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Of actors, bolting horses, and drops in oceans!
  1. F Cremonini,
  2. M Camilleri
  1. Emeritus Professor of Medicine, University of Ottawa, Ottawa, Ontario, Canada. K2H 8C4; wgthompson{at}rogers.com
  1. Correspondence to:
    Dr M Camilleri, Mayo Clinic, Charlton 8-110, 200 First Street SW, Rochester, MN 55905, USA;
    camilleri.michael{at}mayo.edu

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Does serotonin mediate postprandial symptoms in irritable bowel syndrome?

Postprandial symptoms are a common feature in patients with irritable bowel syndrome (IBS). In one study, one half of patients presenting with IBS reported symptom occurrence or exacerbation following a meal.1 This effect of meals on gastrointestinal symptoms has been attributed to an increased colonic contractile response to meals in IBS patients. This colonic response has several components.

The first and most rapid component occurs within a few minutes of distension of the stomach by the meal and is mediated by gastric mechanoreceptors that evoke colonic contraction through a vagally mediated afferent pathway.

A second phase, mediated by chemoreceptors in the small intestine, results in colonic contraction that may last up to two hours after meal ingestion.2 Prolonged manometry3 and barostat studies4 demonstrated that the increase in colonic motility after meals was almost immediate, and subsequently we and others reported that patients with diarrhoea and urgency predominant IBS experienced these symptoms in association with repetitive high amplitude propagated contractions that induce mass movements in the colon.5,6

The third phase of the colonic contraction after the meal results from ileal stimulation by chyme and has been documented best in animals as it occurs 2–6 hours post-meal ingestion,7 a time when humans are often ingesting another meal and stimulating the first two components!

The first two phases of the colonic response to food involve serotonergic pathways: thus, antagonism of the serotonin (5-hydroxytryptamine (5-HT3)) receptor reduces both components of the colonic response to meal ingestion.8

In this issue of Gut, Houghton and colleagues9 provide further support for the role of serotonin in mediating this response [see page 663]. They report increased postprandial serotonin levels in patients with diarrhoea predominant IBS and meal related symptoms; serotonin levels were higher than those of patients with IBS without meal related symptoms. There were also higher fasting levels of serotonin in IBS patients compared with controls and increased intraplatelet concentrations of serotonin, but no differences in the area under the curve of postprandial plasma serotonin between IBS patients and healthy controls.

WHAT IS THE SIGNIFICANCE AND INTERPRETATION OF THESE FINDINGS?

This paper extends prior observations in a pilot study of five IBS patients whose serotonin levels were high relative to healthy controls.10 The observations are of interest as they relate postprandial exacerbation of symptoms to serotonin levels in both plasma and platelets. Several questions arise from consideration of the data.

Firstly, is the peak in postprandial serotonin really responsible for meal related symptoms in these patients? The timing of symptoms and that of serotonin would be expected to coincide if there was an association between serotonin and symptoms. The peak serotonin concentration in plasma was reached 2–3 hours after the meal in all study groups, well after the occurrence of postprandial symptoms. Peak serotonin levels appear to coincide with the later, chemoreceptor mediated or ileal, phase of the colonic response to the meal. The timing of postprandial symptoms is earlier and is more likely attributable to a neural or hormonal response, that may also be mediated by other mechanisms initiated by gastric mechanoreceptors or upper intestinal chemoreceptors stimulating the colonic response to feeding. It would be reasonable to infer that the horse has bolted long before circulating levels of serotonin peaked! Other mediators released within the foregut or midgut, such as gastrin, cholecystokinin, secretin, pancreatic polypeptide, motilin, the vasoactive intestinal polypeptide family (including PHI/PHM), and neurotensin may be candidate mediators of the colonic response and the associated postprandial symptoms. To date, one small study in humans11 evaluated concurrently colonic motility and circulating neuropeptides or hormones, and has shown no significant differences in postprandial levels of these mediators between IBS patients and controls. The size of the sample of IBS patients was not sufficient to characterise any differences between IBS patients with or without postprandial symptoms, in whom an exaggerated sensory response to the meal has also been proposed.11

The similarity in areas under the curve of plasma serotonin likely reflects the integrity of the enterochromaffin cells, and the fact that mechanical and chemical stimuli produce similar integrated responses to the meal over several hours. The integrated responses would be less sensitive to differences in the time or level of the serotonin peak concentration. One might therefore conclude that in the presence of an essentially intact gastrointestinal mucosa in IBS patients, release of mucosal peptides into the circulating peripheral (rather than portal) plasma is a relatively insensitive method to evaluate their potential mechanistic role because of the immense dilution of released mediator in the large plasma volume . . . it is a mere drop in the ocean!

Secondly, circulating plasma serotonin levels have to be interpreted in the context of the dynamic interplay between food mediated release, high or low capacity serotonin reuptake mechanisms, and storage in circulating platelets. Physiological regulation of serotonin levels is complex: there are reuptake mechanisms in neuronal cells, gut epithelial cells, and platelets that utilise a high affinity (but relatively low capacity) serotonin transporter (SERT). The liver and kidneys are other important sites of serotonin uptake through the organic cation transport system, which has a lower affinity but a higher capacity compared with SERT. These are the sites where serotonin is metabolised to 5-hydroxyindoleacetic acid (5-HIAA). The SERT is regarded as a major determinant of plasma serotonin concentration and it contributes to the prevention of the dangerous effects of abnormally high serotonin levels on vascular tone, fibrogenic effects, and blood clotting.12 The sclerosing effects of high serotonin levels contribute to the cardiac valvular lesions and sclerosing mesenteritis in carcinoid syndrome when the neuroendocrine tumour produces serotonin in excess of the inactivating mechanisms.

Differences in circulating serotonin levels in IBS may conceivably result from changes in mucosal enteroendocrine cells numbers,13 hypersensitivity of chemoreceptors in the mucosa resulting in greater release of serotonin, or altered inactivation or reuptake of the transmitter. In the latter case, differences in serotonin levels could result from functional polymorphisms of the SERT gene, associated with reduced serotonin reuptake in gut epithelia or platelets in patients with postprandial symptoms. Houghton and colleagues9 found increased platelet levels of serotonin and this suggests there were no deficiencies in reuptake mechanisms. This may also explain why the serotonin area under the curve was not different in the three groups. Differences in fasting serotonin levels in the entire group of IBS patients compared with healthy controls are not easily explained given the fact that serotonin is released by the meal stimulated enteroendocrine cells, and the normal functional capacity of SERT suggested by the normal postprandial area under the curve. Pata et al have reported differences in the prevalence of SERT-P genotypes in diarrhoea predominant IBS relative to controls and other IBS groups14 in a Turkish population. Specifically, they identified the short homozygous or heterozygous polymorphisms to be significantly more prevalent than the homozygous long polymorphism in diarrhoea predominant IBS. Theoretically, these polymorphisms would be associated with reduced reuptake of serotonin by the presynaptic membrane.15 Functional SERT polymorphisms may be responsible for pharmacogenetic differences, as has been demonstrated in the colonic transit response to the 5-HT3 receptor antagonist alosetron.16

However, data from our laboratory (HJ Kim, M Camilleri, R Urrutia, unpublished observation) suggest that such differences in genotype prevalence are not observed in IBS patients (despite a fivefold higher sample size) in a US population. Indeed, the sample size needed to detect significant differences in genetic polymorphisms to explain the observed differences in platelet serotonin between IBS patients and a control group would likely be an order of magnitude higher than the size of the group studied.9 Future studies will have to attempt to define the contribution of these polymorphisms to plasma and platelet levels of serotonin.

A third major consideration is that the effects of serotonin may be neurally mediated and unrelated to plasma circulating levels. Thus antagonist studies show unequivocally that 5- HT1A, 5-HT1B/D, and 5-HT3 receptors17,18 are involved in the response to feeding. One can conclude that the observations by Bearcroft and colleagues10 and Houghton and colleagues9 add an interesting piece to the puzzle but the case for the role (at least in part) of serotonin would be no weaker if these data were unavailable. Nevertheless, it is also important to remember that while serotonin is a prominent actor which may contribute to alterations in motor, sensory, and epithelial barrier functions,13 other mediators are available to modulate its actions as well as the postprandial function of the gut. Given the redundancy of mechanisms able to modulate these functions in the gut, it is unlikely that the colonic response to feeding represents a soliloquy or a one act play. Rather, it represents the integrated effects of an orchestra of players that “have their exits and their entrances” at different times on the postprandial stage and present physiological targets for novel therapies.

Acknowledgments

This paper was supported by grants #R01-DK54681 and #K24-DK02638 from the National Institutes of Health. We thank Ms Cindy Stanislav for secretarial support.

Does serotonin mediate postprandial symptoms in irritable bowel syndrome?

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