No abstract

SUMMARYAlterations in motility, secretion and visceral sensation are hallmarks of irritable bowel syndrome. As all of these aspects of gastrointestinal function involve serotonin signalling between enterochromaffin cells and sensory nerve fibres in the mucosal layer of the gut, potential alterations in mucosal serotonin signalling have been explored as a possible mechanism of altered function and sensation in irritable bowel syndrome. Literature related to intestinal serotonin signalling in normal and pathophysiological conditions has been searched and summarized.Elements of serotonin signalling that are altered in irritable bowel syndrome include: enterochromaffin cell numbers, serotonin content, tryptophan hydroxylase message levels, 5-hydroxyindoleacedic acid levels, serum serotonin levels and expression of the serotonin-selective reuptake transporter. Both genetic and epigenetic factors could contribute to decreased serotonin-selective reuptake transporter in irritable bowel syndrome. A serotonin-selective reuptake transporter gene promoter polymorphism may cause a genetic predisposition, and inflammatory mediators can induce serotonin-selective reuptake transporter downregulation.While a psychiatric co-morbidity exists with IBS, changes in mucosal serotonin handling support the concept that there is a gastrointestinal component to the aetiology of irritable bowel syndrome. Additional studies will be required to gain a more complete understanding of changes in serotonin signalling that are occurring, their cause and effect relationship, and which of these changes have pathophysiological consequences.

Inflammatory bowel disease patients had an increased risk of influenza compared with those without IBD and were more likely to require hospitalization. Steroids were the only medication class independently associated with flu risk.

Anxiety and depression are common in the setting of IBD and are strongly associated with surgical history, disease complications (including extra-intestinal manifestations), smoking, and female gender. Inflammatory bowel disease patients with A&D are also more likely to require therapy and to utilize healthcare resources. This study refines our understanding of A&D development and its impact in IBD and provides additional considerations for management in this setting.

Serotonin-selective reuptake transporter (SERT) expression is decreased in animal models of intestinal inflammation and in individuals with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), and it is possible that resultant changes in intestinal serotonin signalling contribute to the manifestation of clinical features associated with these disorders. The objective of this investigation was to determine whether inhibition of SERT function leads to changes in gut motility and sensitivity. Mice underwent a 14-day treatment with the SERT inhibitor, paroxetine (20 mg kg(-1)), or vehicle (saline/propylene glycol). Gastrointestinal (GI) transit following charcoal gavage, colonic motility, stool frequency and visceromotor responses to colorectal distension were evaluated. In mice treated with paroxetine, stool output was decreased, upper GI transit was delayed, and colonic sensitivity to a nociceptive stimulus was attenuated. These results demonstrate that reduced SERT function (via pharmacological blockade) significantly alters GI motility and sensitivity in mice, and support the concept that altered SERT expression and function could contribute to symptoms associated with IBS and IBD.

Insights discussed in this review have strong potential to lead to new diagnostic and therapeutic tools to improve the management of IBD and other related disorders. Specifically, strategies that focus on modifying the activity of selective serotonin receptors and reuptake transporters in the gut could be effective for controlling disease activity and/or its associated symptoms. Further studies in humans are required, however, to more completely understand the pathophysiological mechanisms underlying the roles of 5-HT in this setting.

OBJECTIVES-Changes in mucosal serotonin (5-HT) signaling have been detected in a number of functional and inflammatory disorders of the gastrointestinal tract. This study was undertaken to determine whether chronic constipation (CC) is associated with disordered 5-HT signaling and to evaluate whether constipation caused by opiate use causes such changes.METHODS-Human rectal biopsy samples were obtained from healthy volunteers, individuals with idiopathic CC, and individuals taking opiate medication with or without constipation. EC cells were identified by 5-HT immunohistochemistry. 5-HT content and 5-HT release levels were determined Correspondence: Gary M. Mawe, Ph.D., D403A Given Building, Department of Anatomy and Neurobiology, University of Vermont, Burlington, VT, USA 05405, (802) 656-8257 (phone), (802) 656-8704 (fax), gary.mawe@uvm.edu. * MMC and MDC contributed equally to this work, with MMC concentrating primarily on the chronic constipation arm of the study and MDC working primarily on the opiate constipation experiments. Conflict of interest items 1. Guarantor of the manuscriptGary M. Mawe, PhD 2. Roles of each author Meagan M Costedio: patient screening, obtaining consent, tissue acquisition, tissue processing, data analysis, and manuscript preparation and editing Matthew D Coates: patient screening, obtaining consent, tissue acquisition, tissue processing, data analysis, and manuscript preparation and editing Elice M Brooks: tissue acquisition, data acquisition, and data analysis Lisa M Glass: data acquisition, and data analysis. Eric K Ganguly: aided in conception of the project, acquiring IRB approval, obtaining informed consent, and tissue acquisition. Hagen Blaszyk: evaluation of sections and blind scoring of inflammation levels in the chronic constipation component of the study Allison L. Ciolino: evaluation of sections and blind scoring of inflammation levels in the opiate constipation component of the study Michael J Wood: involved in obtaining informed consent, and tissue acquisition. Doris Strader: involved in obtaining informed consent, and tissue acquisition. Neil H Hyman: involved in study conceptualization, planning, and identifying potential candidates for the chronic constipation component of the study. Peter L Moses: involved in study conceptualization, planning, obtaining informed consent, and tissue acquisition, data analysis, and manuscript preparation and editing Gary M Mawe: involved in study conceptualization, planning, data analysis, and manuscript preparation and editing. All authors reviewed and approved the manuscript prior to submission. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript by enzyme immunoassay, and mRNA levels for the synthetic enzyme, tryptophan hydroxylase 1 (TpH1) and the serotonin transporter (SERT) were assessed by quantitative real-time RT-PCR.RESULTS-CC was associated with increases in TpH1 transcript, 5-HT content, and 5-HT release under basal and stimulated conditions, whereas EC cell numbers and SERT transcript leve...

Diverticulosis is extremely common in Western societies and is associated with complications in up to 15%of cases. Altered motility is an important feature of the pathogenesis of diverticular disease, and serotonin (5-HT) release is a primary trigger of gut motility. This study aims to determine whether colonic 5-HT signaling is altered in patients with diverticulosis or diverticulitis, and whether differences in serotonin signaling may distinguish patients with asymptomatic diverticulosis from those who develop disease specific complications. Sigmoid colon biopsies were obtained from healthy control subjects, individuals with asymptomatic diverticulosis, and those with a history of CT-proven diverticulitis within the preceding 6 months. The key elements of 5-HT signaling including content, release, and 5-HT transporter (SERT) expression were analyzed. A significant decrease in SERT transcript levels was present in the mucosa of patients with a history of diverticulitis when compared with controls, but not in those with asymptomatic diverticulosis. Mucosal 5-HT content, enterochromaffin (EC) cell numbers, and TpH-1 mRNA levels were comparable amongst the groups, as were basal and stimulated 5-HT release. Alterations in 5-HT signaling do not appear to be responsible for the development of diverticula. However, patients with a recent history of acute diverticulitis have a significant attenuation in SERT expression and function, likely secondary to previous inflammation. Our findings may explain the persistent symptoms of pain and altered motility so often observed in patients with diverticulitis long after recovery from the acute inflammatory response.