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Discussion Starter · #1 ·
FYIIntrinsic bowel defects linked to irritable bowel syndromeLast Updated: 2004-06-09 16:20:02 -0400 (Reuters Health)NEW YORK (Reuters Health) - For the first time researchers have identified molecular alterations specific to the GI tract of patients with irritable bowel syndrome (IBS).These alterations, which involve defects in serotonin signaling, support the hypothesis that the GI dysfunction seen with IBS involves intrinsic changes in the gut and is not simply of psychosomatic origin. The new study, which is reported in the June issue of Gastroenterology, involved an analysis of rectal biopsy specimens obtained from 34 healthy subjects, 22 patients with ulcerative colitis, 15 with IBS with diarrhea and 16 with IBS with constipation.Specifically, Dr. Peter L. Moses, from the University of Vermont in Burlington, and colleagues were interested in knowing whether serotonergic signaling mechanisms were altered.In all three patient groups, mucosal levels of serotonin and related enzyme mRNA were significantly reduced, the authors state. In patients with severe ulcerative colitis, but not in IBS patients, enterochromaffin cells were decreased in the test samples. Further testing of these cells revealed normal basal and stimulated serotonin release in all of the patient groups."These data demonstrate that ulcerative colitis and IBS are associated with similar molecular changes in serotonergic signaling mechanisms," the authors state. "While ulcerative colitis and IBS have distinct pathophysiological properties, these data suggest that shared defects in serotonin signaling may underlie the altered motility, secretion, and sensation."Gastroenterology 2004;June issue:000-000. Molecular Defect Found for the First Time in IBS Patients http://www.ibsgroup.org/cgi-local/ubbcgi/u...c&f=10&t=000940
 

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I wonder how long until GI doctors start using this test rather than the Rome criteria? It would be nice to know that IBS is what I have and not something else. Regardless, this is great news and a lot should come of it!
 

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I wonder how long until GI doctors start using this test rather than the Rome criteria? It would be nice to know that IBS is what I have and not something else. Regardless, this is great news and a lot should come of it!
 

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Hmmm...I had a nice talk with my gastro today at length when they worked me because I had so much pain an pressure I was very worried I would end up in ER.Same old story...just another chapter... He says though that I may have SOD and or gastroparesis... and it is probably caused by a virus... This was news to me.... Here we go again.... We treat the symtpoms...and we don't always know the cause...IBS is grand....
 

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Hmmm...I had a nice talk with my gastro today at length when they worked me because I had so much pain an pressure I was very worried I would end up in ER.Same old story...just another chapter... He says though that I may have SOD and or gastroparesis... and it is probably caused by a virus... This was news to me.... Here we go again.... We treat the symtpoms...and we don't always know the cause...IBS is grand....
 

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Discussion Starter · #8 ·
gastroenterology Editoral5-hydroxytryptamine, ulcerative colitis, and irritable bowel syndrome: molecular connections5-Hydroxytryptamine (5-HT serotonin) is contained in and released from enteric neurons1�3 and from enterochromaffin (EC) cells in the mucosal layer of the small and large intestines.4�6 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.4,5 Activation of calcium-permeable ion channels or some G-protein-linked receptors leads to a rise in intracellular calcium and 5-HT secretion.4,5 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.4,5 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.7 5-HT released from EC cells can then initiate gastrointestinal motor reflexes such as peristalsis.7 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.8�10 5-HT released from EC cells initiates antidromic action potentials in the intestinal primary afferent neurons,8 which then activate downstream interneurons and motoneurons in enteric neural circuits mediating peristalsis.9,10 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.5 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.11 This response is mediated by 5-HT3 receptors localized to vagal nerve endings in the colonic mucosa.11 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.12 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.13 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).6 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 IBS14; tegaserod, a 5-HT4 receptor agonist used to treat constipation-predominant IBS15; and tricyclic antidepressant drugs, which alter 5-HT uptake.16 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.17 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.18 in this issue of GASTROENTEROLOGY.Coates et al.18 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.18 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.18 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.19 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.19 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.18 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.20 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.18 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.21 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.18 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.18 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.18 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. http://www2.us.elsevierhealth.com/scripts/...007231&nav=full
 

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Discussion Starter · #9 ·
gastroenterology Editoral5-hydroxytryptamine, ulcerative colitis, and irritable bowel syndrome: molecular connections5-Hydroxytryptamine (5-HT serotonin) is contained in and released from enteric neurons1�3 and from enterochromaffin (EC) cells in the mucosal layer of the small and large intestines.4�6 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.4,5 Activation of calcium-permeable ion channels or some G-protein-linked receptors leads to a rise in intracellular calcium and 5-HT secretion.4,5 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.4,5 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.7 5-HT released from EC cells can then initiate gastrointestinal motor reflexes such as peristalsis.7 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.8�10 5-HT released from EC cells initiates antidromic action potentials in the intestinal primary afferent neurons,8 which then activate downstream interneurons and motoneurons in enteric neural circuits mediating peristalsis.9,10 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.5 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.11 This response is mediated by 5-HT3 receptors localized to vagal nerve endings in the colonic mucosa.11 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.12 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.13 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).6 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 IBS14; tegaserod, a 5-HT4 receptor agonist used to treat constipation-predominant IBS15; and tricyclic antidepressant drugs, which alter 5-HT uptake.16 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.17 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.18 in this issue of GASTROENTEROLOGY.Coates et al.18 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.18 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.18 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.19 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.19 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.18 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.20 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.18 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.21 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.18 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.18 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.18 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. http://www2.us.elsevierhealth.com/scripts/...007231&nav=full
 

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Am I supposed to understand all of that? I'm new here so your talking way over my head.I just got told that there is nothing wrong with intestines. I feel really angry and affronted, and totally de-pressed.I must have imagined the half hour I spent in the bathroom tonight. Ihate this stuff.Tibby
 

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Am I supposed to understand all of that? I'm new here so your talking way over my head.I just got told that there is nothing wrong with intestines. I feel really angry and affronted, and totally de-pressed.I must have imagined the half hour I spent in the bathroom tonight. Ihate this stuff.Tibby
 
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