Christopher N. Andrews

Alterations in Mucosal Immunity Identified in the Colon of Patients With Irritable Bowel Syndrome

BACKGROUND & AIMS Irritable bowel syndrome (IBS) has been associated with mucosal dysfunction, mild inflammation, and altered colonic bacteria. We used microarray expression profiling of sigmoid colon mucosa to assess whether there are stably expressed sets of genes that suggest there are objective molecular biomarkers associated with IBS. METHODS Gene expression profiling was performed using Human Genome U133 Plus 2.0 (Affymetrix) GeneChips with RNA from sigmoid colon mucosal biopsy specimens from 36 IBS patients and 25 healthy control subjects. Real-time quantitative polymerase chain reaction was used to confirm the data in 12 genes of interest. Statistical methods for microarray data were applied to search for differentially expressed genes, and to assess the stability of molecular signatures in IBS patients. RESULTS Mucosal gene expression profiles were consistent across different sites within the sigmoid colon and were stable on repeat biopsy over approximately 3 months. Differentially expressed genes suggest functional alterations of several components of the host mucosal immune response to microbial pathogens. The most strikingly increased expression involved a yet uncharacterized gene, DKFZP564O0823. Identified specific genes suggest the hypothesis that molecular signatures may enable distinction of a subset of IBS patients from healthy controls. By using 75% of the biopsy specimens as a validation set to develop a gene profile, the test set (25%) was predicted correctly with approximately 70% accuracy. CONCLUSIONS Mucosal gene expression analysis shows there are relatively stable alterations in colonic mucosal immunity in IBS. These molecular alterations provide the basis to test the hypothesis that objective biomarkers may be identified in IBS and enhance understanding of the disease.

Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans

Glucagon-like peptide-1 (GLP-1), an incretin, which is used to treat diabetes mellitus in humans, inhibited vagal activity and activated nitrergic pathways. In rats, GLP-1 also increased sympathetic activity, heart rate, and blood pressure (BP). However, the effects of GLP-1 on sympathetic activity in humans are unknown. Our aims were to assess the effects of a GLP-1 agonist with or without alpha(2)-adrenergic or -nitrergic blockade on autonomic nervous functions in humans. In this double-blind study, 48 healthy volunteers were randomized to GLP-1-(7-36) amide, the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-l-arginine acetate (l-NMMA), the alpha(2)-adrenergic antagonist yohimbine, or placebo (i.e., saline), alone or in combination. Hemodynamic parameters, plasma catecholamines, and cardiac sympathetic and parasympathetic modulation were measured by spectral analysis of heart rate. Thereafter, the effects of GLP-1-(7-36) amide on muscle sympathetic nerve activity (MSNA) were assessed by microneurography in seven subjects. GLP-1 increased (P = 0.02) MSNA but did not affect cardiac sympathetic or parasympathetic indices, as assessed by spectral analysis. Yohimbine increased plasma catecholamines and the low-frequency (LF) component of heart rate power spectrum, suggesting increased cardiac sympathetic activity. l-NMMA increased the BP and reduced the heart rate but did not affect the balance between sympathetic and parasympathetic activity. GLP-1 increases skeletal muscle sympathetic nerve activity but does not appear to affect cardiac sympathetic or parasympathetic activity in humans.

Description of prescribing practices in patients with upper gastrointestinal bleeding receiving intravenous proton-pump inhibitors: A multicentre evaluation

BACKGROUND Intravenous forms of proton pump inhibitors (IV PPI) are routinely used for patients with acute upper gastrointestinal bleeding, but a significant concern for their inappropriate use has been suggested. patients and METHODS All consecutive patients who received IV PPI (pantoprazole) over 20 months in six Canadian hospitals were reviewed. Prescribing practices, endoscopic findings and outcomes were recorded. RESULTS A total of 854 patients received IV PPI. Over 90% of patients were given IV PPI for treatment of known or suspected active upper gastrointestinal bleeding. Most patients (69%) underwent upper endoscopy, and 58% of these patients had peptic ulcer disease (PUD). The majority of patients who had endoscopy (57%) had IV PPI administered in advance of the procedure. Of the 334 patients who had IV PPI given in advance, 46 (13.8%) were found to have high risk bleeding PUD stigmata at endoscopy. The remaining 288 patients (86.2%) with advance IV PPI had low-risk PUD lesions or non-PUD lesions; IV PPI was continued after endoscopy in 164 (56.9%) of these patients. CONCLUSIONS IV PPI is often used before endoscopy in suspected upper gastrointestinal bleed and maintained, regardless of endoscopic findings, after the endoscopy in many Canadian centres. Further study is required to support these clinical practices.

The etiology, assessment, and treatment of fecal incontinence.

Fecal incontinence is a common symptom that often impairs quality of life. It is generally caused by a variety of conditions that are associated with anorectal sensorimotor dysfunction and/or diarrhea. Assessment should be tailored to age and symptom severity. Modulation of disordered bowel habits is the key to management; biofeedback and surgery might also be beneficial.

Effect of tolterodine on gastrointestinal transit and bowel habits in healthy subjects

Abstract  Clinical trials and observations suggest that constipation is an uncommon side effect of treating overactive bladder with the muscarinic receptor antagonist tolterodine. Because muscarinic antagonism inhibits gastrointestinal motor activity, we evaluated the effects of tolterodine on bowel habits, gastrointestinal and colonic transit in healthy subjects. In this double‐blind study, 36 healthy subjects were randomized to tolterodine extended release (ER, 4 mg daily) or placebo for 6 days. Gastric emptying (GE), small bowel and colonic transit were assessed on days 4–6 by scintigraphy. Bowel habits were recorded by diaries. Tolterodine did not significantly affect half‐time for GE (GE thalf) [116 ± 6 min (mean ± SEM) for placebo vs 126 ± 7 min for tolterodine], small bowel transit measured by colonic filling at 6 h (45 ± 6% for placebo vs 36 ± 6% for tolterodine) or the geometric center of colonic transit at 24 h (2.9 ± 0.2 for placebo vs 2.6 ± 0.3 for tolterodine). Subjects who received tolterodine had slightly fewer bowel movements (i.e. 1.34 ± 0.1 stools per day for placebo vs 1.0 ± 0.1 for tolterodine; P = 0.02 for treatment effect). Tolterodine did not significantly affect stool consistency or ease of defecation. At the therapeutic dose used to treat overactive bladder, tolterodine did not significantly affect gastrointestinal or colonic transit and had minor effects on bowel habits in healthy subjects. Further studies are necessary to elucidate whether these observations are explained by tolterodine effects at muscarinic receptors which stimulate and inhibit gastrointestinal motility.

Effects of glucagon-like peptide-1 and sympathetic stimulation on gastric accommodation in humans.

Abstract   In humans, glucagon‐like peptide‐1 (GLP‐1) delays gastric emptying by inhibiting vagal activity and also increases gastric volumes, by unclear mechanisms. Because GLP‐1 inhibits intestinal motility by stimulating the sympathetic nervous system in rats, we assessed the effects of a GLP‐1 agonist and yohimbine, an α2‐adrenergic antagonist, on gastric volumes in humans. In this double‐blind study, 32 healthy volunteers were randomized to placebo, a GLP‐1 agonist, yohimbine or GLP‐1 and yohimbine. Gastric volumes (fasting predrug and postdrug, and postprandial postdrug) were measured by 99mTc single photon emission computed tomography imaging. Plasma catecholamines and haemodynamic parameters were assessed. Compared with placebo, GLP‐1 increased (P = 0.03) but yohimbine did not affect fasting gastric volume. However, GLP‐1 plus yohimbine increased (P < 0.001) postprandial gastric accommodation vs placebo and vs GLP‐1 alone [postprandial volume change = 542 ± 29 mL (mean ± SEM, placebo), 605 ± 31 mL (GLP‐1), 652 ± 54 mL (yohimbine) and 810 ± 37 mL (GLP‐1 and yohimbine)]. Plasma noradrenaline and dihydroxyphenylglycol concentrations were higher for yohimbine vs placebo and for GLP‐1 and yohimbine vs GLP‐1. Yohimbine stimulates central sympathetic activity and in combination with GLP‐1, augments postprandial accommodation in humans.

gastroesophageal reflux symptoms not responding to proton pump inhibitor: geRD, neRD, naRD, esophageal hypersensitivity or dyspepsia?

Gastroesophageal reflux (GER) is a common gastrointestinal process that can generate symptoms of heartburn and chest pain. Proton pump inhibitors (PPIs) are the gold standard for the treatment of GER; however, a substantial group of GER patients fail to respond to PPIs. In the past, it was believed that acid reflux into the esophagus causes all, or at least the majority, of symptoms attributed to GER, with both erosive esophagitis and nonerosive outcomes. However, with modern testing techniques it has been shown that, in addition to acid reflux, the reflux of nonacid gastric and duodenal contents into the esophagus may also induce GER symptoms. It remains unknown how weakly acidic or alkaline refluxate with a pH similar to a normal diet induces GER symptoms. Esophageal hypersensitivity or functional dyspepsia with superimposed heartburn may be other mechanisms of symptom generation, often completely unrelated to GER. Detailed studies investigating the pathophysiology of esophageal hypersensitivity are not conclusive, and definitions of the various disease states may overlap and are often confusing. The authors aim to clarify the pathophysiology, definition, diagnostic techniques and medical treatment of patients with heartburn symptoms who fail PPI therapy.

Relationship of cytochrome P450 pharmacogenetics to the effects of yohimbine on gastrointestinal transit and catecholamines in healthy subjects

Abstract  Alpha‐2 adrenergic receptors tonically inhibit colonic motility and the α2‐adrenergic antagonist yohimbine, given intravenously, increased colonic tone in humans. However, the effect of yohimbine on colonic transit in humans is unknown. In this study, 30 healthy volunteers were randomized to yohimbine 16.2 mg p.o. t.i.d. or identical placebo for 7 days. We evaluated gastric emptying, small intestinal, and colonic transit by scinitigraphy, bowel habits, haemodynamics and plasma catecholamines. As cytochrome P450 enzymes metabolize yohimbine, P450 genotypes (CYP2D6 and CYP3A4) were determined in 25 of 30 subjects who consented to genetic studies. The relationship between drug metabolizer status predicted by CYP2D6 and CYP3A4 and effects of yohmibine were assessed. Compared to placebo, yohimbine increased (P ≤ 0.02) diastolic blood pressure, plasma noradrenaline concentrations and maximum tolerated volume during the satiation test [yohimbine (1241 ± 88, mean ± SEM) vs placebo (1015 ± 87), P = 0.054]. However, yohimbine did not affect gastrointestinal transit. Based on CYP2D6 and CYP3A4 alleles, seven and 18 subjects were, respectively, extensive (EM) and poor (PM) metabolizers of yohimbine. Compared to EM, PM of yohimbine had a greater increase in plasma noradrenaline (P = 0.1 for PM vs EM), lower maximum tolerated volumes (1120 ± 95 vs 1484 + 131 mL, P = 0.02), and faster colonic transit (i.e. GC24 was 3.0 ± 0.4 vs 2.1 ± 0.5, P = 0.1). These data suggest that CYP2D6 and CYP3A4 genotypes which determine the metabolism of yohimbine may influence its sympathetic and gastrointestinal effects.

Transcutaneous Intraluminal Impedance Measurement for Minimally Invasive Monitoring of Gastric Motility: Validation in Acute Canine Models

Transcutaneous intraluminal impedance measurement (TIIM) is a new method to cutaneously measure gastric contractions by assessing the attenuation dynamics of a small oscillating voltage emitted by a battery-powered ingestible capsule retained in the stomach. In the present study, we investigated whether TIIM can reliably assess gastric motility in acute canine models. Methods. Eight mongrel dogs were randomly divided into 2 groups: half received an active TIIM pill and half received an identically sized sham capsule. After 24-hour fasting and transoral administration of the pill (active or sham), two force transducers (FT) were sutured onto the antral serosa at laparotomy. After closure, three standard cutaneous electrodes were placed on the abdomen, registering the transluminally emitted voltage. Thirty-minute baseline recordings were followed by pharmacological induction of gastric contractions using neostigmine IV and another 30-minute recording. Normalized one-minute baseline and post-neostigmine gastric motility indices (GMIs) were calculated and Pearson correlation coefficients (PCCs) between cutaneous and FT GMIs were obtained. Statistically significant GMI PCCs were seen in both baseline and post-neostigmine states. There were no significant GMI PCCs in the sham capsule test. Further chronic animal studies of this novel long-term gastric motility measurement technique are needed before testing it on humans.

Lichen Planus Is an Uncommon Cause of Nonspecific Proximal Esophageal Inflammation

Background/Aims Esophageal lichen planus (LP) has been described as a cause of nonspecific esophagitis that may cause dysphagia, but its incidence is unknown. We aimed to estimate the incidence of esophageal LP in a defined geographic region and describe the clinical characteristics of affected patients. Methods A histopathology database for a population of 1 million people was searched for all esophageal mucosal biopsy results over an 8-year period. Cases showing inflammation or abnormalities without a diagnosis after three or more biopsies were reviewed for findings of LP. Results Of 13,589 esophageal biopsies, only one received a diagnosis of LP. Seven patients (four male; mean age, 59 years; range, 39 to 76 years) were identified as having chronic dysphagia and nonspecific proximal esophagitis for which no diagnosis could be made. All patients had proximal inflammation, and six of seven had full-thickness lymphocytic infiltration. Elongation of the lamina propria papillae was noted in all patients, whereas six patients had parakeratosis and ballooning. Only one patient had findings potentially consistent with, but not sufficient for, a diagnosis of esophageal LP. Conclusions Esophageal LP appears to be extremely uncommon in this North American population, and esophageal biopsy alone is likely not sufficient to establish a diagnosis of LP.