# "Pathophysiology of IBS



## eric (Jul 8, 1999)

FYI"Pathophysiology of IBSThe pathophysiology of IBS is a work in progress. Roughly 200 years after its initial description by the English physician William Powell, our understanding of what causes IBS symptoms remains incompletely understood. For most of the second half of the 20th century, tremendous attention was paid to the concept of altered gut motility as a cause of IBS symptoms.[20] However, several difficulties are apparent in this approach. First, although altered motility of the colon and small bowel can be demonstrated in patients with IBS, there is a very poor correlation between IBS symptomatology and the presence of alterations in gastrointestinal motility.[21] Likewise, drugs that alter gastrointestinal motility alone, such as antispasmodic[22,23] and prokinetic drugs like metoclopramide and cisapride,[24,25] have not been shown to be of any significant benefit in relieving IBS symptoms.The third dilemma facing investigators in this area is that no pathognomonic pattern of gut dysmotility can be identified specifically with IBS, as opposed to other functional or organic disorders of the gut.[20] Altered motility, as occurs in IBS, is currently seen as one of many epiphenomena associated with the disorder, as opposed to being a cause of the disorder itself.In the early 1980s, it was discovered that upon balloon distention in the rectum, individuals suffering from IBS were more sensitive to distention than were individuals who did not suffer from IBS.[26] This means that IBS patients feel discomfort at lower levels of balloon inflation in the rectum and lower bowel than do normal controls. This finding has been replicated in numerous studies, and the concept of "visceral" hypersensitivity has been established.[27] A second level of investigation in this area is the fascinating finding that individuals with IBS not only have a unique local response (in the rectum) to visceral stimulation, but they also tend to process signals in the brain differently from non-IBS controls. Mertz and others[27] have shown that IBS patients have differential responses in the anterior cingulate cortex and other areas of the brain when stimulated with rectal or sigmoid colon distention, compared with controls. These findings have been replicated by other investigators.[28] These data certainly suggest the possibility of a "brain-gut axis" where peripheral symptoms are processed in the end organ (ie, the colon), and then neural signals are carried via visceral afferents to the spinal cord, and then to the brain, where they are subject to additional processing.[29] It is this brain-gut axis that has received considerable attention recently in IBS research. The findings of enhanced visceral sensitivity in the colon and rectum, as well as altered processing of signals in the brain, have provided new insight. Regarding the pathophysiology of IBS, the altered processing of neural sensation in IBS patients logically raises the question as to which neurotransmitters play a role in this abnormal signal transmission.A large number of neuropeptides are involved in the regulation of both gastrointestinal motility and sensation in the gut. These include motolin, gastrin, peptide Y, cholecystokinin, serotonin, and others.Serotonin has received the most interest for a number of reasons. The first reason is the dramatic impact that modulation of serotonin has had on psychiatric disorders. The development of selective serotonin reuptake inhibitor (SSRI) medications in the late 1980s revolutionized the practice of psychiatry. The ability to treat depression with far fewer side effects than seen with earlier drugs made depression treatment more acceptable both to patients and physicians. The success of these medications led to increased interest in the role of serotonin in the nervous system. The second reason is that almost all (ie, more than 90%) of the serotonin contained in the body is found in the gut and not in the central nervous system.[29] This fact raises the reasonable question of whether modulation of serotonin action in the gut could influence IBS and other functional bowel symptoms.Serotonin (5-HT) is an interesting molecule. There are at least 15 subtypes of the 5-HT molecule. 5-HT1 and 5-HT2 are contained almost exclusively in the central nervous system. These are the target neurotransmitters for the SSRIs. The subtypes of serotonin contained in the gut consist mainly of 5-HT3 and 5-HT4, which has led to the development of drugs designed specifically to act on these serotonin subtypes (see detailed discussion in the Management section below). Identifying the role of serotonin in the pathophysiology of IBS symptomatology has led to the investigation of other neurotransmitters. Cholecystokinin antagonist and various neurokinin antagonists are all actively being investigated for their potential to influence IBS symptomatology.[30] This has led to a whole new era of gastrointestinal pharmacology based on a brain-gut axis. The opportunity to develop interventions at the level of the bowel, spinal cord, and brain based on this pathophysiologic conceptual model is considerable."http://www.medscape.com/viewarticle/463481_3


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