IntroductionMany patients with irritable bowel syndrome (IBS) have walked into their physician's office and said, "The last doctor told me my symptoms were all in my head." Those physicians may have been right, but not in a way they anticipated.Over the past 50 years, evolving conceptual mechanisms have been proposed to explain the pathophysiology of IBS. These mechanisms have ranged from a purely psychological disorder to such physiologic conditions as a primary abnormality in gastrointestinal (GI) motility or visceral hypersensitivity. However, recent scientific data have increasingly supported that a dysregulation in brain-gut interactions resulting in alterations in GI motility, secretion, and sensation is the principal pathophysiologic mechanism underlying IBS. Brain-gut interactions are mediated largely by the autonomic nervous system, which is comprised of the parasympathetic (vagal and sacral parasympathetic), sympathetic, and enteric nervous systems (ENS). Many factors (both central and peripheral) may contribute to an altered brain-gut axis, including genetic predisposition, chronic stress, inflammation/infection, and environmental parameters. These alterations may subsequently lead to disturbances in intestinal motility, visceral sensitivity, and mucosal immune response and permeability. In IBS, these disturbances result in symptoms of abdominal pain or discomfort and altered bowel function, the defining characteristics of this disorder.There are many neurotransmitters and hormones that mediate bidirectional brain-gut communication. Serotonin (5-hydroxytryptamine [5-HT]) is one of the key mediators of gut motility, secretion, and sensation. Most of the serotonin is localized in the GI tract and is found in enterochromaffin (EC) cells and enteric neurons. EC cells sense luminal factors such as food or mechanical distension in the gut, and release serotonin; 5-HT receptors on intrinsic primary afferent neurons (IPANs) as well as extrinsic spinal or vagal afferent neurons are activated. The ENS regulates secretion and peristalsis, whereas vagal and spinal afferents modulate nonpainful and painful sensations, respectively. There are at least 7 main classes of 5-HT receptors. Particularly important for lower gut function and regulation are the 5-HT1P, 5-HT3, and 5-HT4 receptors. These receptors have been the focus of research evaluating the pathophysiologic mechanisms of IBS as well as targets for the development of novel agents in the treatment of functional gastrointestinal disorders. There is also evidence to suggest that other older serotonergic agents -- that is, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) -- may modulate intestinal function as well. The roles of other neuropeptides and their receptors are also currently being explored as potential molecular targets for drug development.The development of more effective treatment for IBS is crucial because it is one of the most common disorders seen by gastroenterologists and primary-care physicians, but patients are often not satisfied with traditional therapies. In addition, proper diagnosis and treatment are particularly critical for a number of reasons. Studies have demonstrated the dramatic impact of this disorder on the quality of life of patients with IBS compared with the general population and with individuals with other chronic health conditions.[5,6] In addition, patients with IBS utilize the healthcare system for both GI and non-GI complaints more than patients without IBS. The latter in turn impacts the productivity of patients with IBS such that their absenteeism from work or school has been found to be 3 times higher than that of patients without IBS. Not surprisingly, economic studies have demonstrated that this disorder is costly to the healthcare system and to the economic system as a whole, resulting in an annual associated cost of up to $30 billion.[9,10]The challenge for clinicians is to identify individuals with IBS despite the fact that no diagnostic biologic marker currently exists for this disorder, and to manage their symptoms despite the lack of effective treatment. Studies evaluating the utility of symptom-based criteria and medical tests in the diagnosis of IBS vs organic GI disorders have resulted in recent recommendations for a more cost-effective diagnostic approach. Although many patients may respond to reassurance, life-style changes, and traditional therapies, it is important for healthcare providers to familiarize themselves with advances in the pathophysiologic mechanisms of IBS that have subsequently led to the development of novel therapeutic agents, such as the serotonergic medications. In addition, these advances have inspired a new look at older medications that affect the serotonin receptors.Diagnosis of IBSSymptom-Based Diagnostic CriteriaDue to the lack of a diagnostic biologic marker for IBS, the diagnosis is made using symptom-based criteria. A number of symptom-based criteria have been used in the past; however, the currently accepted criteria are those that have been developed by the Rome II committee, a group comprised of experts specializing in functional gastrointestinal disorders. IBS is most recently defined as abdominal pain or discomfort not explained by biochemical or structural abnormalities that is present for at least 12 weeks (not necessarily consecutive) over the past 12 months and associated with at least 2 of the following features: (1) relief with defecation; (2) a change in stool consistency (eg, watery/loose or hard/lumpy); and/or (3) a change in stool frequency.The Rome II criteria are a simplification of the Rome I Criteria. The Rome I criteria were similar to the above indicated features, but also stated that 2 or more of the following features must be present as least 25% of the time: (1) abnormal stool form; (2) passage of mucus; (3) bloating or distension; (4) abnormal stool passage (feeling of incomplete evacuation, straining, or urgency); and (5) altered stool frequency (> 3 bowel movements/day or < 3 bowel movements/week). These symptoms are presently used as supportive symptoms for the diagnosis of IBS.Because patients may present with diarrhea and/or constipation, patients are often subgrouped by predominant bowel habit. However, GI symptoms may fluctuate over time and, therefore, a special task force of the American College of Gastroenterology has suggested that patients with IBS be identified using the following designations: IBS associated with abdominal pain, fecal urgency, and diarrhea; IBS associated with abdominal discomfort, bloating, and constipation; and IBS associated with alternating diarrhea and constipation.Diagnostic ConsiderationsOnce a dominant symptom complex is identified in the patient, it is also useful to exclude possible "red flags" that might be indicative of an organic disorder. Table 1 outlines the potential "alarm" symptoms that need to be considered when evaluating a patient with IBS.Table 1. Alarm Symptoms Suggestive of Organic DiseaseHistoryWeight loss > 10 lbs Nocturnal symptoms Initial onset at age > 50 years Significant travel history Severe diarrhea or constipation Rectal bleeding Arthritis/rashes Family HistoryColon cancer Inflammatory bowel disease Celiac disease Physical FindingsFever Oral ulcers Palpable abdominal mass Guaiac-positive stool Other physical finding (eg, abdominal mass, distension) Rectal bleeding or obstruction Laboratory EvaluationIncreased white blood cell count Anemia Abnormal chemistry Increased thyroid-stimulating hormone Elevated erythrocyte sedimentation rate or C-reactive protein Once a thorough medical history and physical examination are performed, a variety of laboratory tests that have been advocated in the literature may be considered.[1,13] These diagnostic tests include: (1) complete blood count (CBC); (2) thyroid-stimulating hormone (TSH) level; (3) erythrocyte sedimentation rate (ESR); (4) complete metabolic profile; (5) stool for ova and parasites (O&P); (6) stool culture and examination; (7) fecal occult blood testing; and (8) celiac sprue panel. Other diagnostic tests include flexible sigmoidoscopy, colonoscopy, or barium enema, and hydrogen breath tests, which should be considered on an individual basis. It is generally recommended that clinicians take an evidence-based medicine approach in their medical evaluation and consider the pretest probability of a test for diagnosing another medical condition (eg, colon cancer, inflammatory bowel disease, celiac sprue) before ordering it. The presence of alarm symptoms would suggest a higher pretest probability of an organic disorder that needs to be ruled out. The differential diagnosis of IBS often depends on the predominant symptom (eg, diarrhea or constipation), as outlined in Table 2.Table 2. Differential Diagnosis of IBS*Malabsorption Dietary Factors Intestinal disorders Lactose intolerance Pancreatic insufficiency Alcohol/caffeine Postgastrectomy Sorbitol/high fructose corn syrup Gas-producing foods Infection High-fat foods Bacteria Wheat (celiac disease) Parasites HIV and associated infections Psychological Disorders Inflammatory Bowel Disease Panic disorder Crohn's disease Somatization Ulcerative colitis Depression Microscopic/collagenous colitis Gynecologic Disorders Endometriosis Malignancies Dysmenorrhea Endocrine tumors Ovarian cancer Colon cancer Neurologic Disorders Parkinson's disease Medicationsâ€ Multiple sclerosis Antibiotics Spinal cord lesions Nonsteroidal anti-inflammatory drugs Chemotherapy Endocrine/Metabolic Disorders Opiates Diabetes Calcium-channel blockers Hypo/hyperthyroidism Antidepressants Hypercalcemia *Consider dominant bowel symptomâ€ Not an all-inclusive listStudies of reasonably good quality have suggested that the diagnostic yield associated with performing most of these tests is not very high -- for many, in fact, less than 2%.[14,15] However, there are a few exceptions. One exception is lactose intolerance, which is present in approximately 25% of the population. However, lactose intolerance is often coexistent with IBS and, when treated, the patient still has symptoms of IBS. The other exception is celiac sprue. The pretest probability in the patient with IBS is significantly higher than that found in the general population (4.67% vs 0.25% to 0.50%).[16,17] Therefore, screening with endomysial antibody, among other such screening tests, may be indicated, particularly if the patient has failed to respond to treatment. Seven percent of patients with celiac disease are IgA deficient and, therefore, the clinician may want to measure the IgA level as well when celiac disease is a diagnostic consideration.Although the pretest probability of finding an etiology for symptoms by colonoscopy is not high, most gastroenterologists would agree that patients >/= 50 years of age should undergo this examination (or, alternatively, a flexible sigmoidoscopy and barium enema) if a previous screening examination has not been done. This age threshold should be lowered to 40 years if there is a significant family history of colon cancer.Another condition to consider excluding from the differential diagnosis when managing a patient with symptoms of IBS is bacterial overgrowth. Two studies from the same research group found that 78% to 84% of patients with IBS had bacterial overgrowth.[18,19] In patients with evidence of bacterial overgrowth, those treated with neomycin had a >/= 35% reduction in clinical response (ie, improvement) compared with an 11% reduction in patients on placebo. Although these data are extremely intriguing, there are some methodologic limitations in these studies and, therefore, the use of widespread hydrogen breath testing for bacterial overgrowth is still not generally advocated.The diagnosis of IBS is primarily symptom-based, and the literature suggests that once made, the clinician can be confident of his/her diagnosis. Retrospective views of patients have suggested that the diagnosis is an enduring one, with 92% to 97% of the individuals maintaining the same diagnosis over 2-13 years.[20,21]Pathophysiology of IBS and Serotonin SignalingAbnormal GI MotilityThe 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 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 HypersensitivityThe 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.Central Nervous System ModulationIn 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. 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 IBSStress 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. 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. 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.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. 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 MediatorsIBS-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). A subset of patients with IBS can trace the development of their symptoms to an episode of infectious diarrhea, primarily bacterial or amebic, and possibly even viral, 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.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. 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 IBSThe 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). 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 TransporterThere 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. 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 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.Pharmacologic Treatment of IBS: ContextAlthough there are a number of traditional and novel therapies for IBS, for contextual purposes, the scope of this review will be limited to discussion of the serotonergic agents. Excellent systematic reviews of IBS clinical treatment trials can be read for a more comprehensive discussion of available therapeutic agents.[47,48] As reiterated in these reviews, many of the traditional therapies are used to treat specific IBS symptoms because they have not been shown to significantly relieve global symptoms, which would improve an overall sense of well-being. However, the discovery of the serotonergic molecular targets has led to the development of novel medications and reevaluation of relatively older pharmacologic agents that also act on the serotonin system. In well-designed, multicenter clinical trials, these novel serotonergic agents have been shown to be effective in treating global symptoms in patients with IBS compared with placebo.