Secondary Logo

Journal Logo

Original articles

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

Spiller, Robin

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



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.


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).


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.


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).


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).


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.

Evidence of mucosal inflammation 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.


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).


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.


1. Thompson WG, Heaton KW, Smyth GT, et al. Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut 2000; 46:78–82.
2. Wells NE, Hahn BA, Whorwell PJ. Clinical economics review: irritable bowel syndrome. Aliment Pharmacol Ther 1997; 11:1019–1030.
3. Longstreth GF, Hawkey CJ, Mayer EA, et al. Characteristics of patients with irritable bowel syndrome recruited from three sources: implications for clinical trials. Aliment Pharmacol Ther 2001; 15:959–964.
4. Chaudhary NA, Truelove SC. The irritable colon syndrome. Q J Med 1962; 123:307–322.
5. Dunlop SP, Jenkins D, Neal KR, et al. Clinical and histological features of post-infectious IBS: relative importance of enterochromaffin cell hyperplasia, anxiety, and depression. Gastroenterology 2003; 125:1651–1659.
6. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ 1997; 314:779–782.
7. McKendrick MW, Read NW. Irritable bowel syndrome—Post salmonella infection. J Infect 1994; 29:1–3.
8. Gwee KA, Graham JC, McKendrick MW, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996; 347:150–153.
9. Thornley JP, Jenkins D, Neal K, et al. Relationship of Campylobacter toxigenicity in vitro to the development of postinfectious irritable bowel syndrome. J Infect Dis 2001; 184:606–609.
10. Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003; 125:1651–1659.
11. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut 2004; 53:1096–1101.
12. Ji S, Park H, Lee D, et al. Post-infectious irritable bowel syndrome in patients with Shigella infection. J Gastroenterol Hepatol 2005; 20:381–386.
13. Mearin F, Perez-Oliveras M, Perello A, et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 2005; 129:98–104.
14. Rodriguez LA, Ruigomez A. Increased risk of irritable bowel syndrome after bacterial gastroenteritis: cohort study. BMJ 1999; 318:565–566.
15. Parry SD, Stansfield R, Jelley D, et al. Does bacterial gastroenteritis predispose people to functional gastrointestinal disorders? A prospective, community-based, case-control study. Am J Gastroenterol 2003; 98:1970–1975.
16. Gwee KA, Leong YL, Graham C, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999; 44:400–406.
17. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000; 47:804–811.
18. Wheatcroft J, Wakelin D, Smith A, et al. Enterochromaffin cell hyperplasia and decreased serotonin transporter in a mouse model of postinfectious bowel dysfunction. Neurogastroenterol Motil 2005; 17:863–870.
19. Kamal M, Wakelin D, Ouellette AJ, et al. Mucosal T cells regulate Paneth and intermediate cell numbers in the small intestine of T. spiralis-infected mice. Clin Exp Immunol 2001; 126:117–1125.
20. De Ponti F. Pharmacology of serotonin: what a clinician should know. Gut 2004; 53:1520–1535.
21. Foley S, Harrison C, Johnson M, et al. Increased spontaneous 5HT release from jejunum of Trichinella infected mice. Neurogastroenterol Motil 2005; 17(Suppl 2):P47.
22. Weston AP, Biddle WL, Bhatia PS, et al. Terminal ileal mucosal mast cells in irritable bowel syndrome. Dig Dis Sci 1993; 38:1590–1595.
23. O'Sullivan M, Clayton N, Breslin NP, et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000; 12:449–457.
24. Chadwick VS, Chen W, Shu D, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002; 122:1778–1783.
25. Dunlop SP, Jenkins D, Spiller RC. Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am J Gastroenterol 2003; 98:1578–1583.
26. Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126:693–702.
27. Dunlop SP, Hebden JM, Naesdal J, et al. Abnormal intestinal permeability in subgroups of diarrhoea predominant irritable bowel syndromes. Am J Gastroenterol 2006; 101:1288–1294.
28. Gwee KA, Collins SM, Read NW, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut 2003; 52:523–526.
29. Scully P, O'Brien SO, Quigley EM, et al. Plasma levels of cytokines in patients with irritable bowel syndrome (IBS) compared to healthy controls. Gastroenterology 2005; 128(Suppl 2):A332.
30. O'Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005; 128:541–551.
31. Dunlop SP, Coleman NS, Blackshaw E, et al. Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol 2005; 3:349–357.
32. Atkinson W, Lockhart S, Whorwell PJ, et al. Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome. Gastroenterology 2006; 130:34–43.
33. Linden DR, Chen JX, Gershon MD, et al. Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol 2003; 285:G207–G216.
34. Coleman N, Foley S, Dunlop SP, et al. Abnormalities of serotonin metabolism and its relation to symptoms in untreated celiac disease. Clin Gastroenterol Hepatol 2006; 4:874–881.
35. El Salhy M, Danielsson A, Stenling R, et al. Colonic endocrine cells in inflammatory bowel disease. J Intern Med 1997; 242:413–419.
36. Coates MD, Mahoney CR, Linden DR, et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 2004; 126:1657–1664.
37. Torres GE, Gainetdinov RR, Caron MG. Plasma membrane monoamine transporters: structure, regulation, and function. Nat Rev Neurosci 2003; 4:13–25.
38. Bellini M, Rappelli L, Blandizzi C, et al. Platelet serotonin transporter in patients with diarrhea-predominant irritable bowel syndrome both before and after treatment with alosetron. Am J Gastroenterol 2003; 98:2705–2711.
39. Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Neurogastroenterol Motil 2003; 15:79–86.
40. Evans BW, Clark WK, Moore DJ, et al. Tegaserod for the treatment of irritable bowel syndrome. Cochrane Database System Rev 2004; 1:CD003960.

Infection; Inflammation; Irritable bowel syndrome; Serotonin

© 2007 Lippincott Williams & Wilkins, Inc.