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HeatherAdministrator

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Pathophysiology of IBS and Serotonin Signaling
      07/05/05 03:22 PM

Pathophysiology of IBS and Serotonin Signaling

From: IBS: Improving Diagnosis, Serotonin Signaling, and Implications for Treatment CME

Authors: Lucinda Harris, MD; Lin Chang, MD


Abnormal GI Motility
The pathophysiology of IBS has evolved tremendously over the last 50 years. IBS was previously considered a disorder primarily due to abnormal intestinal motility. In the 1950s, a study by Thomas Almy[22] demonstrated that gut motility was increased in both normal individuals and patients with IBS when presented with a stressful situation. Subsequent research demonstrated that patients with IBS had increased motility abnormalities related to meals (ie, after eating) compared with control subjects.[23,24] Studies have also demonstrated GI motility abnormalities, such as clustered contractions, prolonged propagated contractions, and high-amplitude propagating contractions more commonly in patients with IBS compared with healthy individuals.[25-28] Although these motility abnormalities may be, but are not always, associated with IBS symptoms, there does not appear to be a consistent motility abnormality to explain the etiology of symptoms in all patients, and therefore, they are not currently used as diagnostic markers.

Visceral Hypersensitivity
The initial clinical observations that led to the hypothesis that patients with IBS have visceral hypersensitivity include recurring abdominal pain, tenderness during palpation of the sigmoid colon on physical examination, and excessive pain during endoscopic evaluation of the sigmoid colon. Experimental evidence suggests that a variety of perceptual alterations exist in patients with IBS: visceral hypersensitivity involving the upper and lower GI tract, as well as a heightened perception of physiologic intestinal contractions. Multiple studies using various balloon distension paradigms have reported lowered colorectal perceptual thresholds, increased sensory ratings, and viscerosomatic referral areas in patients with IBS compared with healthy individuals.[29-33] By contrast, most studies have demonstrated that patients with IBS do not exhibit generalized hypersensitivity to noxious somatic stimulation.[30,34,35] At least 2 underlying, distinct mechanisms contribute to the visceral hypersensitivity in IBS: a hypervigilance towards expected aversive events arising from the viscera, and a hyperalgesia that is inducible by sustained noxious visceral stimulation.[32]

Central Nervous System Modulation
In the 1980s and 1990s, a greater appreciation for the role of the "brain-gut" axis was achieved, and it was recognized that patients with IBS had a dysregulation between these 2 areas.[36] In general, brain-gut interactions play a key role in the modulation of GI functioning in health and disease. Signals from the brain to the gut play an important role in ensuring optimal digestive function, reflex regulation of the GI tract, and modulation of mood states. Proposed alterations in the brain-gut axis in IBS are best supported by recent findings in functional neuroimaging studies. Using distal colonic stimulation, several studies have demonstrated alterations in regional brain activation in patients with IBS compared with healthy control subjects.[37,38] These brain regions include the anterior and midcingulate cortices, insula, and dorsal pons (in the region of the periaqueductal grey) -- which are some of the most consistently activated brain areas in response to visceral as well as somatic nociceptive stimuli.

One area that is consistently activated to a greater degree in patients with IBS compared with control subjects is the anterior midcingulate cortex, a brain region concerned with cognitive processing of sensory input, including attentional processes and response selection. Furthermore, midcingulate activation correlates with the subjective unpleasantness of visceral and somatic pain. These observations suggest that patients with IBS may fail to use central nervous system downregulating mechanisms in response to incoming or anticipated visceral pain. They further show altered activation or deactivation of brain areas involved in the emotional or cognitive processing of visceral stimuli, ultimately resulting in the amplification of pain perception.

Role of Stress and Psychological Factors in IBS
Stress is widely believed to play a major role in the pathophysiology and clinical presentation of IBS. It has been postulated that in the predisposed individual, sustained stress can result in permanent increased stress responsiveness of central stress circuits and vulnerability to develop functional and affective disorders.[39] Stress may be central (eg, psychological distress) or peripheral (eg, infection, surgery) in origin. Numerous studies indicate that patients with IBS report more lifetime and daily stressful events, including abuse, compared with patients with organic GI conditions or healthy individuals.[1] In addition, in patients with IBS, stress is strongly associated with symptom onset, exacerbation, and severity. Even though the effects of stress on gut function are universal, patients with IBS appear to have greater reactivity to stress compared with healthy individuals.[40]

A large proportion of patients with IBS or other functional bowel disorders have concurrent psychological disturbances, particularly those with severe symptoms or those seen in tertiary care referral centers. Psychosocial factors have been recognized to modify the illness experience and influence healthcare utilization and treatment outcome. These psychosocial factors include a history of emotional, sexual, or physical abuse, stressful life events, chronic social stress, anxiety disorders, or maladaptive coping styles.[1] A current conceptual model regarding the role of psychosocial factors and stress in IBS suggests that adverse life experiences (past and present) influence stress responsiveness, physiologic responses, and susceptibility to developing and exacerbating this functional disorder via amplification of brain-gut interactions.

Role of Immune or Inflammatory Mediators
IBS-like symptoms have been reported in 7% to 30% of patients who have had a recent history of proven bacterial gastroenteritis; this has been termed postinfectious IBS (PI-IBS).[41] A subset of patients with IBS can trace the development of their symptoms to an episode of infectious diarrhea, primarily bacterial[42] or amebic,[43] and possibly even viral,[44] in etiology. Risk factors for PI-IBS include female sex, duration of acute diarrheal illness, and the presence of significant life stressors occurring around the time of the infection.[41]

Investigators have found that there are colonic mucosal abnormalities in PI-IBS. One study compared rectal mucosal cellularity and intestinal permeability in patients at 2, 6, and 12 weeks and 1 year after an acute infection with Campylobacter enteritis with those of patients with a history of PI-IBS and healthy controls.[45] Compared with controls, patients with a previous Campylobacter infection were found to have increased numbers of intraepithelial lymphocytes and EC cells and increased intestinal permeability, even after 1 year, as did the patients with PI-IBS. When the secretory granules of the EC cells were evaluated, patients with PI-IBS had granules containing mainly serotonin. The EC cells in healthy control subjects had granules containing primarily PYY, a peptide associated with antisecretory effects. It is conceivable that these findings play a role in the GI symptoms (eg, diarrhea, mucus in the stool) in at least a subset of patients with IBS.

Role of Serotonin in GI Function and IBS
The ENS plays a key role in regulation of both gut motility and secretion. A number of neuropeptides are involved in regulation of motility and secretion, including serotonin, which can modulate both of these functions. Ninety-five percent of serotonin is found in the gut, with 90% localized within the EC cells and 10% in the enteric neurons. Serotonin is an important mediator of the peristaltic reflex. The excitatory 5-HT1P, 5-HT3, and 5-HT4 receptors have been found to be particularly important in modulating this motor activity. Following mucosal stimulation (eg, mechanical or chemical stimulation), serotonin is released from EC cells. Serotonin acts on the 5-HT1P receptor located on the terminals of IPANs within the submucosal plexus. 5-HT4 receptors are located on the presynaptic terminals of these afferent nerves and, when activated, facilitate the release of acetylcholine and calcitonin gene-related peptide (CGRP).[3] Following activation of interneurons within the ENS, acetylcholine and substance P are released from enteric motor neurons proximally (orad), which leads to a contractual response. Release of vasoactive intestinal peptide and nitric oxide distally (caudad) result in relaxation in the gut. Peristaltic activity of the gut then occurs. 5-HT3 receptors are located on enteric nerves within the myenteric plexus as well as on vagal and spinal afferents. These receptors are thought to play a role in other intestinal reflexes and modulation of nonpainful (eg, nausea) and painful sensations, respectively.

Serotonin Reuptake Transporter
There is likely an evolutionary advantage to having physiologic mechanisms that regulate serotonin levels and activity, because it could be quite harmful without these regulatory mechanisms.[3] One of the primary mechanisms the body has for regulating availability of serotonin within the extracellular space is the serotonin reuptake transporter (SERT). SERT is present in the brain and gut. The amount of serotonin reuptake that occurs from the extracellular space is genetically determined and is based on whether there are long, short, or heterozygous polymorphisms in the promoter for synthesis of SERT. For instance, homozygosity for the short variant and presence of the heterozygous variant result in less transcript, less protein expression, and thus, less reuptake of serotonin. SERT activity is obviously an important factor influencing serotonin availability to act on postsynaptic receptors, and would possibly affect the response to serotonergic medications such as SSRIs, in the treatment of depression, and to the novel agents tegaserod and alosetron, for IBS.

Camilleri and colleagues[46] hypothesized that differences in SERT polymorphisms in patients may influence a patient's response to the 5-HT3 antagonist alosetron. It was noted that there were both sex effects and interindividual effects in the way that the medication worked in patients, slowing intestinal transit in some with IBS more than in others. Therefore, a small study of 30 patients (15 women) with IBS with diarrhea was performed in which the patients were given alosetron 1 mg orally twice daily for 6 weeks and their colonic transit measured via scintigraphy at the end of treatment. Only 23 (12 women) of these patients actually submitted blood for analysis, but 8 long homozygous, 4 short homozygous, and 11 heterozygous SERT polymorphisms were identified. When colonic transit was measured, the patients with a long homozygous polymorphism (associated with more serotonin reuptake, ie, there is conceivably less serotonin around to stimulate the gut and peristalsis and therefore gut motility is slowed) had greater slowing of colonic transit with alosetron than heterozygotes. The importance of SERT and its effect on colonic transit response to alosetron on its clinical efficacy, as well as the vulnerability to adverse events associated with the drug, such as constipation and ischemic colitis, need to be examined.


http://www.medscape.com/viewarticle/463521_3

Copyright © 2003 Medscape.

--------------------
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Entire thread
Subject Posted by Posted on
* Brain-Gut HeatherAdministrator 07/14/03 01:59 PM
. * How the Gut's Second Brain Influences Mood and Well-Being HeatherAdministrator   07/15/14 03:08 PM
. * Does bacteria connect the brain and the gut? HeatherAdministrator   09/27/13 11:44 AM
. * Women With IBS Show Changes In Their Brains HeatherAdministrator   07/28/10 11:01 AM
. * Brain-gut axis dysfunction in IBS HeatherAdministrator   03/16/10 11:27 AM
. * Olfactory and gustatory function in irritable bowel syndrome HeatherAdministrator   03/16/10 11:24 AM
. * Mind/Body psychological treatments for irritable bowel syndrome HeatherAdministrator   03/18/09 05:47 PM
. * Women With IBS Can't Switch Off Pain Response HeatherAdministrator   01/18/08 12:39 PM
. * Daily stress and gastrointestinal symptoms in women with irritable bowel syndrome HeatherAdministrator   12/06/07 04:41 PM
. * Colonic Hypersensitivity in IBS - Brain or Gut? HeatherAdministrator   09/13/07 12:04 PM
. * Stress, the Brain-Gut Axis, and IBS HeatherAdministrator   07/17/07 11:34 AM
. * The Effectiveness of Hypnotherapy in the Management of Irritable Bowel Syndrome HeatherAdministrator   10/26/06 10:16 AM
. * An international study of irritable bowel syndrome: Family relationships and mind-body attributions HeatherAdministrator   06/04/06 12:28 PM
. * A Neurobiology of Sensitivity? HeatherAdministrator   06/04/06 12:16 PM
. * Pathophysiology of IBS and Serotonin Signaling HeatherAdministrator   07/05/05 03:22 PM
. * Serotonin receptors and transporters — roles in normal and abnormal gastrointestinal motility HeatherAdministrator   11/08/04 04:38 PM
. * Alterations of sensori-motor functions of the digestive tract in the pathophysiology of IBS HeatherAdministrator   09/12/04 03:44 PM
. * Visceral Sensitivity Index: Development and Validation of a GI Symptom-Specific Anxiety Scale HeatherAdministrator   07/24/04 01:54 PM
. * Brain activity during distention of the descending colon in humans HeatherAdministrator   07/11/04 02:07 PM
. * Irritable bowel syndrome: a model of the brain-gut interactions HeatherAdministrator   05/25/04 12:28 PM
. * The human enteric nervous system HeatherAdministrator   05/11/04 07:10 PM
. * Images Show a Snub Really Is Like Kick in the Gut HeatherAdministrator   10/20/03 03:43 PM
. * The Brain-Gut Connection HeatherAdministrator   09/01/03 11:43 AM
. * The Neurobiology of Stress and Emotions, and IBS HeatherAdministrator   07/23/03 10:35 AM
. * Gut Feelings: The Surprising Link Between Mood and Digestion HeatherAdministrator   07/23/03 10:31 AM
. * Sleep and gastric function in irritable bowel syndrome: derailing the brain-gut axis HeatherAdministrator   07/18/03 12:42 PM
. * The autonomic nervous system in functional bowel disorders. HeatherAdministrator   07/18/03 12:40 PM
. * Regional cerebral activation in irritable bowel syndrome HeatherAdministrator   07/18/03 12:36 PM
. * Intestinal reactivity to words with emotional content and brain information processing in IBS HeatherAdministrator   07/18/03 12:35 PM
. * Perceptual hyperreactivity to auditory stimuli in patients with irritable bowel syndrome. HeatherAdministrator   07/18/03 12:33 PM
. * The gut as a neurological organ. HeatherAdministrator   07/18/03 12:28 PM
. * Brain research in functional gastrointestinal disorders. HeatherAdministrator   07/18/03 12:24 PM
. * The gut has a mind of its own HeatherAdministrator   07/14/03 04:07 PM

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