Review Article: Intestinal Serotonin Signalling in Irritable Bowel Syndrome

G. M. Mawe; M. D. Coates; P. L. Moses

Disclosures

Aliment Pharmacol Ther. 2006;23(8):1067-1076. 

In This Article

Concluding Remarks

The studies summarized here provide compelling evidence for a role for altered mucosal 5-HT signalling in IBS, as well as in IBD and other GI disorders. While the data reported in these studies represent snapshots of 5-HT signalling in what are generally chronic conditions, it is clear that the sequence of events responsible for 5-HT signalling can be remodelled in response to various physiological and pathophysiological conditions. Although the cause and effect relationship of these changes has not been established, it is quite likely that altered 5-HT signalling contributes to abnormal gut function and heightened sensitivity in IBS. Further studies will be required to gain a more complete picture of the changes that are occurring, and which of these changes have pathophysiological consequences.

One part of the picture that is missing is the status of 5-HT receptors in IBS, and also in IBD. Similar to SERT, 5-HT receptor expression is dynamic and could be affected by the amount of 5-HT that is available and by other factors such as inflammatory mediators. For example, adaptive changes in 5-HT3 receptor expression by enteric neurones have been detected in SERT knockout mice.[59] Studies of 5-HT receptor expression in the intestinal mucosa have been hampered by the fact that mRNA for these receptors is in the neuronal cell bodies, and is therefore not acquired in a mucosal biopsy. As effective receptor-selective antisera become available, progress may be made in this area. A comprehensive understanding of mucosal 5-HT signalling in IBS and IBD will require a thorough appreciation of the status of receptors that mediate the actions of 5-HT.

It is highly unlikely that one given defect or alteration is responsible for the various changes in gut function and sensitivity that are encountered in disorders of GI function. In other words, a universal aetiology for IBS is not likely to exist. For example, in addition to the alterations in 5-HT signalling that are summarized here, it is clear that a co-morbidity exists between psychiatric disorders and IBS, and that many cases of IBS-D involve a previous infectious inflammatory event (postinfectious IBS). Furthermore, mounting evidence suggests a role of the stress hormone, corticotropin-releasing factor, in IBS.[60] Therefore, the variability reported in many IBS studies may be due to the heterogeneity of the patient population. In line with this, it is unlikely that a given therapy will be highly effective in all individuals with IBS, or even a subtype of IBS. Further elucidation, at the molecular level, of the various changes that contribute to the symptoms of the various forms of IBS will hopefully enhance our ability to treat these individuals effectively. In order to make progress in this regard, it will be crucial for investigators to take care in defining the phenotypes of the individuals that are included in a given study, including their predominant GI symptoms, their psychiatric and past medical histories. Furthermore, DNA samples should be acquired for genotyping of these individuals as we identify candidate genes. This type of approach will improve our understanding of the role of 5-HT and other contributing factors in IBS. While the Rome criteria are adequate for making the diagnosis of IBS, assays for detecting molecular abnormalities that are found to contribute to the disorder may assist in identifying those individuals who are most likely to respond to a given treatment plan. This is a significant goal that would ease the frustration and burden of health care providers and patients alike.


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