Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that affects millions of Americans. Care for patients with IBS often falls to the primary care physician. The pathophysiology of the disorder is still not entirely clear, and current treatment options are ineffective in many patients. At the 2000 American College of Gastroenterology's Annual Meeting, attendees convened for the presentations of three experts in the field, who outlined the latest research on the pathogenesis and treatment of this clinically challenging condition.
This program was sponsored by the University of Kentucky through an unrestricted educational grant from Novartis Pharmaceuticals Corporation and Bristol-Myers Squibb Company.
Brain Imaging: CNS Abnormalities in Patients with IBS
The lack of a clearcut pathophysiology and an often noted association between physical and psychological symptoms has led some clinicians to dismiss irritable bowel syndrome (IBS) as a condition that is "all in their head." However recent findings showing CNS abnormalities in patients with IBS may offer a new perspective on the etiology of this debilitating condition, characterized by abdominal discomfort and pain and altered bowel habits. Until recently, the presence and severity of IBS were measured only by gut function and the subjective perceptions of the patient. "Now, the use of functional brain imaging techniques is contributing to an increased under- standing of the pathophysiology of this disease and new target areas for treatment," said Emeran A. Mayer, MD, Professor of Medicine, Physiology, and Biobehavioral Sciences, and Director of the CURE Neuroenteric Disease Program at the University of California, Los Angeles.
Pathophysiology of IBS
IBS is a disease that develops as the result of an abnormally altered brain-gut interaction (Table 1). One manifestation of this alteration consists of aberrant output patterns of the emotional motor system, a part of the limbic system in the brain, in response to external (psychosocial) or internal (immune, nutrient) stressors. Outputs from the limbic system in the form of autonomic, pain modulatory, and neuroendocrine responses can be modu- lated by cognitive factors, such as the beliefs, thoughts, and emotions of the patient. Aberrant output of the emotional motor system in large part accounts for the constellation of symptoms that makes up IBS. "A hyperresponsiveness of circuits in the brain may be one common link to both the abnormal responses to internal inflammatory stressors and external psychosocial stressors," Dr. Mayer explained. Treatment is chosen with consideration of altered motility, visceral hypersensitivity, and the brain's role in modulating these factors.
The autonomic regulatory systems affect not only muscle cells in the gut, but also other cell types, such as mast cells, enterochromaffin cells, and nerve cells of the enteric nervous system. Responses of some of these cells to autonomic modulation, for example in the form of tryptase secretion by mast cells or serotonin secretion by enterochromaffin cells, may play a role in the modulation of visceral afferent sensitivity. According to Dr. Mayer, such mechanisms may play a role in the development of stress-induced visceral hyperalgesia. Another form of visceral hypersensitivity may be related to altered arousal or hypervigilance toward visceral sensations. Such hypervigilance can result in decreased tolerance to balloon distension and lower discomfort thresholds. A cognitive factor involved in the development of hypervigilance is an increased threat appraisal of visceral sensations.
Functional Brain Imaging Techniques
Recently, functional brain imaging techniques have been used to assess directly the activation of certain regions of the brain in response to
visceral stimulation. Today, these techniques, particularly functional magnetic resonance imaging, are being used to assess activation of brain circuits that process visceral afferent information from the gut.
Dr. Mayer noted that there are distinct but overlapping brain circuits that relate to subjective perception of gut sensations, autonomic responses, and pain modulatory responses. Even in terms of subjective gut sensations, different overlapping circuits are present for intensity coding of the stimulus; threat appraisal of the stimulus; and attribution of primary affect, or "unpleasantness".
Both serial and parallel pathways are involved in the processing of visceral sensory information and the control of descending modulatory systems. Input from the gut is derived from multiple channels, such as spinothalamic, vagal, and dorsal column pathways; different regions of the brain then code for intensity, appraise the threat of the stimulus, and determine the level of attention the brain attributes to the stimulus and the unpleasantness the patient experiences. These processes are modulated both by the stress- or arousal- activated system and by recollection of past experiences.
Intensity Coding, Threat Appraisal, and Unpleasantness
Intensity coding. As visceral sensory information is delivered via the spinal cord, it is encoded for intensity in the anterior aspects of the insula, or visceral sensory cortex. PET scan studies of somatic and visceral experimental pain have shown that the insula most objectively and reliably encodes information. Interestingly, studies have also demonstrated a greater activation of the insula in male IBS patients, compared with female patients, when exposed to the same stimulus intensity.
Threat appraisal and unpleasantness. The information that reaches the insula is "appraised" in the dorsal aspects of the anterior cingulate cortex. Blood flow changes in this part of the brain may also correlate with attentional processes and the subjective unpleasantness ratings in response to a somatic stimulus. The ventral (perigenual) cingulate cortex, which is rich in muopioid receptors, functions to encode the affective quality of the stimulus.
In a study by Mayer and colleagues, rectal and sigmoid distension resulted in a lower activation of the ventral anterior cingulate cortex in patients with IBS compared with healthy controls, but an increased activation of the dorsal aspects of the anterior cingulate. Increased activation of an unspecified region of the anterior cingulate was also reported by Mertz and colleagues, in a functional MRI study.
Modulatory factors. Finally, the CNS processing of sensory experience may be simultaneously modulated by two parallel pathways: memory-based modulation and stress- or arousal-induced modulation. The posterior parietal cortex, or sensory association cortex, forms a network with the hippocampus and the amygdala (the brain's memory centers) as well as with the lateral prefrontal cortex. Somatic pain studies have shown that, in response to a stimulus, the recall of a similar past event, along with subsequent interpretation of this memory in the lateral prefrontal cortex, plays a major role in the threat appraisal of a sensory experience. The second modulatory effect is the stress- or arousal-induced response. The pontine locus ceruleus is activated in response to potentially threatening experiences. This region then projects to nearly all other regions of the brain that receive visceral input, causing secretions of norepinephrine and arousal of these sections of the brain. When the secretion of norepinephrine is excessive, these target regions are inhibited. It is of interest that descending projections from the locus coeruleus complex to the sacral spinal cord appear to play a major role in the modulation of distal colonic motor and secretory function.
Conclusion
Brain imaging and other studies of IBS pathophysiology indicate that the perception of gut stimuli and altered autonomic responses to these stimuli are affected by activation of various parts of the brain, resulting in increased attention to these stimuli, greater unpleasantness of the subjective experience, greater threat appraisal, and greater arousal in response to visceral sensations. Further study may lead to new developments in treatment for persons with IBS.
Table 1. Clinical Relevance of Altered Brain-Gut Interaction
Altered attentional mechanisms
o Greater awareness of normally subliminal visceral afferent stimuli
Altered affective stimulus processing
o Greater unpleasantness of visceral sensations, including heartburn, bloating, fullness, abdominal pain, incomplete rectal evacuation
Altered threat appraisal
o Leads to fears such as not being close enough to a bathroom anything eaten may trigger abdominal pain
Enhanced arousal
o Shared by clinical conditions frequently overlapping IBS, such as anxiety, panic disorder and PTSD
o Arousal reduced by sedatives, anxiolytics, low-dose tricyclics
o May respond to relaxation exercises
Post-Infective Irritable Bowel Syndrome
Among many postulated causes of irritable bowel syndrome (IBS), one of the most intriguing is that the syndrome represents sequelae of an acute enteric infection. In fact, such an association is not just an interesting theory. According to Stephen M. Collins, MBBS, FRCP, FRCPC, Professor of Medicine and Director of Gastroenterology at McMaster University in Hamilton, Ontario, Canada, "Acute enteric infection appears to be a significant contributing cause to the development of irritable bowel syndrome." The changes associated with such enteric infection appear to be reversible, introducing the opportunity for new treatment strategies for persons at high risk for irritable bowel syndrome (IBS).
Clinical observations have suggested that transient infection in the gut can lead to persistent neuromotor dysfunction, and possible symptom generation in persons with IBS. In a large review, Chaudhary and Truelove found that 33% of persons with IBS reported an acute onset to their symptoms. Indeed, a recent controlled study showed that enteric infection was a strong risk factor for developing IBS.
Animal Studies: Neuromuscular Dysfunction Post-Infection
In one animal study by Tougas, Collins and colleagues infected mice with Trichinella spiralis. The results showed that the infection was accompanied by inflammation, reaching its peak in week 2. By week 3, the parasite had been expelled and inflammation had subsided. However, accompanying muscle hypercontractility persisted for up to 6 weeks' post-infection.
In a second study by Tougas, the colons of the infected mice were distended using a small balloon and there was evidence of increased afferent nerve activity not only during the infection, but also 4 to 6 weeks' post-infection. Together, these results suggest that transient infection and subsequent inflammation in the gut can alter muscle contraction and increase sensory activity in the colon, suggesting a possible basis for dysmotility and hyperalgesia that occurs in post-infective IBS. But are these effects reversible?
In a third study, animals were infected and allowed to recover. After 3 weeks, a short course of dexamethasone was administered. In the animals treated with steroids, muscle hypercontractility was prevented or reversed by day 28 post-infection. "Post-infective changes appear to be reversible and thus provide a basis for designing new experimental approaches in patients," said Dr. Collins.
Clinical Association Between Infection and IBS
Five recent studies showed that 7% to 31% of persons having food poisoning-associated bacterial gastroenteritis developed IBS, 3 to 12 months' post-infection. This phenomenon has also been observed with parasitic infection; however, the role of viral gastroenteritis is not yet known. The development of IBS appears to be due to a convergence of infection, inflammatory stimuli, central nervous system stimuli, and psychological factors. "The response to inflammatory stimuli is enhanced under stress, with the timing of the stress in relation tostimuli being important," Dr. Collins explained. Psychological factors, however, do not appear to be the sole determinants of whether someone develops IBS post-infection and other human studies suggest that local alterations in response to inflammatory stimuli may be important; this may be, in part, genetically determined.
One study showed that 32% of persons with Salmonella-related gastroenteritis developed IBS symptoms within 2 years' post-infection. Biopsies showed no overt inflammatory presence; however, a semiquantitative approach showed an increase in inflammatory cells in those with IBS. Indeed, there was an increased number of lymphocytes and hyperplasia of the serotonin-containing enterochromaffin cells, a major source of 5-HT in the gut. "It is likely that 5-HT measurements would be increased in this subgroup, affording new therapeutic opportunities for these patients," Dr. Collins said. In addition, other studies have shown a potential role for lumenal factors and for cholestyramine-type factors, especially for diarrhea-dominant disease.
Conclusion
In closing, Dr. Collins noted that post-infection effects associated with IBS appear to be reversible, warranting further clinical investigation of anti-inflammatory agents and other innovative therapies for persons at risk for IBS.
Treatment Options in Irritable Bowel Syndrome
Primary care physicians often refer patients with irritable bowel syndrome (IBS) to gastroenterologists because of difficulty finding an effective treatment. IBS is a condition characterized by abdominal pain, as well as diarrhea, constipation, or an alternating of the two. Treatment options for IBS are targeted to relieve either diarrhea, constipation, or pain, depending on the patient's predominant symptom (Table 1). For many patients, available therapies have not been successful in relieving their IBS, making further study and development of new products essential, said Anthony J. Lembo, MD, Instructor at Harvard Medical School and Director of the GI Motility Center at Beth Israel Deaconess Medical Center, in Boston. Focusing on pain-predominant IBS, Dr. Lembo profiled current and emerging new therapies.
Recent studies suggest that the new smooth muscle relaxants can be effective against pain-predominant IBS and that antidepressants can be beneficial in treating functional gastrointestinal disorders. According to Dr. Lembo, these agents, together with newer 5-HT4 agonists, may offer promise for persons with pain-predominant IBS.
Antispasmodic Agents
Antispasmodic agents are beneficial to some patients with IBS because they interfere with the exaggerated gastrocolic response that occurs with IBS, thereby reducing postprandial motor activity. The three main classes of antispasmodics include anticholinergics, peppermint oil, and the newer direct smooth muscle relaxants. Of four randomized double-blind studies of anticholinergics in IBS, only one showed a significant global symptom improvement over placebo. In this study, more than 50% of patients developed anticholinergic side effects.
Of five randomized, double-blind studies of peppermint oil products, three showed significant global symptom improvement over placebo. However, significant side effects occurred with treatment, and the studies consisted of small sample sizes and short duration of
followup. Constipation is one potentially significant side effect of antispasmodic agents. In a recent meta-analysis of all antispasmodic agents, Poynard and colleagues found that antispasmodics did benefit patients in terms of global symptom improvement in general, and pain, in particular. The antispasmodics that were most effective were the newer smooth muscle relaxants not currently available in the United States.
Antidepressant Agents
Antidepressant agents, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors, are used in persons with IBS (particularly pain-predominant) because they are effective against chronic pain (especially TCAs); pain reduction is independent of effects on mood; and they are effective against conditions that often overlap with IBS. Side effects with these agents might include sedation, agitation, anticholinergic effects, and constipation.
5-HT3 Antagonists and 5-HT4 Agonists
There are four main types of 5-HT receptors, of which 5-HT3 and 5-HT4 are most relevant to the treatment of IBS. 5-HT3 receptors are associated with the provocation and perception of pain, the emesis reflex, and gut motility and secretion; while 5-HT4 receptors are associated with emesis reflex, visceral sensation, secretion, and activation of neurotransmitter release and gut motility.
5-HT3 antagonists have been shown to increase colonic compliance, reduce postprandial rectal sensitivity and motility, enhance jejunal water and sodium absorption, and prolong left colon transit time. Alosetron has been the only U.S. Food and Drug Administration (FDA)-approved 5-HT3 antagonist for the treatment of IBS (in women); however, Glaxo Wellcome has since voluntarily withdrawn this drug from the market after some reports of ischemic colitis and severe constipation.
"Studies have shown 5-HT4 agonists to decrease small bowel transit time in persons with constipation-predominant IBS; to dose dependently inhibit afferent nerve activity to rectal distention in cats; and to inhibit visceral discomfort in rats," said Dr. Lembo. When serotonin is released from enterochromaffin cells in the gut, it stimulates 5-HT4 receptors on primary intrinsic afferent nerves, which in turn stimulate both ascending excitation and descending inhibition of motor neurons, resulting in peristaltic contraction in the gastrointestinal tract. 5-HT4 receptor agonists, such as tegaserod maleate, directly stimulate the peristaltic reflex and accelerate gastrointestinal transit. In a study of tegaserod, 881 persons having IBS-associated constipation and abdominal pain, were treated. Those taking tegaserod showed significant symptom improvement over placebo. In addition, tegaserod was associated with a significant increase in number of stools, improvement in stool consistency, and decrease in bloating. A significant response was achieved in women; small sample sizes of men studied thus far make these data difficult to interpret. Side effects included transient diarrhea (12% vs 5% in placebo), but there were no effects on QTc intervals. Tegaserod is currently under review by the FDA.
In closing, Dr. Lembo emphasized that, "promising new agents-such as new muscle relaxants and 5-HT4 agonists-may soon mean more treatment options and greater relief for persons with IBS."
Table 1. Treatment Options for IBS
Diarrhea-Predominant IBS
o Antidiarrheal agents (loperamide, diphenoxylate, cholestyramine)
o Alosetron, a 5-HT3 receptor antagonist*
Constipation-Predominant IBS
o Fiber
o Osmotic cathartics (sorbitol, lactulose)
o Nonosmotic cathartics (polyethylene glycol)
o Tegaserod, a 5-HT4 partial agonist that may be available in future**
Pain-Predominant IBS
o Antispasmodics (anticholinergics, peppermint oil, smooth muscle relaxants†)
o Antidepressants (tricyclic antidepressants or selective serotonin reuptake inhibitors)
o Alosetron for diarrhea-related pain*
o Tegaserod for constipation-related pain, perhaps in near future**
*Glaxo Wellcome has voluntarily withdrawn alosetron from the market.
**Tegaserod is not yet approved by the FDA.
†Most new direct smooth muscle relaxants are not yet available in the United States.
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