Vip No

ACh PACAP CGRP

Myenteric/ y submucosal plexus

Mucosa

Enterochromaffin cells in GI tract release 5HT

Figure 1 The peristaltic reflex.51'52'58,59 (Adapted from Grider, J. R.; Foxx-Orenstein, A. E.; Jin, J. G. Gastroenterology 1998, 115, 370-380 © 1998. With permission from the American Gastroenterological Association. A version of this figure was originally published in Baker, D. E. Am. J. Health Syst. Pharm. 2005, 62, 700-711 © 2005, American Society of Health-System Pharmacists, Inc. All rights reserved. Adapted with permission.)

and in humans, the answer to this question remains unclear. However, from studies in animals, the current hypothesis is that 5HT released from EC cells binds to 5HT1P and 5HT3 receptors on mucosal terminals of IPANs, initiating a nerve signal that triggers IPANs to release the excitatory neurotransmitters CGRP and ACh on to postsynaptic neurons within the ganglia. This signal then travels along proximal and distal interneurons to create proximal contraction and distal relaxation of circular smooth muscle, resulting in propulsive waves that propel the bolus forward. 5HT4 receptors are located presynaptically on terminals of IPANs and interneurons,62-64 and in this position their activation results in enhancement, or amplification, of peristaltic neurotransmission via increased release of additional neurotransmitters (e.g., ACh and tachykinins).45'52'65'66 Thus, initiation of peristalsis involves activation of 5HT1P and 5HT3 receptors, whereas 5HT4 amplifies the response. Here, it might be useful to think of a radio, in which 5HT1P and 5HT3 receptors are the aerial antennae receiving the signal and 5HT4 receptors turn up the volume. 5HT is also involved in maintaining stool water content. For example, activation of 5HT4 receptors results in increased secretion of chloride ions, enhancing the net movement of water into the intestine.68,69

6.29.2.1.2.2 5-Hydroxytryptamine and visceral sensation

With greater than 90% of vagal fibers being afferent nerves (i.e., communicating information from the gut to the brain), sensory perception is a critical aspect of the bowel.40 5HTacts primarily via 5HT3 receptors to activate vagal and spinal afferent nerves.70,71 However, recent data demonstrate an additional role for 5HT4 in the inhibition of spinal afferents, although whether this is a direct effect is uncertain.72-74 Overall, 5HT is among the key neurotransmitters involved in modulating pain transmission signals from the bowel to the CNS45 and therefore has an important role to play in the sensory symptoms of patients with IBS.45,54

6.29.2.1.2.3 5-Hydroxytryptamine receptors

To date, 14 subtypes of 5HT receptors have been identified; those considered the most relevant to motor, secretory, and sensory activities of the lower GI tract include 5HT1P, 5HT3, and 5HT4, but several others have also been implicated, including 5HT1, 5HT2, and 5HT7. Because effective therapeutic agents have been developed for both 5HT3 and 5HT4 subtypes, these are described in Section 6.29.5. However, an interesting recent development around 5HT1P receptor deserves mention here. Although a distinct 5HT1P receptor has not yet been cloned, its numerous actions on the submucosal plexus of the ENS have been identified and are referred to as 5HT1P activity. Most recent evidence suggests that the molecular entity that underlies this 5HT1P activity is a dimer, formed from the association of 5HT1B and dopamine D2 receptors.75 As discussed, 5HT1P receptor activation is responsible for initiating peristaltic and secretory reflexes by activating the submucosal IPANs.40

6.29.2.2 Clinical Observations with Potential Links to Irritable Bowel Syndrome Symptoms

Given the heterogeneity of symptoms of IBS and the lack of definitive organic markers of this disorder, the development of a unifying hypothesis explaining its underlying pathophysiology has been challenging. Nonetheless, substantial progress has been made. Whereas three decades ago the etiology of IBS focused on altered GI motility, research advances (particularly during the last 15-20 years) have led to a greater understanding of the additional critical role played by efficient communications along the brain-gut axis, particularly with respect to sensory symptoms of the disease (abdominal pain, bloating, urgency, incomplete evacuation). The putative role of immune-system alterations, genetic links, and environmental factors has also been studied. Although this research has brought us closer than ever before to understanding IBS as a real condition with a pathophysiological basis, there is a long way to go before the underlying mechanisms of this complex disorder are fully defined.

6.29.2.2.1 Gastrointestinal dysmotility

The GI tract neuromuscular system necessarily is highly coordinated, such that preprogrammed patterns of neuronally driven contractile activity, along with local and extrinsic modulating inputs based upon environmental factors, provide for the effective digestion of food and elimination of waste. Simply put, gut contents need to spend certain amounts of time in specific parts of the GI tract, where they may need to be mixed and distributed along its surface area to allow the addition of digestive enzymes and absorption of nutrients before subsequently being expelled. This is a highly regulated system that requires precise orchestration. Dysmotility describes a state in which the GI tract fails to perform the necessary concerto of contractile activity, such that GI transit is impaired and symptoms result. The orchestra analogy is perhaps useful here because there can be multiple reasons the system breaks down: the extrinsic control or conductor (the CNS via the efferent autonomic inputs), the local controllers or first violin (the intrinsic sensory neuron that sets the pace of reflex activity in the ganglia), or the musicians (the nerves, muscles, interstitial cells, inflammatory cells, neurotransmitters, etc.) who actually perform the work in a very professional and attentive manner, such that the output is concordant and comfortable.

Local contractile activity needs to follow specific patterns so that it is propulsive when it is time to move gut contents along the lumen. As discussed, this propulsive contractile activity is called peristalsis, and this pattern consists of contraction of the muscle behind the contents and relaxation ahead of them so that the contents are pushed along from behind, like squeezing the toothpaste along and out of the tube. An example of dysmotility is a breakdown of this peristaltic reflex, such that the contractile pattern becomes uncoordinated and nonpropulsive. This type of dysmotility can therefore result in impaired or slow intestinal transit, resulting in constipation. Other patterns of activity also occur, and dysmotility in the upper-GI tract, e.g., leading to reduced gastric emptying or accommodation, is associated with symptoms of dyspepsia and reflux disease. It is beyond the scope of this chapter to describe them all, but some have been linked to IBS symptoms and deserve mention. The migrating motor complex describes the cyclical motor activity that normally occurs approximately once every 60-90 min in the stomach and small bowel in the unfed state. Abnormalities in contractile activity of the colon and small bowel have been suggested to be present in between 25% and 75% of patients with IBS.76 Patients with IBS-C have fewer than normal fast colonic and propagated contractions, as well as fewer highamplitude propagated contractions (resulting in slowing of whole-gut transit). Conversely, patients with IBS-D may have a greater than normal number of fast colonic contractions and propagated contractions (resulting in accelerated motility).76 However, no single motility abnormality has been demonstrated consistently in patients with IBS, and these abnormalities are not always associated with IBS symptoms. Furthermore, the specificity of the qualitative intestinal motor changes is low (i.e., similar changes can occur in non-IBS conditions, as well as in healthy individuals).77 Therefore, although the presence of motility abnormalities is clear, they are not considered a diagnostic marker for IBS.55,77

An interesting area of study in recent years has been the dynamics of intestinal transit of gas.78'79 Gas, either swallowed (or not expelled via a belch) during a meal or produced locally by gut flora, also needs to be moved along the gut lumen and expelled as flatus. When gas transit is impaired, symptoms of bloating and abdominal distension occur, and this is common in patients with IBS-C. While studies have not demonstrated abnormalities in the amount or content of intestinal gas in these patients, it has been shown that they may expel gas more slowly than normal through the GI tract and/or experience reduced tolerance to gas sensation (i.e., report more abdominal discomfort than healthy subjects).80 Studies of patients with IBS have also shown that ingestion of dietary lipids results in delayed intestinal gas transit and symptoms of abdominal bloating.81,82 Therapy with promotility agents, which provide relief of bloating in patients with IBS-C, has been demonstrated to accelerate transit of gas from the small to the large intestine,83 whereas the opposite is true for fiber supplements, which are linked to a worsening of bloating in these patients.84 The link between gas transit, sensory symptoms, and the efficacy of therapeutic agents will be an interesting area of future research.

6.29.2.2.2 Altered brain-gut axis communication

Normal GI function (including the processes of intestinal motility, secretion, and sensation) depends on efficient communications along bidirectional parallel circuits (known as the brain-gut axis) that integrate intestinal motor and sensory activities occurring in the ENS and extrinsic sensory nerves (spinal and vagal) with activities in the autonomic nervous system and CNS. The presence of dysregulated interactions at any level along this axis can lead to the cardinal IBS symptoms of altered GI motility, altered intestinal secretion, and enhanced visceral sensation.47'52 Put simply, although the gut can contract and secrete in complete isolation, the extrinsic innervation provided by vagal and spinal sensory afferent and autonomic efferent nerves is essential to the coordination of overall digestive function and sensory perception, when required.

6.29.2.2.3 Visceral sensitivity and hypersensitivity

As discussed, although the ENS can operate essentially independently of CNS input, the two nervous systems usually work together to ensure proper GI function. It is therefore necessary for the CNS to be aware of events occurring in the bowel, particularly the enteric lumen. Such CNS awareness may be unconscious information concerning content of the bowel (chemosensory, mechanosensory, pH, etc.) or the conscious perception of sensations such as the presence of stool, the urge to defecate, bloating, or pain. Although we have all experienced noxious sensations from our bowel, such as nausea, or bloating, or pain, alterations in CNS integration and processing of signals along the brain-gut axis may lead to heightened (and inappropriate) awareness of bowel events, such that normal activity is perceived as noxious. Such inappropriate sensations resulting from visceral hypersensitivity are thought to play a key role in IBS symptoms.85-89 Thus, visceral hypersensitivity describes a phenomenon by which patients experience either an exaggerated response to normal stimuli or increased sensitivity to painful stimuli in the bowel. It is a common manifestation of IBS and may underlie the most distressing symptoms of the disorder.40,45,87 Various balloon distension studies (designed to detect patients' discomfort and pain thresholds) have demonstrated that patients with IBS sense pain at lower levels of balloon inflation (in the rectum, as well as other intestinal areas) compared with healthy controls or patients with other GI disorders, confirming the presence of differences in visceral perception between IBS and non-IBS patient populations.55,87,90,91 Interestingly, although this hypersensitivity appears not to be restricted to specific areas of the GI tract, patients with IBS have not been shown to experience generalized hypersensitivity to painful somatic stimuli.55

Brain-imaging studies have demonstrated differences in central mechanisms for pain modulation between patients with IBS and healthy controls. Patients with IBS may differ from patients without IBS in the way signals from the gut are received and/or processed by the CNS. For example, using positron emission tomography, one study demonstrated that the anterior cingulate cortex (ACC) was activated upon colorectal distension in healthy volunteers, but not in patients with IBS.92 In another study using positron emission tomography, patients with IBS were shown to have increased activation of the dorsal ACC (involved in perception of emotional stimulus, such as fear, anxiety) and decreased activation of the periaquiductal gray region (involved in inhibition of endogenous pain). This combination of enhanced activation of perception to visceral stimulus and potential deficiency in cortical activation of endogenous pain inhibitory mechanisms may account for the visceral hypersensitivity commonly experienced by patients with IBS.93

In a study using functional magnetic resonance imaging, upon painful visceral stimulation, the ACC was activated in both patients with IBS and controls; however, those with IBS experienced greater pain sensitivity and heightened perception of visceral afferent signals along the brain-gut axis. These signals corresponded with subjective pain symptoms.94 Based on results of brain imaging studies in patients with IBS for whom aversive visceral stimuli did not lead to increased activation of the insular cortex (which acts as the viscerosensory cortex), it has been suggested that the visceral afferent input received by the brain from the colon is not increased, but rather the management of the peripheral signal is enhanced.95

6.29.2.2.4 5-Hydroxytryptamine signaling abnormalities: role of altered release and/or reuptake

The importance of effective 5HT signaling in the ENS and the brain-gut axis to normal gut function was discussed. Perhaps unsurprisingly, recent evidence suggests that abnormalities in serotonin signaling play a critical role in IBS pathophysiology.45'76'96'97 5HT signaling refers to numerous components, including the synthesis, storage, release, receptor activation, reuptake, and degradation of 5HT. Research advances have demonstrated that patients with IBS may have alterations in several of these elements.97-103

Following a meal, 5HT is released into the GI tract wall. The distance separating EC cells from the nerves upon which they act is large; therefore, delivery of sufficient quantities of 5HT to neural receptors necessitates the secretion of very large amounts (both constitutively and especially upon stimulation). This mechanism leads to an overflow of 5HT into the portal circulation and intestinal lumen. Because extracellular enzymes do not catabolize 5HT, termination of signaling requires an efficient removal mechanism from the extracellular space to prevent overstimulation (potentially leading to diarrhea), eventual receptor desensitization (leading to constipation), or frank toxicity.40 This is primarily accomplished through a specific serotonin reuptake transporter (SERT). This transporter is present in the plasma membranes of serotonergic neurons in the ENS and the brain, but, most importantly for our purposes, also in epithelial cells of the GI mucosa.40'52

Some researchers have used postprandial levels of 5HTas a surrogate marker for its release in the GI tract.100,102,103 Although there are recognized issues with such techniques, direct measurement of release from the bowel wall in human subjects is clearly problematic. Others have tried to circumvent these problems by using in vitro techniques to study release from tissue biopsy specimens,97 but this approach has its own inherent drawbacks, not the least of which is that the studies cannot be correlated with meal ingestion, symptoms, and so on, and the obvious loss of all extrinsic influences present in the in vivo state. However, these issues being accepted, the evidence supports a role for a dysfunction in serotonin release and/or reuptake in patients with IBS.

The easiest of these data to understand are those demonstrating altered postprandial serotonin levels in patients with IBS with differing phenotypes of the disease. Put simply, there appear to be exaggerated postprandial plasma levels of serotonin in patients whose major GI symptom is diarrhea101,103 and reduced postprandial levels in those whose primary symptom is constipation.100 The extrapolation to a conclusion that IBS-D is due to exaggerated release of 5HT and IBS-C is due to a blunting of this release is a tempting one, but the definitive experiments are still required.

A role for changes in SERT activity in patients with GI dysfunction has been demonstrated in both animal models and human studies. In a genetically manipulated mouse model, deletion of the SERT gene led to symptom manifestations of IBS-A: i.e., diarrhea, presumably caused by excessive 5HTsignaling, and constipation, perhaps caused by desensitized 5HT receptors or hyperexcitability of enteric nerves, such that the coordination of reflexes breaks down.104 Inflammation also can regulate SERTexpression. In a study using a guinea pig model, during the first 7 days, induction of ileitis led to reduced SERTexpression, an increased number of EC cells, and increased 5HTavailability, with levels normalized by day 14.105 Studies evaluating patients with IBS-C, IBS-D, and ulcerative colitis demonstrated reduced SERT gene and protein expression in the GI mucosa compared with healthy controls, supporting the concept that a diminution in SERT activity can lead to altered GI function.97 This study also demonstrated molecular differences in other 5HT signaling components in patients with IBS compared with controls. Although numbers of EC cells and mucosal 5HTrelease did not differ, reductions in levels of tryptophan hydroxylase 1 (the rate-limiting enzyme in 5HT synthesis), SERT immunoreactivity, and 5HT content were shown.97 Although the precise nature of the serotonin signaling dysfunction is unclear at this time, it is clear that the system is plastic, regulated, and plays a role in both physiology and pathophysiology of the bowel.

6.29.2.2.5 Role of stress/psychosocial factors

The presence of acute stress leads to release of stress-related hormones (e.g., corticotropin-releasing factor (CRF), associated with the hypothalamic-pituitary axis), which may lead to altered effects on GI motility, sensation, and inflammation. Studies using rat models have shown that acute stress affects the content of histamine in mast cells in the gut via release of interleukin-1 and CRF.106 A recent study has demonstrated that infusion of CRF in patients with IBS leads to an exaggerated colonic motility response (likely as a result of CRF-induced activation of mast cells and release of mediators).107 Patients who seek healthcare for IBS symptoms have been shown to have a high rate of psychiatric comorbidity (54-90%; e.g., depression, anxiety, hostility, somatization).34 However, others have shown that only a small percentage of patients with IBS in tertiary referral centers have a high degree of distress; the majority do not demonstrate clinically evident psychosocial dysfunction.108 It is important to note here that current evidence suggests that, although psychological factors do not cause IBS, they may affect how its symptoms are experienced (e.g., regularity, severity, or perception of severity), how they cope (whether they visit a physician), and the ultimate clinical outcome; this concept is known as the biopsychosocial model of IBS.77,109

6.29.2.2.6 Previous infection

Postinfectious IBS (PI-IBS) refers to the development of IBS symptoms (predominantly abdominal pain, diarrhea, and urgency) after an enteric infection, particularly with Salmonella, Shigella, or Campylobacter species. In prospective studies, recovery from bacterial gastroenteritis was followed by the development of IBS symptoms in 7-32% of patients.76,110 Numerous risk factors for PI-IBS have been identified, including female sex, younger age, acute infectious gastroenteritis that lasts a long time and is severe, concomitant occurrence of psychological disturbances (e.g., anxiety, depression), presence of increased numbers of EC cells, and use of antibiotics to treat the acute bacterial gastroenteritis.76'77'98'110 Studies have shown the presence of low-grade inflammation in the colonic mucosa of patients in whom symptoms have persisted after resolution of acute infection, suggesting difficulty in downregulation of intestinal inflammation.110 It is also important to note that as an initial barrier to the external environment, there is a continual state of low-level inflammation in the GI mucosa. However, compared with healthy controls, patients with PI-IBS have demonstrated specific colonic changes that may explain the presence of altered bowel function and enhanced perception of symptoms, including increased mucosal EC cells (leading to excess production of 5HT?), increased permeability of the gut, and increased concentrations of mast cells and T lymphocytes in the lamina propria r i 76 77 99

of the gut mucosa.

6.29.2.2.7 Immune-system alterations/gut flora/food allergy

An interaction between the ENS and the gut immune system may partially explain the presence of IBS symptoms in a subset of patients. The colonic and ileal mucosa in certain patients with IBS has elevated numbers of inflammatory cells, including activated inflammatory cells (e.g., T lymphocytes, mast cells, macrophages) located within close proximity to colonic mucosal nerve endings, potentially resulting in the release of inflammation-related mediators (e.g., histamine, interleukins, nitric oxide) that can affect motor/secretory actions in the ENS.98,111-113 These mediators can also affect gut-related sensory innervation, thereby enhancing visceral sensation and resultant abdominal pain/ discomfort.77 A change in intestinal microflora is another putative mechanism leading to IBS symptoms.110,114 In patients with IBS, bacterial fermentation of foods may be increased.115 In one study, the presence of small-intestinal bacterial overgrowth, a condition that most commonly affects patients predisposed to motility or structural abnormalities, was found in patients with IBS.116,117 The possible role of gut microflora in IBS pathophysiology therefore deserves further study.

Although a concrete link between IBS symptoms and food intolerance has not been established, some patients link their IBS symptoms to intolerance to particular foods and report symptom relief as a result of eliminating specific foods from their diet. However, true detection of food intolerance is difficult because of the unclear cause and the nonspecific nature of symptoms. Similarly, use of an exclusion diet is time-consuming and generally difficult to implement. In the past, the majority of tests for food intolerance have focused on testing for immediate-type reactions triggered by the presence of IgE-mediated antibody response, which may occur rarely in patients with IBS. Recent research has evaluated the possibility that food-related symptoms in patients with IBS might be caused by immunoglobulin G (IgG) antibodies, which are associated with a more delayed onset following antigen exposures.118,119 In a recently published randomized clinical trial, patients with IBS receiving an exclusion diet (based on food to which they demonstrated IgG antibodies) experienced significantly greater improvements in symptoms than patients for whom these foods were not excluded; reintroduction of the respective foods resulted in a return of symptoms.118

6.29.2.2.8 Genetic links

Although genetic factors may play a role in IBS development, the presence of environmental factors likely is an important contributor to the specific ways the condition is expressed, as well as patients' coping strategies, including healthcare-seeking behavior. Data demonstrate that IBS runs in families,120 and studies show that the prevalence of IBS in monozygotic twins is twice as high as that in dizygotic twins.121,122 Additionally, specific genotypes and polymorphisms in some genes have been associated with the disease (including interleukin-10, SERT, the a-adrenoceptor, and the G-protein GNb3).77,101,110,123-125 Whereas all these are interesting findings, the data do not support an unequivocal association with IBS at this time.

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