5-hydroxytryptamine, ulcerative colitis, and irritable bowel syndrome: molecular connections

Abstract

5-Hydroxytryptamine (5-HT serotonin) is contained in and released from enteric neurons1Gershon M.D Tamir H Release of endogenous 5-hydroxytryptamine from resting and stimulated enteric neurons.Neuroscience. 1981; 6: 2277-2286Crossref PubMed Scopus (69) Google Scholar, 2Costa M Furness J.B Cuello A.C Verhofstad A.A Steinbusch H.W Elde R.P Neurons with 5-hydroxytryptamine-like immunoreactivity in the enteric nervous system their visualization and reactions to drug treatment.Neuroscience. 1982; 7: 351-363Crossref PubMed Scopus (226) Google Scholar, 3Kurian S.S Ferri G.L De Mey J Polak J.M Immunocytochemistry of serotonin containing nerves in the human gut.Histochemistry. 1983; 78: 523-529Crossref PubMed Scopus (25) Google Scholar and from enterochromaffin (EC) cells in the mucosal layer of the small and large intestines.4Racke K Reimann A Schworer H Kilbinger H Regulation of 5-HT release from enterochromaffin cells.Behav Brain Res. 1996; 73: 83-87Crossref PubMed Scopus (201) Google Scholar, 5Minami M Endo T Hirafuji M Mamaue N Liu Y Hiroshige T Nemoto M Saito H Yoshioka M Pharmacological aspects of anticancer drug induced emesis with emphasis on serotonin release and vagal nerve activity.Pharmacol Ther. 2003; 99: 149-165Crossref PubMed Scopus (106) Google Scholar, 6Crowell M.D Shetzline M.A Moses P.L Mawe G.M Talley N.J Enterochromaffin cells and 5-HT signaling in the pathophysiology of disorders of gastrointestinal function.Curr Opin Invest Drugs. 2004; 5: 55-60PubMed Google Scholar Most of the total 5-HT content in the body is localized in gastrointestinal EC cells. EC cells release 5-HT in a regulated and calcium-dependent manner and they express mechano- and chemosensitive ion channels, a variety of ligand-gated ion channels, and G-protein-coupled receptors on the EC cell surface.4Racke K Reimann A Schworer H Kilbinger H Regulation of 5-HT release from enterochromaffin cells.Behav Brain Res. 1996; 73: 83-87Crossref PubMed Scopus (201) Google Scholar, 5Minami M Endo T Hirafuji M Mamaue N Liu Y Hiroshige T Nemoto M Saito H Yoshioka M Pharmacological aspects of anticancer drug induced emesis with emphasis on serotonin release and vagal nerve activity.Pharmacol Ther. 2003; 99: 149-165Crossref PubMed Scopus (106) Google Scholar Activation of calcium-permeable ion channels or some G-protein-linked receptors leads to a rise in intracellular calcium and 5-HT secretion.4Racke K Reimann A Schworer H Kilbinger H Regulation of 5-HT release from enterochromaffin cells.Behav Brain Res. 1996; 73: 83-87Crossref PubMed Scopus (201) Google Scholar, 5Minami M Endo T Hirafuji M Mamaue N Liu Y Hiroshige T Nemoto M Saito H Yoshioka M Pharmacological aspects of anticancer drug induced emesis with emphasis on serotonin release and vagal nerve activity.Pharmacol Ther. 2003; 99: 149-165Crossref PubMed Scopus (106) Google Scholar Regulated secretion of 5-HT by EC cells can be enhanced or inhibited by the action of signaling molecules released from surrounding cells and by nerve terminals supplying the mucosa.4Racke K Reimann A Schworer H Kilbinger H Regulation of 5-HT release from enterochromaffin cells.Behav Brain Res. 1996; 73: 83-87Crossref PubMed Scopus (201) Google Scholar, 5Minami M Endo T Hirafuji M Mamaue N Liu Y Hiroshige T Nemoto M Saito H Yoshioka M Pharmacological aspects of anticancer drug induced emesis with emphasis on serotonin release and vagal nerve activity.Pharmacol Ther. 2003; 99: 149-165Crossref PubMed Scopus (106) Google Scholar Modulation of 5-HT release from EC cells is critical to normal and perhaps abnormal gastrointestinal function. Because EC cell are sensory transducers that respond to mechanical or chemical stimuli applied to the mucosa causing 5-HT release.7Bulbring E Lin R The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis, the local production of 5-hydroxytryptamine and its release in relation to intraluminal pressure and propulsive activity.J Physiol. 1958; 140: 381-407PubMed Google Scholar 5-HT released from EC cells can then initiate gastrointestinal motor reflexes such as peristalsis.7Bulbring E Lin R The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis, the local production of 5-hydroxytryptamine and its release in relation to intraluminal pressure and propulsive activity.J Physiol. 1958; 140: 381-407PubMed Google Scholar For example, mechanical stimuli applied to the mucosa in the small intestine of guinea pigs releases 5-HT into the lamina propria. 5-HT then acts at 5-HT3, 5-HT4, and 5-HT1P receptors localized on the terminals of primary afferent nerves intrinsic to the enteric nervous system.8Bertrand P.P Kunze W.A Furness J.B Bornstein J.C The terminals of myenteric intrinsic primary afferent neurons of the guinea pig ileum are excited by 5-hydroxytrypamine acting at 5-hydroxytrypamine-3 receptors.Neuroscience. 2000; 101: 459-469Crossref PubMed Scopus (170) Google Scholar, 9Pan H Gershon M.D Activation of intrinsic afferent pathways in submucosal ganglia of the guinea pig small intestine.J Neurosci. 2000; 20: 3295-3309PubMed Google Scholar, 10Grider J.R Kuemmerle J.F Jin J.G 5-HT released by mucosal stimuli initiates peristalsis by activating 5-HT4/5-HT1P receptors on sensory CGRP neurons.Am J Physiol. 1996; 270: G778-G782PubMed Google Scholar 5-HT released from EC cells initiates antidromic action potentials in the intestinal primary afferent neurons,8Bertrand P.P Kunze W.A Furness J.B Bornstein J.C The terminals of myenteric intrinsic primary afferent neurons of the guinea pig ileum are excited by 5-hydroxytrypamine acting at 5-hydroxytrypamine-3 receptors.Neuroscience. 2000; 101: 459-469Crossref PubMed Scopus (170) Google Scholar which then activate downstream interneurons and motoneurons in enteric neural circuits mediating peristalsis.9Pan H Gershon M.D Activation of intrinsic afferent pathways in submucosal ganglia of the guinea pig small intestine.J Neurosci. 2000; 20: 3295-3309PubMed Google Scholar, 10Grider J.R Kuemmerle J.F Jin J.G 5-HT released by mucosal stimuli initiates peristalsis by activating 5-HT4/5-HT1P receptors on sensory CGRP neurons.Am J Physiol. 1996; 270: G778-G782PubMed Google Scholar 5-HT released from EC cells is also involved in transmitting sensory information from the gut lumen to the central nervous system. It is well established that 5-HT released from EC cells in response to the actions of chemotherapeutic agents can initiate emesis via a vagally mediated pathway.5Minami M Endo T Hirafuji M Mamaue N Liu Y Hiroshige T Nemoto M Saito H Yoshioka M Pharmacological aspects of anticancer drug induced emesis with emphasis on serotonin release and vagal nerve activity.Pharmacol Ther. 2003; 99: 149-165Crossref PubMed Scopus (106) Google Scholar However, 5-HT released in response to chemical stimulation of the mucosa by using local application of short chain fatty acids can stimulate propulsive contractions in the colon via a vagally mediated pathway as well.11Fukumoto S Tatewaki M Yamada T Fujimya M Mantyh C Voss M Eubanks S Harris M Pappas T.N Takahashi T Short chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats.Am J Physiol. 2002; 284: R1269-R1276Google Scholar This response is mediated by 5-HT3 receptors localized to vagal nerve endings in the colonic mucosa.11Fukumoto S Tatewaki M Yamada T Fujimya M Mantyh C Voss M Eubanks S Harris M Pappas T.N Takahashi T Short chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats.Am J Physiol. 2002; 284: R1269-R1276Google Scholar In addition to activating vagal afferent nerve fibers in the colon, 5-HT acting on 5-HT3 receptors also activates spinal sensory nerve fibers supplying the colon.12Hicks G.A Coldwell J.R Schindler M Ward P.A Jenkins D Lynn P.A Humphrey P.P Blackshaw L.A Excitation of rat colonic afferent fibers by 5-HT3 receptors.J Physiol. 2002; 544: 861-869Crossref PubMed Scopus (97) Google Scholar These nerve fibers would carry mechanosensory information to the central nervous system but they could also carry nociceptive signals under some conditions. Release of 5-HT by EC cells is one mechanism by which 5-HT signaling can be modulated in the gut. Clearance of 5-HT subsequent to release is also an important determinant of the strength and duration of excitatory signals transmitted by the action of 5-HT. Clearance of 5-HT in the lamina propria is accomplished through the activity of a specific high-affinity serotonin transporter (SERT). SERT is expressed in high concentrations by enterocytes, and the enterocyte SERT is identical to the SERT expressed by neurons in the central nervous system.13Wade P.R Chen J Jaffe B Kassem I.S Blakely R.D Gershon M.D Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract.J Neurosci. 1996; 16: 2352-2364PubMed Google Scholar Drugs that block SERT in the brain also inhibit 5-HT clearance in the mucosa of the gastrointestinal tract. Based on the summary provided above, it is not surprising that disorders of 5-HT signaling have been implicated in the pathogenesis of some disorders of gastrointestinal motility, particularly irritable bowel syndrome (IBS).6Crowell M.D Shetzline M.A Moses P.L Mawe G.M Talley N.J Enterochromaffin cells and 5-HT signaling in the pathophysiology of disorders of gastrointestinal function.Curr Opin Invest Drugs. 2004; 5: 55-60PubMed Google Scholar Because locally released 5-HT contributes to the initiation of motor reflexes and the transduction of nociceptive stimuli, its potential role in IBS in which there are both motor and visceral sensitivity abnormalities is reasonable. This suggestion is also supported by clinical studies that have established that drugs that alter 5-HT signaling have some therapeutic benefit in the treatment of patients with IBS. These drugs include alosetron, a 5-HT3 receptor antagonist, which is effective in treating symptoms in female, diarrhea-predominant patients with IBS14Lembo A Weber H.C Farraye F.A Alosetron in irritable bowel syndrome strategies for its use in a common gastrointestinal disorder.Drugs. 2003; 63: 1895-1905Crossref PubMed Scopus (26) Google Scholar; tegaserod, a 5-HT4 receptor agonist used to treat constipation-predominant IBS15Wagstaff A.J Frampton J.E Croom K.F Tegaserod a review of its use in the management of irritable bowel syndrome with constipation in women.Drugs. 2003; 63: 1101-1120Crossref PubMed Scopus (45) Google Scholar; and tricyclic antidepressant drugs, which alter 5-HT uptake.16Jackson J.L O’Malley P.G Tomkins G Balden E Santoro J Kroenke K Treatment of functional gastrointestinal disorders with anti-depressants a meta-analysis.Am J Med. 2000; 108: 65-72Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Although a centrally mediated action of tricyclic antidepressants contributes to the therapeutic benefit provided by these drugs in IBS, peripheral sites of action also play a role in their effectiveness.17Drossman D.A Camilleri M Mayer E.A Whitehead W.E AGA technical review on the irritable bowel syndrome.Gastroenterology. 2002; 123: 2108-2131Abstract Full Text Full Text PDF PubMed Scopus (1199) Google Scholar The potential contribution of alterations in peripheral 5-HT synthesis, release, and/or uptake in patients with IBS must also be considered in light of the article by Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar in this issue of Gastroenterology. Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar studied markers of 5-HT-mediated signaling in rectal biopsy specimens obtained from healthy subjects, patients with ulcerative colitis (UC), and patients with diarrhea-predominant and constipation-predominant IBS. It was found that UC, diarrhea-predominant, and constipation-predominant patients with IBS shared a common profile in markers of altered 5-HT signaling. In all patients, tissue concentrations of 5-HT and messenger RNA for tryptophan hydroxylase, a key enzyme in the 5-HT biosynthetic pathway, were reduced compared with levels found in specimens from control subjects. Immunoreactivity and messenger RNA for SERT were also reduced in tissues from patients with UC and IBS. Interestingly, the authors found that basal release and mechanically stimulated 5-HT release from UC and IBS tissues were not different from those measured in control specimens. Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar also found that the number of EC cells was similar among control, IBS, and moderate UC specimens. The number of EC cells was reduced in tissues obtained from patients with severe UC; this result was attributed to inflammation-induced changes in the mucosa. The finding that 5-HT synthesis may be reduced while release is maintained in the same tissues is paradoxical. However, the authors suggest that there may be surplus stores of 5-HT in EC cells so that reduction in steady state levels may not alter the 5-HT concentration in a readily releasable pool. It is also possible that impaired 5-HT reuptake (as suggested by reduced SERT levels) in UC and IBS tissues may make more 5-HT available for the overflow measurements used in this study. Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar concluded that changes in 5-HT synthesis, reuptake, and, perhaps, storage by colonic EC cells contribute to the motility alterations and visceral hypersensitivity that occur in patients with UC and IBS. The data in human subjects summarized previously were prefaced by studies performed on an animal model of colonic inflammation: trinitrobenzene sulfonate (TNBS)- induced colitis in the guinea pig colon.19Linden D.R Chen J.X Gershon M.D Sharkey K.A Mawe G.M Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis.Am J Physiol. 2003; 285: G207-G216Crossref PubMed Scopus (249) Google Scholar In the colon of TNBS-colitis guinea pigs, 5-HT levels and the number of EC cells were increased compared with those found in control animals. However, SERT levels were reduced in TNBS colitis. The decrease in SERT levels coupled with the increase in 5-HT and EC cell number would account for the increased 5-HT release seen in inflamed colons.19Linden D.R Chen J.X Gershon M.D Sharkey K.A Mawe G.M Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis.Am J Physiol. 2003; 285: G207-G216Crossref PubMed Scopus (249) Google Scholar However, it was also found that colonic propulsion, studied in vitro, was reduced in the colon from TNBS-colitis guinea pigs. In addition, a mixed 5-HT3/5-HT4-receptor antagonist, delayed propulsion in the colon in vitro of normal guinea pigs but this effect was impaired in the colon taken from TNBS-colitis guinea pigs. It was concluded that increased 5-HT release in inflamed colons leads to 5-HT receptor desensitization and this accounted for the decreased colonic propulsion seen in tissues from TNBS-colitis animals. The previous study in guinea pigs is relevant to the study of Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar because it suggests that altered 5-HT signaling may be a consequence of inflammation and not a contributing factor to the development of inflammation or altered motility changes. It is not known if inflammatory processes precede the changes in 5-HT signaling detected in tissues from patients with IBS or if altered 5-HT signaling is a primary disorder in these patients. This question is also relevant because a previous study of rectal biopsy specimens from patients who had experienced an acute episode of Campylobacter enteritis and subsequent development of diarrhea-predominant IBS symptoms showed EC cell hyperplasia. However, it was also found that subjects who had an acute episode of Campylobacter enteritis but did not develop postinfectious IBS had EC cell numbers similar to control patients.20Dunlop S.P Jenkins D Neal K.R Spiller R.C Relative importance of enterochromaffin cell hyperplasia, anxiety and depression in postinfectious IBS.Gastroenterology. 2003; 125: 1651-1659Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar These observations suggest that factors in addition to enteritis and inflammation contribute to EC cell hyperplasia in patients with postinfectious diarrhea-predominant IBS. Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar have shown that SERT levels are reduced in biopsy samples of patients with UC and IBS. Because SERT is a critical determinant of 5-HT availability, it is possible that SERT may modify EC cell responses to infection and inflammation or to the development of motility and sensory alterations associated with IBS. Recent studies have indicated that a specific SERT polymorphism may influence alosetron effectiveness in treating symptoms in diarrhea-predominant IBS.21Camilleri M Atanasova E Carlson P.J Ahmad U Kim H.J Viramontes B.E McKinzie S Urrita R Serotonin transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome.Gastroenterology. 2002; 123: 425-432Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar It is possible that similar SERT polymorphic variability influences EC cell responses to enteric infections and inflammation. EC cell responses to inflammation could include decreased tryptophan hydroxylase or SERT synthesis/function and/or changes in the 5-HT storage and release machinery. Although a role for 5-HT in the pathophysiology of IBS has been suggested for some time, the study by Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar is one of the first to present evidence for molecular changes responsible for altered 5-HT disposition in the gastrointestinal tract of patients with IBS or UC. The changes that Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar described occurred in the colonic mucosa. It will be important for future studies to determine if similar changes in 5-HT signaling also occur in the enteric nervous system. It would also be of value to know if alterations in 5-HT signaling in patients with IBS are gut specific. That is, do similar decreases in tryptophan hydroxylase, SERT, and 5-HT synthesis also occur in the central nervous system of patients with IBS. The provocative findings of Coates et al.18Coates M.D Mahoney C.R Linden D.R Sampson J.E Chen J Blaszyk H Crowell M.D Sharkey K.A Gershon M.D Mawe G.M Moses P.L Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar provide a rational basis for the continued study of the role of 5-HT in controlling visceral sensitivity, gastrointestinal motility, and secretion. These new data also support the need for continued efforts to develop drugs that may correct abnormal 5-HT signaling in functional motility disorders.