Gerald Holtmann

Gastric Helicobacter pylori infection accelerates healing of reflux esophagitis during treatment with the proton pump inhibitor pantoprazole.

BACKGROUND & AIMS In previous studies an exaggerated effect of proton pump inhibitors (PPIs) on intragastric pH in Helicobacter pylori-infected patients was observed. Because healing and improvement of symptoms in patients with gastroesophageal reflux disease (GERD) is directly associated with an increase of intragastric pH during treatment, we hypothesized that the response to treatment with a PPI in patients with reflux esophagitis would be better in H. pylori-infected patients than in patients without H. pylori infection. METHODS We recruited 971 patients with endoscopically verified reflux esophagitis grades II and III (Savary/Miller). At study entry, H. pylori status was assessed by a 13C-urea breath test and baseline characteristics were recorded. Physicians and patients were not notified about the results of the breath test until completion of the study. All patients underwent treatment with pantoprazole, 40 mg orally once daily for 4 weeks. Healing was verified by endoscopy after 4 or 8 weeks of treatment. If the esophagitis had not completely healed at this time, treatment was continued for a further 4-week period. Healing rates and symptom relief were compared for patients with and without H. pylori infection. RESULTS The prevalence of H. pylori was 39.9% (95% confidence interval [CI], 36.9-42.9), and neither gender, smoking, nor alcohol consumption were associated with the H. pylori infection (P > 0.4). The trial was completed by 846 patients without protocol violation. Overall healing rates of reflux esophagitis were 80.4% (95% CI, 77.7-83.1) and 93.6% (95% CI, 91.8-95.2) after 4 and 8 weeks, respectively. In H. pylori-positive patients, healing rates were significantly higher after 4 (86.6% vs. 76.3%; P = 0.0005) and 8 weeks (96.4% vs. 91.8%; P < 0.004). Relief of symptoms after 4 weeks was also significantly (P < 0.05) better in H. pylori-infected patients than in uninfected patients. CONCLUSIONS Patients with reflux esophagitis and H. pylori infection respond significantly better than H. pylori-negative patients to the PPI pantoprazole.

Prokinetics in Patients with Gastroparesis: A Systematic Analysis

Background: The relative potency of prokinetics in patients with gastroparesis has not been systematically studied. This study, therefore, aimed to assess the available data and to compare the effects of different prokinetics on symptoms and gastric emptying rates in patients with gastroparesis. Methods: A systematic search of the literature was performed, covering the period 1980 to March 1998. All identified studies were reviewed and the following data elements assessed: characteristics of study populations; sample sizes; treatment regimes; drug doses; study design; main outcome variables, and the validity of measurements. Results: In 36 studies, 514 patients were treated with prokinetics p.o. Most studies had methodological limitations (i.e. nonvalidated measurement of symptoms or unblinded treatment). The mean improvement in gastric emptying and the reduction in the symptom score was higher in the open trial group than in patients treated double-blind. Overall, erythromycin seems to have had the strongest effect on gastric emptying as compared to domperidone, cisapride or metoclopramide. Concerning gastrointestinal symptoms, the symptom scores appeared to improve more during treatment with erythromycin than with domperidone, metoclopramide or cisapride. Conclusions: Most of the available trials have methodological limitations; this limits the conclusions. However, the data suggest that the motilin-agonist erythromycin is superior with regard to the acceleration of gastric emptying, while both erythromycin and domperidone appear to be the most effective with regard to improvements in the symptom score. Additionally, there is a lack of association between changes in gastric emptying times and improvements in symptoms.

The ion channel TRPA1 is required for normal mechanosensation and is modulated by algesic stimuli

BACKGROUND & AIMS The transient receptor potential (TRP) channel family includes transducers of mechanical and chemical stimuli for visceral sensory neurons. TRP ankyrin 1 (TRPA1) is implicated in inflammatory pain; it interacts with G-protein-coupled receptors, but little is known about its role in the gastrointestinal (GI) tract. Sensory information from the GI tract is conducted via 5 afferent subtypes along 3 pathways. METHODS Nodose and dorsal root ganglia whose neurons innnervate 3 different regions of the GI tract were analyzed from wild-type and TRPA1(-/-) mice using quantitative reverse-transcription polymerase chain reaction, retrograde labeling, and in situ hybridization. Distal colon sections were analyzed by immunohistochemistry. In vitro electrophysiology and pharmacology studies were performed, and colorectal distension and visceromotor responses were measured. Colitis was induced by administration of trinitrobenzene sulphonic acid. RESULTS TRPA1 is required for normal mechano- and chemosensory function in specific subsets of vagal, splanchnic, and pelvic afferents. The behavioral responses to noxious colonic distension were substantially reduced in TRPA1(-/-) mice. TRPA1 agonists caused mechanical hypersensitivity, which increased in mice with colitis. Colonic afferents were activated by bradykinin and capsaicin, which mimic effects of tissue damage; wild-type and TRPA1(-/-) mice had similar direct responses to these 2 stimuli. After activation by bradykinin, wild-type afferents had increased mechanosensitivity, whereas, after capsaicin exposure, mechanosensitivity was reduced: these changes were absent in TRPA1(-/-) mice. No interaction between protease-activated receptor-2 and TRPA1 was evident. CONCLUSIONS These findings demonstrate a previously unrecognized role for TRPA1 in normal and inflamed mechanosensory function and nociception within the viscera.

Selective role for TRPV4 ion channels in visceral sensory pathways.

BACKGROUND & AIMS Although there are many candidates as molecular mechanotransducers, so far there has been no evidence for molecular specialization of visceral afferents. Here, we show that colonic afferents express a specific molecular transducer that underlies their specialized mechanosensory function: the transient receptor potential channel, vanilloid 4 (TRPV4). METHODS We found TRPV4 mRNA is highly enriched in colonic sensory neurons compared with other visceral and somatic sensory neurons. TRPV4 protein was found in colonic nerve fibers from patients with inflammatory bowel disease, and it colocalized in a subset of fibers with the sensory neuropeptide CGRP in mice. We characterized the responses of 8 subtypes of vagal, splanchnic, and pelvic mechanoreceptors. RESULTS Mechanosensory responses of colonic serosal and mesenteric afferents were enhanced by a TRPV4 agonist and dramatically reduced by targeted deletion of TRPV4 or by a TRP antagonist. Other subtypes of vagal and pelvic afferents, by contrast, were unaffected by these interventions. The behavioral responses to noxious colonic distention were also substantially reduced in mice lacking TRPV4. CONCLUSIONS These data indicate that TRPV4 contributes to mechanically evoked visceral pain, with relevance to human disease. In view of its distribution in favor of specific populations of visceral afferents, we propose that TRPV4 may present a selective novel target for the reduction of visceral pain, which is an important opportunity in the absence of current treatments.

Treatment of irritable bowel syndrome with herbal preparations: results of a double-blind, randomized, placebo-controlled, multi-centre trial

Background : Herbal medications have been used in many countries for the treatment of patients with irritable bowel syndrome. Controlled data supporting the efficacy of these treatments in patients with irritable bowel syndrome are lacking.

Asia-Pacific consensus on the management of gastroesophageal reflux disease: update.

Background and Aims:  Since the publication of the Asia‐Pacific GERD consensus in 2004, more data concerning the epidemiology and management of gastroesophageal reflux disease (GERD) have emerged. An evidence based review and update was needed.

Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia

Background—Abnormal visceral mechanosensory and vagal function may play a role in the development of functional gastrointestinal disorders. Aims—To assess whether vagal efferent and afferent function is linked with small intestinal mechanosensory function. Methods—In seven patients with functional dyspepsia, six patients with a history of Billroth I gastrectomy and/or vagotomy, and seven healthy controls, intestinal perception thresholds were tested by a randomised ramp distension procedure performed with a barostat device. On a separate day, an insulin hypoglycaemia test was performed to assess the plasma levels of pancreatic polypeptide (PP) in response to hypoglycaemia, as a test of efferent vagal function. Results—First perception of intestinal balloon distension occurred at significantly lower pressures in patients with functional dyspepsia (median 19.3, range 14.7–25.3 mm Hg) compared with healthy controls (median 26.0, range 21.7–43.7 mm Hg, p<0.01). Sensory thresholds were significantly lower in patients after gastrectomy (median 12.2, range 8.0–14.7 mm Hg, p<0.05 versus all others). In healthy controls and patients with functional dyspepsia, insulin hypoglycaemia significantly (p<0.001) increased plasma PP levels. However, only two out of seven patients with functional dyspepsia had a more than twofold increase in PP values whereas all healthy controls had a more than twofold increase in PP levels after insulin hypoglycaemia (p<0.05). In contrast, there was no significant PP response in the gastrectomised patients (median 2%, range −10 to +23%). PP responses and visceral sensory thresholds were significantly correlated (r=0.65, p<0.002). Conclusions—The diminished PP response after insulin hypoglycaemia indicates disturbed efferent vagal function in a subgroup of patients with functional dyspepsia. The data also suggest that the intact vagal nerve may exert an antinociceptive visceral effect.

Controversies surrounding the comorbidity of depression and anxiety in inflammatory bowel disease patients: A literature review

Abstract Psychological disorders are highly prevalent in patients with inflammatory bowel disease (IBD). Anxiety and depression are known to independently affect quality of life and may additionally impair quality of life in IBD over and above the IBD itself. Some researchers have further proposed that anxiety and depression may influence the clinical course of IBD. However, despite the potential for anxiety and depression to play an important role in the clinical picture of IBD, there is little prospective well‐controlled research in this area. Probably because of this lack of clear data, researchers dispute the actual role of these psychological disorders in IBD, with a number of conflicting opinions expressed. This article reports on a review of the literature in this field. Herein we discuss the five main areas of controversy regarding IBD and the specific psychological comorbidities of depression and anxiety: 1) the relative rate of cooccurrence of these psychological disorders with IBD; 2) the cooccurrence of these psychological disorders with particular phase of IBD; 3) the cooccurrence of these psychological disorders with the specific type of IBD; 4) the rate of these psychological comorbidities compared both to healthy subjects and to other disease states; and 5) the timing of onset of psychological comorbidity with respect to onset of IBD. Methodological weaknesses of the reviewed studies make it impossible to resolve these controversies. However, the results clearly show that anxiety/depression and IBD frequently interact. Given the long‐term illness burden patients with IBD face, further prospective, appropriately controlled studies are needed to adequately answer the question of the precise interplay between anxiety/depression and IBD. (Inflamm Bowel Dis 2007)

Sensory neuro-immune interactions differ between Irritable Bowel Syndrome subtypes

Objective The gut is a major site of contact between immune and sensory systems and evidence suggests that patients with irritable bowel syndrome (IBS) have immune dysfunction. Here we show how this dysfunction differs between major IBS subgroups and how immunocytes communicate with sensory nerves. Design Peripheral blood mononuclear cell supernatants from 20 diarrhoea predominant IBS (D-IBS) patients, 15 constipation predominant IBS (C-IBS) patients and 36 healthy subjects were applied to mouse colonic sensory nerves and effects on mechanosensitivity assessed. Cytokine/chemokine concentration in the supernatants was assessed by proteomic analysis and correlated with abdominal symptoms, and expression of cytokine receptors evaluated in colonic dorsal root ganglia neurons. We then determined the effects of specific cytokines on colonic afferents. Results D-IBS supernatants caused mechanical hypersensitivity of mouse colonic afferent endings, which was reduced by infliximab. C-IBS supernatants did not, but occasionally elevated basal discharge. Supernatants of healthy subjects inhibited afferent mechanosensitivity via an opioidergic mechanism. Several cytokines were elevated in IBS supernatants, and levels correlated with pain frequency and intensity in patients. Visceral afferents expressed receptors for four cytokines: IL-1β, IL-6, IL-10 and TNF-α. TNF-α most effectively caused mechanical hypersensitivity which was blocked by a transient receptor potential channel TRPA1 antagonist. IL-1β elevated basal firing, and this was lost after tetrodotoxin blockade of sodium channels. Conclusions Distinct patterns of immune dysfunction and interaction with sensory pathways occur in different patient groups and through different intracellular pathways. Our results indicate IBS patient subgroups would benefit from selective targeting of the immune system.

Dyspepsia in healthy blood donors : pattern of symptoms and association with Helicobacter pylori

WhetherHelicobacter pylori is causally linked to dyspepsia remains controversial. The aims of this study were to assess in healthy blood donors the prevalence of dyspepsia and dyspepsia subgroups, determine ifH. pylori is associated with different categories of dyspeptic symptoms, and evaluate the association between dyspepsia and nicotine, alcohol, and analgesic use. Consecutive blood donors (N=180) who had no clinical evidence of organic disease were included. Abdominal symptoms were measured by means of a standardized questionnaire that has been previously validated. Subjects with dyspepsia (defined as pain localized to the upper abdomen) were further subdivided into those with ulcer-like, dysmotility-like, reflux-like, or nonspecific dyspepsia. A total of 65 subjects reported abdominal pain or discomfort during the prior 12 months [36.1%, 95% confidence interval (CI) 29.1–43.1]; 44 subjects (24.4%, 95% CI 18.2–30.7) had dyspepsia. Dysmotility-like, reflux-like, and ulcer-like symptoms were reported by 19.4% (95% CI 13.7–25.2), 17.2% (95% CI 11.7–22.7), and 16.7% (95% CI 11.2–22.1) of subjects with dyspepsia, respectively. Fifty-seven subjects (31.7%, 95% CI 24.9–38.5) wereH. pylori positive; 26% of subjects withH. pylori and 24% withoutH. pylori had dyspepsia (P>0.50). The seroprevalence ofH. pylori was also similar among the different categories of dyspepsia. We conclude that infection withH. pylori is not associated with abdominal complaints in otherwise healthy subjects.