). However, some patients with symptoms of DES have rapid contractions with a normal DL. The aim of this study was to characterize these patients and compare their clinical characteristics to those of patients classified as DES. METHODS: We retrospectively compared clinical characteristics and high-resolution manometry findings of patients with rapid contractions with normal latency to those meeting the Chicago classification criteria for DES. KEY RESULTS: Over a 3-year period, nine patients were diagnosed with DES and 14 showed rapid contractions in the distal esophagus with normal latency. The latter were younger than DES patients (60 ± 4 vs 72 ± 3 years, p < 0.05). Dysphagia and retrosternal pain occurred to a similar degree in both groups. Weight loss and abnormal barium esophagogram tended to be more frequent in DES patients. There was no difference in contractile front velocity (CFV) and in distal contractile integral (DCI) between patients with DES and rapid contractions with normal latency. Lower esophageal sphincter pressures were not different between groups. However, IRP was significantly higher in DES compared to rapid contractions with normal latency (11.7 ± 0.6 mmHg vs 7.6 ± 1.2 mmHg, p < 0.05), albeit still within the normal range. CONCLUSIONS & INFERENCES: These data suggest that patients with simultaneous contractions with normal latency represent a group of patients with many features similar to DES.

Mechanisms contributing to visceral hypersensitivity: focus on splanchnic afferent nerve signaling.

BACKGROUND: Visceral hypersensitivity is a main characteristic of functional bowel disorders and is mediated by both peripheral and central factors. We investigated whether enhanced splanchnic afferent signaling in vitro is associated with visceral hypersensitivity in vivo in an acute and postinflammatory rat model of colitis. METHODS: Trinitrobenzene sulfonic acid (TNBS)-colitis was monitored individually by colonoscopy to confirm colitis and follow convalescence and endoscopic healing in each rat. Experiments were performed in controls, rats with acute colitis and in postcolitis rats. Colonic afferent mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs), and by making extracellular afferent recordings from splanchnic nerve bundles in vitro. Multiunit afferent activity was classified into single units identified as low threshold (LT), wide dynamic range (WDR), high threshold (HT), and mechanically insensitive afferents (MIA). KEY RESULTS: During acute TNBS-colitis, VMRs were significantly increased and splanchnic nerve recordings showed proportionally less MIA and increased WDR and HT afferents. Acute colitis gave rise to an enhanced spontaneous activity of both LT and MIA and augmented afferent mechanosensitivity in LT, WDR and HT afferents. Postcolitis, VMRs remained significantly increased, whereas splanchnic nerve recordings showed that the proportion of LT, WDR, HT and MIA had normalized to control values. However, LT and MIA continued to show increased spontaneous activity and WDR and HT remained sensitized to colorectal distension. CONCLUSIONS & INFERENCES: Visceral hypersensitivity in vivo is associated with sensitized splanchnic afferent responses both during acute colitis and in the postinflammatory phase. However, splanchnic afferent subpopulations are affected differentially at both time points.

Impact of spatial resolution on results of esophageal high-resolution manometry.

BACKGROUND: The Chicago classification for esophageal motility disorders was designed for a 36-channel manometry system with sensors spaced at 1 cm. However, many motility laboratories outside the USA use catheters with a lower resolution in the segments outside the esophagogastric junction. Our aim was to investigate the effect of spatial resolution on the Chicago metrics and diagnosis. METHODS: In 20 healthy volunteers and 47 patients with upper gastrointestinal symptoms, high-resolution manometric studies of the esophagus were retrospectively reanalyzed using the original 1-cm spacing in the segments outside the 7-cm esophagogastric junction segment, and again after manually increasing the spacing between sensors to 2, 3, and 4 cm (above the lower esophageal sphincter region). Measurements were analyzed in random order and the investigator was blinded to the outcome of the analyses performed in another resolution of the same patient. Intra-class correlation coefficients (ICC) and Kappa values were determined. KEY RESULTS: There was a very strong correlation between the 1-cm and 2-cm analysis for all Chicago metrics studied in healthy volunteers (ICCs: distal contractile integral 0.998; contractile front velocity (CFV) 0.964; distal latency 0.919; peristaltic break size 0.941). The 2-cm spacing analysis also correlated very well with the 1-cm analysis for the different Chicago diagnoses obtained in the patients (Kappa values ranging from 0.665 to 1.000). When the sensor spacing was increased to 3 and 4 cm, the correlation was reduced to moderate for the Chicago metrics, especially for break size and CFV of peristalsis. CONCLUSIONS & INFERENCES: The Chicago classification for esophageal motility disorders is still valid and the same normal values can be used when catheters with a slightly lower resolution are used (i.e., 2-cm vs 1-cm spacing). For larger sensor intervals, the classification and the normal values will need to be adjusted.

Differential role of tachykinin NK3 receptors on cholinergic excitatory neurotransmission in the mouse stomach and small intestine.

BACKGROUND AND PURPOSE: Tachykinin NK(3) receptors are widely expressed in the mouse gastrointestinal tract but their functional role in enteric neuromuscular transmission remains unstudied in this species. We investigated the involvement of NK(3) receptors in cholinergic neurotransmission in the mouse stomach and small intestine. EXPERIMENTAL APPROACH: Muscle strips of the mouse gastric fundus and ileum were mounted in organ baths for tension recordings. Effects of NK(3) agonists and antagonists were studied on contractions to EFS of enteric nerves and to carbachol. KEY RESULTS: EFS induced frequency-dependent tetrodotoxin-sensitive contractions, which were abolished by atropine. The cholinergic contractions to EFS in the stomach were enhanced by the NK(3) antagonist SR142801, but not affected by the NK(3) agonist senktide or neurokinin B. The cholinergic contractions to EFS in the small intestine were not affected by SR142801, but dose-dependently inhibited by senktide and neurokinin B. This inhibitory effect was prevented by SR142801 but not by hexamethonium. SR142801, senktide or neurokinin B did not induce any response per se in the stomach and small intestine and did not affect contractions to carbachol. CONCLUSIONS AND IMPLICATIONS: NK(3) receptors modulate cholinergic neurotransmission differently in the mouse stomach and small intestine. Blockade of NK(3) receptors enhanced cholinergic transmission in the stomach but not in the intestine. Activation of NK(3) receptors inhibited cholinergic transmission in the small intestine but not in the stomach. This indicates a physiological role for NK(3) receptors in mouse stomach contractility and a pathophysiological role in mouse intestinal contractility.

TRPV1 receptors on unmyelinated C-fibres mediate colitis-induced sensitization of pelvic afferent nerve fibres in rats.

Patients with inflammatory bowel disease often suffer from gastrointestinal motility and sensitivity disorders. The aim of the current study was to investigate the role of transient receptor potential of the vanilloid type 1 (TRPV1) receptors in the pathophysiology of colitis-induced pelvic afferent nerve sensitization. Trinitrobenzene sulphate (TNBS) colitis (7.5 mg, 30% ethanol) was induced in Wistar rats 72 h prior to the experiment. Single-fibre recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root. Fibres responding to colorectal distension (CRD) were identified in controls and rats with TNBS colitis. The effect of the TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 0.25-5 mg kg(-1)) or its vehicle (hydroxypropyl-beta-cyclodextrin) was tested on the afferent response to repetitive distensions (60 mmHg). Immunocytochemical staining of TRPV1 and NF200, a marker for A-fibre neurons, was performed in the dorsal root ganglia L6-S1. TNBS colitis significantly increased the response to colorectal distension of pelvic afferent C-fibres. BCTC did not significantly affect the C-fibre response in controls, but normalized the sensitized response in rats with colitis. TNBS colitis increased the spontaneous activity of C-fibres, an effect which was insensitive to administration of BCTC. TNBS colitis had no effect on Adelta-fibres, nor was their activity modulated by BCTC. TNBS colitis caused an immunocytochemical up-regulation of TRPV1 receptors in the cell bodies of pelvic afferent NF200 negative neurons. TRPV1 signalling mediates the colitis-induced sensitization of pelvic afferent C-fibres to CRD, while Adelta-fibres are neither sensitized by colitis nor affected by TRPV1 inhibition.

Functional study on TRPV1-mediated signalling in the mouse small intestine: involvement of tachykinin receptors.

Afferent nerves in the gut not only signal to the central nervous system but also provide a local efferent-like effect. This effect can modulate intestinal motility and secretion and is postulated to involve the transient receptor potential of the vanilloid type 1 (TRPV1). By using selective TRPV1 agonist and antagonists, we studied the efferent-like effect of afferent nerves in the isolated mouse jejunum. Mouse jejunal muscle strips were mounted in organ baths for isometric tension recordings. Jejunal strips contracted to the TRPV1 agonist capsaicin. Contractions to capsaicin showed rapid tachyphylaxis and were insensitive to tetrodotoxin, hexamethonium, atropine or L-nitroarginine. Capsaicin did not affect contractions to electrical stimulation of enteric motor nerves and carbachol. Tachykinin NK1, NK2 and NK3 receptor blockade by RP67580, nepadutant plus SR-142801 reduced contractions to capsaicin to a similar degree as contractions to substance P. The effect of the TRPV1 antagonists capsazepine, SB-366791, iodo-resiniferatoxin (iodo-RTX) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC) was studied. Capsazepine inhibited contractions not only to capsaicin but also those to carbachol. SB-366791 reduced contractions both to capsaicin and carbachol. Iodo-RTX partially inhibited the contractions to capsaicin without affecting contractions to carbachol. BCTC concentration-dependently inhibited and at the highest concentration used, abolished the contractions to capsaicin without affecting those to carbachol. From these results, we conclude that activation of TRPV1 in the mouse intestine induces a contraction that is mediated by tachykinins most likely released from afferent nerves. The TRPV1-mediated contraction does not involve activation of intrinsic enteric motor nerves. Of the TRPV1 antagonists tested, BCTC combined strong TRPV1 antagonism with TRPV1 selectivity.

Review article: gastrointestinal sensory and motor disturbances in inflammatory bowel disease - clinical relevance and pathophysiological mechanisms.

BACKGROUND: It is well known that inflammation has a profound impact on the neuromuscular apparatus of the gastrointestinal tract during the inflammatory insult and in periods of remission, at the site of inflammation and at distance from this site. The importance of this interaction is illustrated by the higher prevalence of functional gut disorders in patients with inflammatory bowel disease. AIMS: To document the epidemiological and clinical significance of functional alterations of gut motility and sensitivity in patients with inflammatory bowel disease and to formulate potential pathophysiological mechanisms. RESULTS AND CONCLUSIONS: Functional gut disorders occur frequently in patients with inflammatory bowel disease, both during inflammatory episodes and in periods of remission, and have a major impact on their quality of life. The clinical manifestations of these motility and sensitivity disorders vary and are often difficult to treat, mainly because therapeutic guidelines and specific diagnostic tests to distinguish inflammatory bowel disease from functional gut disorders are lacking. Chronic bowel inflammation results in a complicated interaction between neuroendocrine serotonin-predominant cells of the mucosa, inflammatory cells (particularly mast cells) in the submucosa, the intrinsic and extrinsic innervation and the muscular apparatus including the interstitial cells of Cajal. The outcome of this interaction is a perturbation of gastrointestinal motor function, both locally and at distance from the site of inflammation and during both acute inflammation and remission.

TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats.

Rats with experimental colitis suffer from impaired gastric emptying (GE). We previously showed that this phenomenon involves afferent neurons within the pelvic nerve. In this study, we aimed to identify the mediators involved in this afferent hyperactivation. Colitis was induced by trinitrobenzene sulfate (TNBS) instillation. We determined GE, distal front, and geometric center (GC) of intestinal transit 30 min after intragastric administration of a semiliquid Evans blue solution. We evaluated the effects of the transient receptor potential vanilloid type 1 (TRPV1) antagonists capsazepine (5-10 mg/kg) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 1-10 mg/kg) and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) (150 microg/kg). To determine TRPV1 receptor antagonist sensitivity, we examined their effect on capsaicin-induced relaxations of isolated gastric fundus muscle strips. Immunocytochemical staining of TRPV1 and RT-PCR analysis of TRPV1 mRNA were performed in dorsal root ganglion (DRG) L6-S1. TNBS-induced colitis reduced GE but had no effect on intestinal motility. Capsazepine reduced GE in controls but had no effect in rats with colitis. At doses that had no effects in controls, BCTC and CGRP-(8-37) significantly improved colitis-induced gastroparesis. Capsazepine inhibited capsaicin-induced relaxations by 35% whereas BCTC completely abolished them. TNBS-induced colitis increased TRPV1-like immunoreactivity and TRPV1 mRNA content in pelvic afferent neuronal cell bodies in DRG L6-S1. In conclusion, distal colitis in rats impairs GE via sensitized pelvic afferent neurons. We provided pharmacological, immunocytochemical, and molecular biological evidence that this sensitization is mediated by TRPV1 receptors and involves CGRP release.

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.

Opioids and the gut: pharmacology and current clinical experience.

This article reviews the pharmacology and physiology of opiate receptors and the current and potential uses of opioid agonists and antagonists in clinical gastroenterology. Mu-receptors are involved in motor and sensory functions, and their modulation is established for treatment of diarrhea. Mu-antagonists have potential to reverse endogenous (e.g., postoperative ileus) or iatrogenic dysmotility (e.g., opioid bowel dysfunction). Modulation of the function of kappa-receptors may be a novel approach to control visceral pain in functional gut disorders. Results of formal testing of novel opioid modulators are keenly awaited.

Assessment of gastric accommodation: overview and evaluation of current methods.

Gastric accommodation is considered important in the pathophysiology of several upper gastrointestinal disorders including functional dyspepsia. The gold standard for its measurement is the barostat-balloon study which requires intubation. The aim was explore the reliability and performance characteristics of the techniques proposed for measurement of gastric accommodation. We undertook a literature search using MEDLINE with a broad range of key words. The accommodation reflex and its control are briefly described, based on human data. The performance characteristics of the intragastric barostat, transabdominal ultrasound, magnetic resonance imaging, single photon emission computed tomography, and satiation drinking tests are described. For each technique, we summarize the following: principle, validation studies, advantages, disadvantages, and potential applications. Three-dimensional methods to measure gastric volume non-invasively are promising and among the best validated to date. Simpler techniques would be of considerable appeal for clinical and research studies, but further validation is necessary before satiation drinking tests can be used as surrogates for more sophisticated measurements of gastric accommodation.