Increased mast cells in the irritable bowel syndrome M. O'SULLIVAN, N. CLAYTON,* N. P. BRESLIN, I . HARMAN,* C. BOUNTRA,* A. MCLAREN* &C. A. O'MORAIN Adelaide & Meath Hospitals, Trinity College Dublin, Ireland *GlaxoWellcome Medicines Research Centre, Stevenage, UK Abstract Mast cells (MC) release potent mediators which alter enteric nerve and smooth muscle function and may play a role in the pathogenesis of the irritable bowel syndrome (IBS). The aim of this study was to determine if MC were increased in the colon of IBS patients compared to controls. Biopsy specimens were obtained from the caecum, ascending colon, descending colon and rectum of 28 patients: 14 IBS (Rome criteria); seven normal; and seven in¯amma- tory controls. Tissue was stained immunohistochem- ically using a monoclonal mouse antibody for human mast cell tryptase (AA1). Tissue area occupied by tryptase-positive MC (volume density of mast cells) was quanti®ed by image analysis. The number of plasma cells, lymphocytes, eosinophils, neutrophils and macrophages were each graded semiquantita- tively (0±4) in haematoxylin and eosin stained sections. Mast cell volume density was signi®cantly (P < 0.05) higher in IBS (0.91  0.18; CI 0.79; 1.0) than normal controls (0.55  0.14; CI 0.40; 0.69) in the caecum but not at other sites. Apart from MC, there was no evidence of increased cellular in®ltrate in the IBS group. MC were signi®cantly increased in the caecum of IBS patients compared to controls. The multiple effects of the intestinal mast cell alone, or as a participant of a persistent in¯ammatory response, may be fundamental to the pathogenesis of IBS. Keywords functional bowel disorders, irritable bowel syndrome, mast cell, tryptase. INTRODUCTION Poor understanding of the pathophysiology of the irrit- able bowel syndrome (IBS) has made the development of speci®c and effective treatment strategies notori- ously dif®cult. Some of the most innovative and promising advances in our understanding of the underlying mechanisms, in at least a subset of IBS, come from work on gastrointestinal in¯ammation. 1 After an acute in¯ammatory event such as gastro- enteritis, 30% of individuals develop persistent IBS symptoms 2,3 that may be attributable to a persistent in¯ammatory response. 4 Since overt intestinal in¯am- mation precludes a diagnosis of IBS, the focus must be on markers of a low-grade 5 or previous in¯ammatory event. Even mild in¯ammation 6 or that at a remote site 7,8 can cause persistent changes in enteric nerve and muscle function. 9 In IBS, numerous studies show physiological evidence of altered muscle and nerve function. 10±18 Mast cells release potent in¯ammatory and im- mune-modulating mediators that alter nerve 19±21 and muscle 22,23 function and are therefore promising can- didates for involvement in IBS. Although traditionally seen in the context of the type I hypersensitivity response, mast cell degranulation and mediator release is also associated with factors such as stress, 24 nerve damage, 25,26 infection 27 and a variety of in¯ammatory events. 28 The close proximity of the MC to the enteric nerves 29±32 offers important potential for inducing changes in nerve function and the development of heightened visceral sensitivity. Furthermore, sub- stance P, for example, can increase the excitability of mast cells without causing degranulation. In IBS, the mast cell may well be an important mediator in a complex interaction between a physiological events (gut insult, in¯ammation, tissue injury, nerve injury) and psychological factors (stressful events, emotions). Address for correspondence Professor Colm O'Morain, Department of Gastroenterology, Adelaide & Meath Hospital, Tallaght, Dublin 24, Ireland. Tel.: + 353 1414 4152; fax: + 353 1414 3850; e-mail: gastroenterology@amnch.ie Received: 1 October 1999 Accepted for publication: 28 March 2000 This paper was an oral presentation at Digestive Disease Week, New Orleans, USA, 1998. *These co-authors are employees of GlaxoWellcome; remaining authors have no ®nancial links with this company. Neurogastroenterol. Mot. (2000) 12, 449±457 Ó 2000 Blackwell Science Ltd 449