Review Article: Intestinal Serotonin Signalling in Irritable Bowel Syndrome

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


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.

CLICK HERE for subscription information about this journal.



  1. Hahn BA, Yan S, Strassels S. Impact of irritable bowel syndrome on quality of life and resource use in the United States and United Kingdom. Digestion 1999; 60: 77–81.

  2. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology 2002; 123: 2108–31.

  3. Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002; 97 (Suppl. 11): S7–26.

  4. Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J Clin Gastroenterol 2005; 39 (Suppl. 3): S184–93.

  5. 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: 1657–64.

  6. Erspamer V. Occurrence and distribution of 5-hydroxytryptamine (enteramine) in the living organism. Z Vitam Horm Fermentforsch 1957; 9: 74–96.

  7. Blakely RD, Berson HE, Fremeau RT Jr, et al. Cloning and expression of a functional serotonin transporter from rat brain. Nature 1991; 354: 66–70.

  8. Blakely RD, Defelice LJ, Galli A. Biogenic amine neurotransmitter transporters: just when you thought you knew them. Physiology (Bethesda) 2005; 20: 225–31.

  9. Chen JX, Pan H, Rothman TP, Wade PR, Gershon MD. Guinea pig 5-HT transporter: cloning, expression, distribution, and function in intestinal sensory reception. Am J Physiol 1998; 275 (Pt 1): G433–48.

  10. Da Prada M, Tranzer JP, Pletscher A. Storage of 5-hydroxytryptamine in human blood platelets. Experientia 1972; 28: 1328–9.

  11. Erspamer V, Testini A. Observations on the release and turnover rate of 5-hydroxytryptamine in the gastrointestinal tract. J Pharm Pharmacol 1959; 11: 618–23.

  12. Bertaccini G. Tissue 5-hydroxytryptomine and urinary 5-hyroxyindoleacetic acid after partial or total removal of the gastro-intestinal tract in the rat. J Physiol (Lond) 1960; 153: 239–49.

  13. Bearcroft CP, Perrett D, Farthing MJ. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 1998; 42: 42–6.

  14. Miwa J, Echizen H, Matsueda K, Umeda N. Patients with constipation-predominant irritable bowel syndrome (IBS) may have elevated serotonin concentrations in colonic mucosa as compared with diarrhea-predominant patients and subjects with normal bowel habits. Digestion 2001; 63: 188–94.

  15. Dunlop SP, Coleman NS, Blackshaw E, et al. Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol 2005; 3: 349–57.

  16. Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003; 125: 1651–9.

  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: 804–11.

  18. Murphy DL, Lerner A, Rudnick G, Lesch KP. Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv 2004; 4: 109–23.

  19. Lesch KP, Balling U, Gross J, et al. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 1994; 95: 157–62.

  20. Ramamoorthy S, Bauman AL, Moore KR, et al. Antidepressant-and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A 1993; 90: 2542–6.

  21. Lesch KP, Mossner R. Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders? Biol Psychiatry 1998; 44: 179–92.

  22. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–31.

  23. Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL. Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 1999; 88: 83–7.

  24. Nobile M, Begni B, Giorda R, et al. Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38: 1396–402.

  25. Stoltenberg SF, Twitchell GR, Hanna GL, et al. Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism. Am J Med Genet 2002; 114: 230–4.

  26. Hranilovic D, Stefulj J, Schwab S, et al. Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatry 2004; 55: 1090–4.

  27. Sakai K, Nakamura M, Ueno S, et al. The silencer activity of the novel human serotonin transporter linked polymorphic regions. Neurosci Lett 2002; 327: 13–6.

  28. Mortensen OV, Thomassen M, Larsen MB, Whittemore SR, Wiborg O. Functional analysis of a novel human serotonin transporter gene promoter in immortalized raphe cells. Brain Res Mol Brain Res 1999; 68: 141–8.

  29. Willeit M, Stastny J, Pirker W, et al. No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism. Biol Psychiatry 2001; 50: 8–12.

  30. Shioe K, Ichimiya T, Suhara T, et al. No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse 2003; 48: 184–8.

  31. Pata C, Erdal ME, Derici E, Yazar A, Kanik A, Ulu O. Serotonin transporter gene polymorphism in irritable bowel syndrome. Am J Gastroenterol 2002; 97: 1780–4.

  32. Kim HJ, Camilleri M, Carlson PJ, et al. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders. Gut 2004; 53: 829–37.

  33. Lee DY, Park H, Kim WH, Lee SI, Seo YJ, Choi YC. Serotonin transporter gene polymorphism in healthy adults and patients with irritable bowel syndrome. Korean J Gastroenterol 2004; 43: 18–22.

  34. Yeo A, Boyd P, Lumsden S, et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. Gut 2004; 53: 1452–8.

  35. 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: 2705–11.

  36. Blakely RD, Bauman AL. Biogenic amine transporters: regulation in flux. Curr Opin Neurobiol 2000; 10: 328–36.

  37. Magro F, Vieira-Coelho MA, Fraga S, et al. Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig Dis Sci 2002; 47: 216–24.

  38. Ahonen A, Kyosola K, Penttila O. Enterochromaffin cells in macrophages in ulcerative colitis and irritable colon. Ann Clin Res 1976; 8: 1–7.

  39. El-Salhy M, Danielsson A, Stenling R, Grimelius L. Colonic endocrine cells in inflammatory bowel disease. J Intern Med 1997; 242: 413–9.

  40. Linden DR, Chen JX, Gershon MD, Sharkey KA, Mawe GM. Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol 2003; 285: G207–16.

  41. O'Hara JR, Ho W, Linden DR, Mawe GM, Sharkey KA. Enteroendocrine cells and serotonin availability are altered in the mucosa of guinea pigs with TNBS ileitis. Am J Physiol Gastrointest Liver Physiol 2004; 287: G998–1007.

  42. Linden DR, Foley KF, McQuoid C, Simpson J, Sharkey KA, Mawe GM. Serotonin transporter function and expression are reduced in mice with TNBS-induced colitis. Neurogastroenterol Motil 2005; 17: 565–74.

  43. Wheatcroft J, Wakelin D, Smith A, Mahoney CR, Mawe GM, Spiller R. Enterochromaffin cell hyperplasia and decreased serotonin transporter in a mouse model of postinfectious bowel dysfunction. Neurogastroenterol Motil 2005; 17: 863–70.

  44. O'Hara JR, Skinn AC, MacNaughton WK, Sherman PM, Sharkey KA. Consequences of Citrobacter rodentium infection on enteroendocrine cells and the enteric nervous system in the mouse colon. Cell Microbiol 2006; in press.

  45. Oshima S, Fujimura M, Fukimiya M. Changes in number of serotonin-containing cells and serotonin levels in the intestinal mucosa of rats with colitis induced by dextran sodium sulfate. Histochem Cell Biol 1999; 112: 257–63.

  46. Mawe GM, Ciolino A, Foley KF. Inflammatory cytokines decrease serotonin transporter function in colonic epithelial cells. Neurogastroenterol Motil 2005; 17: 613.

  47. Chen JJ, Li Z, Pan H, et al. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: Abnormal intestinal motility and the expression of cation transporters. J Neurosci 2001; 21: 6348–61.

  48. Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD, Gershon MD. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci 1996; 16: 2352–64.

  49. Gershon MD. Review article: serotonin receptors and transporters–roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther 2004; 20 (Suppl. 7): 3–14.

  50. Costall B, Naylor RJ. 5-HT3 receptors. Curr Drug Targets CNS Neurol Disord 2004; 3: 27–37.

  51. Bockaert J, Claeysen S, Compan V, Dumuis A. 5-HT4 receptors. Curr Drug Targets CNS Neurol Disord 2004; 3: 39–51.

  52. Galligan JJ. Ligand-gated ion channels in the enteric nervous system. Neurogastroenterol Motil 2002; 14: 611–23.

  53. Kozlowski CM, Green A, Grundy D, Boissonade FM, Bountra C. The 5-HT(3) receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat. Gut 2000; 46: 474–80.

  54. Liu M, Geddis MS, Wen Y, Setlik W, Gershon MD. Expression and function of 5-HT4 receptors in the mouse enteric nervous system. Am J Physiol Gastrointest Liver Physiol 2005; 289: G1148–63.

  55. Pan H, Galligan JJ. 5-HT1A and 5-HT4 receptors mediate inhibition and facilitation of fast synaptic transmission in enteric neurons. Am J Physiol 1994; 266 (Pt 1): G230–8.

  56. Galligan JJ, Pan H, Messori E. Signalling mechanism coupled to 5-hydroxytryptamine4 receptor-mediated facilitation of fast synaptic transmission in the guinea-pig ileum myenteric plexus. Neurogastroenterol Motil 2003; 15: 523–9.

  57. Grider JR. Desensitization of the peristaltic reflex induced by mucosal stimulation with the selective 5-HT4 agonist, tegaserod. Am J Physiol Gastrointest Liver Physiol 2006; 290: G319–27.

  58. Tonini M, Vicini R, Cervio E, et al. 5-HT(7) Receptors modulate peristalsis and accommodation in the guinea pig ileum. Gastroenterology 2005; 129: 1557–66.

  59. Liu MT, Rayport S, Jiang Y, Murphy DL, Gershon MD. Expression and function of 5-HT3 receptors in the enteric neurons of mice lacking the serotonin transporter. Am J Physiol Gastrointest Liver Physiol 2002; 283: G1398–411.

  60. Tache Y, Martinez V, Million M, Wang L. Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors. Am J Physiol Gastrointest Liver Physiol 2001; 280: G173–7.



Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: