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Original articles

Serotonin, Inflammation, and IBS: Fitting the Jigsaw Together?

Spiller, Robin

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Journal of Pediatric Gastroenterology and Nutrition: December 2007 - Volume 45 - Issue - p S115-S119
doi: 10.1097/MPG.0b013e31812e66da
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Abstract

INTRODUCTION

Irritable bowel syndrome (IBS) is a ubiquitous problem accounting for 3% of all general practitioner consultations (1) and around 40% of all gastroenterology outpatient referrals (2). Those in whom diarrhoea predominates are often referred to exclude coeliac disease and inflammatory bowel disease. However, irritable bowel syndrome, which affects as much as 10% of the population, outnumbers these other diagnoses 10 to 100-fold, and it follows that most patients investigated for diarrhoea and abdominal pain in a gastroenterological outpatient setting will turn out to have IBS.

POSTINFECTIOUS IBS

Some patients with IBS with predominantly diarrhoeal symptoms (IBS-D) describe an acute onset of symptoms following a bout of gastroenteritis (3). These patients have a normal premorbid bowel habit and provide an ideal opportunity to study the evolution of irritable bowel syndrome. Unlike most patients, those with postinfective IBS (PI-IBS) have a clear start time, and when compared with other patients with IBS, they appear to have a better prognosis (4). They also have a lower lifetime incidence of psychiatric disease (5), which in our study was found in only 26% of patients with PI-IBS compared with 54% of patients with IBS without an infectious onset.

Epidemiological studies indicate that 6% to 17% of unselected patients with IBS report acute onset with an infectious illness (3). The criteria we have used for PI-IBS consists of new IBS developing acutely after an illness characterised by 2 or more of the following: fever, vomiting, acute diarrhoea, or a positive stool culture (5). The clinical features are those of IBS-D with abdominal pain 2 (2–7) days per week and loose or water stools 3 (0–7) median (range) days per week, with urgency and bloating also occurring frequently (6). Since the original studies by McKendrick (7), there have been numerous studies (6,8–13) that indicate that the condition is not specific to any particular organism, being found after Salmonella, Campylobacter, and Shigella infections, although in 1 study Salmonella (predominantly Salmonella enteritidis) was less potent than Campylobacter jejuni and Shigella flexneri, which probably relates to the severity of the initial illness (6). Comparing these patients with control subjects, several studies have calculated relative risks ranging from 7.8 (13) to 12.7 (11,14,15).

RISK FACTORS FOR DEVELOPING POSTINFECTIVE IBS

Most studies agree that the severity of initial illness is the best predictor of developing PI-IBS. Those whose initial illness lasted >3 weeks were 11.4 (2.2–58) times (95% confidence interval [CI]) more likely to develop PI-IBS (6). Similarly, Wang et al (11) found those whose diarrhoea lasted >15 days were 4.6 (2.1–9.9) times (95% CI) more likely to develop PI-IBS than those in whom the diarrhoea lasted <1 week. One study that examined 93 cases infected with Campylobacter jejuni found that those bacteria that secreted a toxin causing cytotoxic effects in cultured epithelial cells gave a 10.5-fold increased risk of developing persistent bowel dysfunction (9). Interestingly, patients >60 years old are relatively protected, with a relative risk of 0.36 (95% CI 0.1–0.9) (6), whilst female sex increases the risk 2- to 3-fold (6,16). However, this sex effect appears to be due to confounding because when a multivariate analysis (10,16) including anxiety, depression, and neuroticism is performed, female sex is no longer an independent factor, the increased risk in females being secondary to increased incidence of adverse psychological factors. Gwee et al (16) also found that adverse life events in the previous 3 months doubled the risk of developing PI-IBS.

HISTOLOGICAL EVIDENCE OF INFLAMMATION IN PI-IBS

Several studies have examined endoscopic biopsies obtained from the colon and terminal ileum at various times after the development of PI-IBS (10,11,16,17). The most detailed study, which performed serial biopsies 2, 6, and 12 weeks after infection, shows the expected increase in inflammatory cells, which declines during the next 3 months. Associated with the increase in lymphocytes, there was a proportionate increase in enterochromaffin (EC) cells (17). This link between lymphocytes and EC cells is supported by subsequent human (10) and animal (18) studies showing that EC-cell hyperplasia appears to be T lymphocyte driven. Mice lacking the T cell receptor fail to show either EC (18) or Paneth cell hyperplasia (19).

ROLE OF SEROTONIN (5HT) DURING AND FOLLOWING INFECTION

EC cells are the most important source of serotonin in the intestine. Serotonin (5-hydroxytriptamine, or 5HT) is a key molecule that stimulates secretions, activates afferent nerves, and in excess causes nausea and vomiting. It also mediates the peristaltic response to distension (20). When present in excess, its actions can be seen as a protective response to infection, facilitating rapid removal of infecting organisms from the gut. A recent prospective study compared 28 individuals who developed PI-IBS after infection with C jejuni with 28 infected controls who recovered fully. PI-IBS had a significant increase in both mucosal CD3-positive lymphocytes (10) and EC cells, both being approximately 25% higher than in the controls. Similar findings are seen in animals following Trichinella spiralis infection (18), and subsequent studies indicate that the increased numbers of EC cells were associated with increased 5HT release (21).

EVIDENCE OF INFLAMMATION IN IBS

Numerous studies (see Table 1) have provided evidence of low-grade mucosal inflammation in IBS. Different authors have studied different parameters, but most seem to agree on an increase in CD3 lymphocytes, with some authors showing increased mast cells and others showing increased EC cells. The distribution may well be region specific, with increased mast cells seen particularly by authors who biopsied the terminal ileum (11,22) and right side of the colon (23). Another indicator of mucosal inflammation is altered gut permeability, which has been reported in both PI-IBS and IBS-D (27). Others have shown increased levels of mucosal cytokines, particularly in interleukin-1β (IL-1β) (11,28). Recently, Scully et al (29) have reported elevated levels of IL-6 and IL-8 in the plasma of patients with IBS. The same group reported an abnormally reduced IL-10 to IL-12 ratio in cytokine secretion from peripheral blood mononuclear cells in IBS (30). This was normalised by treatment with probiotics, which also produced a global improvement in symptoms. However, whether evidence of immune activation will prove a reliable marker that would predict response to anti-inflammatory or antiserotonergic drugs remains to be proven.

TABLE 1
TABLE 1:
Evidence of mucosal inflammation in IBS

POSTPRANDIAL 5HT RELEASE IN IBS

When 5HT levels are measured in platelet-poor plasma, they peak at about 1 hour after meal ingestion, remaining elevated for at least 4 hours. The rise is greater in patients with PI-IBS and significantly impaired in those with constipated IBS (IBS-C) (31,32). This second study (32) was valuable because it not only measured 5HT, which shows some considerable variability over time, but also 5-hydroxy-indole-acetic acid (5HIAA), which shows a somewhat smoother profile. Furthermore, because 5HIAA is not stored in platelets, 5HIAA levels are less vulnerable to artefactual increase by unintended platelet activation occurring during blood-taking. It appears from these studies that exaggerated 5HT release is a feature of IBS-D, both of the postinfective and nonpostinfective variety, whilst both studies agree that IBS-C appears to be characterised by an impairment of release.

ABNORMALITIES OF SEROTONIN TRANSPORTER IN DISEASE

The action of 5HT is terminated by a rapid uptake by the ubiquitous serotonin transporter (SERT) into mucosal enterocytes. The intracellular enzymes (monoamine oxidases and UDP-glucuronosyltransferase) metabolise 5HT to 5HIAA and 5-hydroxytryptamine glucuronide, inactive forms that are excreted by the kidneys. SERT is found on EC cells, but because these account for only 1 in 100 of epithelial cells, this is likely to be quantitatively unimportant compared with the enterocyte SERT. Turnover in tissue can be assessed by measuring the ratio of 5HIAA (mainly in enterocytes) to 5HT (mainly in EC cells). This 5HIAA/5HT ratio was shown by Dunlop et al (31) to be decreased in IBS-C, as expected from their impaired turnover. Paradoxically, patients with PI-IBS also had a depressed 5HIAA/5HT ratio in spite of increased release. This implies a reduction in 5HIAA production, either secondary to reduced uptake of 5HT into enterocytes by SERT or impairment of intracellular monamine-oxidases. Several studies have suggested that inflammation in animal models leads to downregulation of SERT, a phenomenon seen acutely in trinitrobenzene-sulfonic acid colitis (33) and more chronically following infection with T spiralis(18). In both models 5HT-containing EC numbers and 5HT release are increased whilst SERT is decreased. Studies in humans are more limited, but abnormalities have been detected in both coeliac disease and inflammatory bowel disease. Coeliac disease is characterised by T lymphocyte infiltration with villous atrophy and crypt hyperplasia, which is associated with an increase in EC cell numbers (34). Furthermore, when the same patients are given a standard test meal of spaghetti and toast, 5HT levels rise significantly greater than in controls. Interestingly, in this study, the peak levels—which in some cases were higher than those seen in carcinoid syndrome—correlated well with the dyspepsia score. Furthermore, as with the patients with IBS, the mucosal 5HIAA/5HT ratio was significantly depressed. Studies in inflammatory bowel disease are more conflicting, possibly because most specimens are taken from patients who have received some form of treatment. Patients undergoing resection of the colon for ulcerative colitis or Crohn disease have been shown to have increased EC cell numbers (35). More controversially, 1 study was published showing that mRNA SERT is decreased, not only in ulcerative colitis, as to be expected from this damaged mucosa, but also in patients with IBS both with constipation and diarrhoea (36). Further studies are plainly needed, although this does partly confirm our own studies on the 5HIAA/5HT ratio. It is possible that SERT is depressed by different mechanisms in IBS-C and IBS-D, with an inflammatory inhibition predominant in IBS-D whilst in IBS-C the change is secondary to reduced release. The activity of SERT appears to be regulated by 5HT transport, which increases the amount expressed on the cell surface, and hence activity, by blocking the action of protein kinase C (37). SERT in intestinal mucosa appears similar to the SERT in platelets, and 1 study at least has found an inverse correlation between the binding capacity of platelet SERT and symptoms in IBS-D (38).

BENEFITS OF 5HT3 ANTAGONISTS AND 5HT4 AGONISTS

The implications for treatment of these findings are that patients with IBS-D with defective SERT and increased 5HT availability may well respond to 5HT3 antagonists. By contrast, patients with IBS-C and impaired release of serotonin may benefit from 5HT4 agonists. Recent large multicentre clinical trials confirmed these suggestions, with benefits seen in 1 in 7 patients with IBS-D when treated with Alosetron 1 mg twice daily (39). Generally, around 1 in 14 patients with IBS-C benefit specifically from Tegaserod, a 5HT4 agonist (40). However, as indicated by the relatively large number needed to treat, we are still far from having reliable markers to indicate who will respond and who will not.

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Keywords:

Infection; Inflammation; Irritable bowel syndrome; Serotonin

© 2007 Lippincott Williams & Wilkins, Inc.