The serotonin signaling system: from basic understanding to drug development for functional GI disorders

Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT(4) partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT(1) agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders.     

Abnormalities of the electrogastrogram in functional gastrointestinal disorders

OBJECTIVE: Cutaneous electrogastrography records gastric electrical activity and detects gastric arrhythmias. Abnormalities of the electrogastrogram have been described in a variety of disorders, but their specificity and their prevalence in patients with functional gastrointestinal disorders has not been reported. The aim of this study was to assess the specificity of electrogastrography as well as the prevalence and pattern of abnormalities in functional dyspepsia and irritable bowel syndrome. METHODS: Electrogastrography was performed in 170 patients with functional dyspepsia, 70 patients with irritable bowel syndrome, 20 patients with gastroesophageal reflux disease, and 30 asymptomatic controls. The abnormal electrogastrogram was defined as <70% normal electrical activity either before or after a test meal. RESULTS: The electrogastrogram was abnormal in 36% of patients with functional dyspepsia and in 25% with irritable bowel syndrome who complained of concurrent dyspepsia. The electrogastrogram was normal in 93% of asymptomatic controls, 90% of patients with gastroesophageal reflux, and 92% of patients with irritable bowel syndrome who did not complain of dyspepsia. As a group, functional dyspepsia patients had a greater degree of tachygastrias both before (p < 0.02) and after (p < 0.01) a test meal. The electrical frequency after the test meal was also more unstable (p < 0.003). CONCLUSIONS: The electrogastrogram is abnormal in approximately 36% of functional dyspepsia patients and has a specificity of approximately 93%. Electrogastrography defines a subgroup of patients with functional dyspepsia and electrical rhythm disturbance. In irritable bowel syndrome, the electrogastrogram is usually abnormal only if concurrent dyspepsia is present.     

Functional gastrointestinal disorders and the potential role of eosinophils

The eosinophil-mast cell-neural pathway may be important in the pathophysiology of functional gastrointestinal disorders characterized by unexplained abdominal pain, disordered defecation, or meal-related discomfort. There is evidence that duodenal eosinophils are increased in functional dyspepsia, whereas mast cells are increased in the lower gut in irritable bowel syndrome, directly supporting a role for a hypersensitivity-type reaction in these disorders. The trigger may be a pathogen, food, or other allergen in the gut mucosa. This trigger may evoke eosinophils, mast cells, and other components to cascade to up-regulate serotonin release, with modulation of the enteric and central nervous systems, creating a vicious cycle. If correct, this theory suggests treatment should specifically target the eosinophil-mast cell pathway.     

Management and pathophysiology of functional gastrointestinal disorders

Since 2005, every annual meeting of the Japanese Gastroenterological Association has included a core symposium for functional gastrointestinal disorders. At the 6th annual meeting, the core symposium was 'Pathophysiology and New Treatment'. At the 7th annual meeting, the core symposium was 'Pathophysiology and Motility'. This review summarizes the papers presented at these meetings. At the 6th meeting, we recognized that Japanese researchers successfully produced and developed many agents that are safe and effective for the treatment of functional gastrointestinal disorders, such as 5-hydroxytryptamine receptor-associated compounds, lubiprostone, Japanese herbal medicine, and other drugs. Data were validated from a clinical as well as an experimental viewpoint. Findings included the effects of sumatriptan and nizatidine, acylated or des-acylated ghrelin, T-cell-activating anti-CD3 antibody, and transient receptor potential vanilloid-1. At the 7th meeting, not only functional dyspepsia and irritable bowel syndrome (IBS), but also non-erosive esophageal reflux disease (NERD) and chronic intestinal pseudo-obstruction were actively discussed from a motility viewpoint, including papers about sham feeding and gastric motility, genetic polymorphism and motility, the role of transient receptor potential A1 on gastric accommodation, esophageal motility and NERD, diagnosis and treatment of chronic intestinal pseudo-obstruction, immunological basis of motility in IBS, developing non-invasive colonic function test, and fecal distribution in IBS patients.     

Delayed gastric emptying in functional dyspepsia

Opinion statement Functional dyspepsia is a complex syndrome with a poorly defined pathophysiology, resulting in uncertainties in its therapeutic approach. Abnormalities in gastrointestinal motility and sensitivity alone or combined seem to play a role in a substantial subgroup of patients. Drugs capable of prokinetic effects, such as antidopaminergics (eg, metoclopramide, domperidone, levosulpiride) and serotonin 5-HT4 receptor agonists (eg, tegaserod) can be potentially used in the treatment of dyspeptic patients. Furthermore, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone which may also contribute to improved symptoms in subsets of patients. Alosetron, a 5-HT3 receptor antagonist, has been investigated mainly in irritable bowel syndrome, and the few studies performed in functional dyspepsia have provided conflicting results. Erythromycin and related derivatives, the motilides, represent another class of prokinetic compounds able to accelerate gastric emptying and potentially indicated in functional dyspepsia. The stimulatory effect on fundic tone and the occurrence of tachyphilaxis hamper the efficacy of these drugs in the long-term treatment. к-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but there are few available results and most are inconclusive. Results are also needed to prove efficacy of antidepressants (tricyclic agents and 5-HT reuptake inhibitors). Future clinical trials should be performed so that the formal structure required by good clinical practice can be adapted to detect significant effects in subgroups of patients with functional dyspepsia. Therapy should be ideally targeted to the different pathophysiologic abnormalities of these subgroups. The identification of the mechanisms leading to symptom generation should facilitate the development of newer and more effective therapeutic strategies in functional dyspepsia.     

Antidepressant therapy in functional gastrointestinal disorders

The available evidence from randomized clinical trials or meta-analyses on the therapeutic efficacy of psychotropic drugs and, specifically, of antidepressants, in functional gastrointestinal disorders (FGD), are recent and still fairly limited. The use of these drugs is based on the frequent association of anxiety and depression or neurosis in patients with FGD who seek medical care and on the demonstrated efficacy of these drugs in relieving chronic pain, whatever its origin or localization, for more than 30 years. Antidepressants, even in doses under the antidepressant range, are antinociceptive due to their central and peripheral neuromodulatory effect, which is completely independent of anticholinergic, spasmolytic or antidepressant effects. This has been demonstrated in both animals and humans and, as occurs with another antinociceptive drugs such as clonidine, is mediated by alpha-adrenoreceptors. The choice of antidepressant depends both on the evidence of its analgesic activity (in general greater with tricyclic antidepressants than with the more modern selective serotonin reuptake inhibitors) and on the presence of drug-related adverse effects, which include not only anticholinergic adverse effects but also the possibility of hypotension or cardiotoxicity, which should be avoided. The main selection criteria are demonstrated efficacy and safety. Antidepressants have been shown to be effective in the specific field of non-coronary chest pain probably originating in the esophagus unrelated to gastroesophageal reflux disease, especially mianserin and trazodone, and the effect is maintained in the long term in nearly three-quarters of treated patients. Tricyclic antidepressants have also been shown to be effective in the treatment of abdominal pain in patients with irritable bowel syndrome, with an OR of 4.2 and an NNT of 3.2 in comparison with placebo. In contrast, there is insufficient evidence to recommend the use of antidepressants in functional dyspepsia.     

Dyspepsia and its overlap with irritable bowel syndrome

Patients with functional dyspepsia and the irritable bowel syndrome are commonly seen in both primary care and gastroenterology subspecialty settings. Although functional dyspepsia and the irritable bowel syndrome can occur separately, recent research suggests that they often appear together as an overlap syndrome and thus may represent different portions of a unifying spectrum of disease. Despite their widespread prevalence, the pathogenesis of these disorders is not well established but may include impaired gastric emptying, gastric dysrhythmias, hypersensitivity (to acid exposure and to stretch), and Helicobacter pylori infection. Once other disorders in the differential diagnosis have been excluded, treatment of patients with functional dyspepsia, irritable bowel syndrome, and the overlap syndrome without alarm signs underscores current prevailing pathophysiologies and is generally empiric and symptom based. It is hoped that management of these disorders will become more targeted and efficacious as our understanding of them improves.     

3 Is functional dyspepsia just a subset of the irritable bowel syndrome?

To determine whether functional dyspepsia and irritable bowel syndrome are different entities, epidemiological data, factor analysis studies, physiological data and associated psychological symptoms were reviewed. Between 30% and 60% of patients with either diagnosis also meet the criteria for the other diagnosis, a level greater than expected to occur by chance but not sufficient to infer an identity. Most factor analysis studies identify independent clusters of symptoms corresponding to functional dyspepsia and irritable bowel syndrome. Visceral hypersensitivity is seen throughout the gastrointestinal tract in both disorders, but the motility patterns seen in association with functional dyspepsia (principally antral hypomotility and delayed gastric emptying) differ from the motility patterns seen in irritable bowel syndrome. Psychological symptoms are similar in these two disorders but are not believed to be aetiological for either of them. Thus, based on a factor analysis of gastrointestinal symptoms and differences in intestinal motility, functional dyspepsia and irritable bowel syndrome appear to be different entities.     

Serotonergic modulation of visceral sensation: lower gut

The role of 5-HT agents in the modulation of lower gastrointestinal function is discussed. Selective serotonin reuptake inhibitors are of potential benefit in functional gastrointestinal diseases although formal evidence is lacking. Novel pharmacological approaches include 5-HT(3) antagonists and 5-HT(4) agonists. These pharmacological classes have shown beneficial effects on a global efficacy end point, and ameliorated more than one symptom of lower gut function in clinical trials. They offer promise for the development of novel therapies for the treatment and control of irritable bowel syndrome.     

Placebo responses and placebo effects in functional bowel disorders

The nature and determinants of the placebo response are widely unknown, as are the underlying psychological and biological mechanisms. Placebo response rates in functional bowel disorders (functional dyspepsia, irritable bowel syndrome) trials are similar to those in nonintestinal pain conditions and are comparable with other organic gastrointestinal diseases (duodenal ulcer, inflammatory bowel diseases). In this narrative review, different methodologies (meta-analyses, reanalyses, and experimental setups) are discussed that have been applied to the study of the placebo response in functional dyspepsia and the irritable bowel syndrome.     

A unifying hypothesis for the functional gastrointestinal disorders: really multiple diseases or one irritable gut?

The functional gastrointestinal disorders are defined by the Rome criteria as a heterogeneous group of symptom-based conditions that have no structural or biochemical explanation. However, this definition now seems outdated, because structural and molecular abnormalities have begun to be recognized in subsets of patients with the irritable bowel syndrome (IBS), the prototypic functional bowel disease. A complex classification system based arbitrarily on symptom criteria does not fit in with a number of emerging facts. For example, the symptom overlap of IBS with gastroesophageal reflux disease is not due to chance, and the emergence of post-infectious IBS, dyspepsia, or both after Salmonella gastroenteritis fits better with a 1-disease model. A new paradigm seems to be needed. All of these disorders may arise after infection or gut inflammation, but the phenotype depends on localized neuromuscular dysfunction in the predisposed human host (the "irritable gut").     

Gastrointestinal motility problems in the elderly patient

Statistics abound demonstrating the aging of the population, and this comes as no news to physicians caring for an increasing number of elderly patients. This group experiences the expected age-related physiologic declines, including systems critical to integrative functions such as immunologic, neurologic, and metabolic systems. Although an increased prevalence of several common gastrointestinal disorders occurs in the elderly person, aging per se appears to have less direct effect on most gastrointestinal functions, in large part because of the functional reserve of the gastrointestinal tract. Although irritable bowel symptoms decrease with aging, there seems to be an increase in many gastrointestinal disorders of function and motility. The gastroenterologist will frequently encounter elderly patients with complaints of dysphagia, anorexia, dyspepsia, and disorders of colonic function. Understanding age-related changes in gastrointestinal physiology and effects of common comorbid illnesses enhances the ability to evaluate and treat these common, troublesome symptoms.     

Acupuncture for functional gastrointestinal disorders

Functional gastrointestinal (GI) symptoms are common in the general population. Especially, motor dysfunction of the GI tract and visceral hypersensitivity are important. Acupuncture has been used to treat GI symptoms in China for thousands of years. It is conceivable that acupuncture may be effective in patients with functional GI disorders because it has been shown to alter acid secretion, GI motility, and visceral pain. Acupuncture at the lower limbs (ST-36) causes muscle contractions via the somatoparasympathetic pathway, while at the upper abdomen (CV-12) it causes muscle relaxation via the somatosympathetic pathway. In some patients with gastroesophageal reflux disease (GERD) and functional dyspepsia (FD), peristalsis and gastric motility are impaired. The stimulatory effects of acupuncture at ST-36 on GI motility may be beneficial to patients with GERD or FD, as well as to those with constipation-predominant irritable bowel syndrome (IBS), who show delayed colonic transit. In contrast, the inhibitory effects of acupuncture at CV-12 on GI motility may be beneficial to patients with diarrhea-predominant IBS, because enhanced colonic motility and accelerated colonic transit are reported in such patients. Acupuncture at CV-12 may inhibit gastric acid secretion via the somatosympathetic pathway. Thus, acupuncture may be beneficial to GERD patients. The antiemetic effects of acupuncture at PC-6 (wrist) may be beneficial to patients with FD, whereas the antinociceptive effects of acupuncture at PC-6 and ST-36 may be beneficial to patients with visceral hypersensitivity. In the future, it is expected that acupuncture will be used in the treatment of patients with functional GI disorders.     

10 Are psychosocial factors of aetiological importance in functional dyspepsia?

The causes of functional dyspepsia remain unclear. Research has linked other functional gastrointestinal disorders, particularly irritable bowel syndrome, to a history of physical or sexual abuse, psychosocial distress and certain psychiatric disorders. In functional dyspepsia, there is a possibility of certain psychiatric disorders, particularly alcohol abuse and eating disorders, indirectly influencing the development of functional dyspepsia-like symptoms. However, the literature on possible psychosocial correlates in functional dyspepsia is not as mature as the literature on irritable bowel syndrome. This paper critically reviews the psychosocial dimensions and implications for the psychotherapeutic treatment of functional dyspepsia.     

Recent insights into digestive motility in functional dyspepsia

Functional gastrointestinal disorders, such as functional dyspepsia (FD) and irritable bowel syndrome, are common pathologies of the gut. FD is a clinical syndrome defined as chronic or recurrent pain or discomfort of unknown origin in the upper abdomen. The pathophysiological mechanisms responsible for FD have not been fully elucidated, but new ideas regarding its pathophysiology and the significance of the pathophysiology with respect to the symptom pattern of FD have emerged. In particular, there is growing interest in alterations in gastric motility, such as accommodation to a meal or gastric emptying, and visceral sensation in FD. The mechanisms underlying impaired gastroduodenal motor function are unclear, but possible factors include abnormal neurohormonal function, autonomic dysfunction, visceral hypersensitivity to acid or mechanical distention, Helicobacter pylori infection, acute gastrointestinal infection, psychosocial comorbidity, and stress. Although the optimum treatment for FD is not yet clearly established, acid-suppressive drugs, prokinetic agents, eradication of H. pylori, and antidepressants have been widely used in the management of patients with FD. The therapeutic efficacy of prokinetics such as itopride hydrochloride and mosapride citrate in the treatment of FD is supported by the results of relatively large and well-controlled studies. In addition, recent research has yielded new therapeutic agents and modalities for dysmotility in FD, including agonists/antagonists of various sensorimotor receptors, activation of the nitrergic pathway, kampo medicine, acupuncture, and gastric electric stimulation. This review discusses recent research on the pathophysiology of and treatment options for FD, with special attention given to digestive dysmotility.     

Treatment of the irritable bowel syndrome from the point of conclusive medicine]

For many years the irritable bowel syndrome therapy was based only on an empirical approach. A lot of information has appeared for this period, which allows making a judgment about the efficacy of either of the ways of the functional bowel disorders treatment. A part of them was not approved in the course of clinical testing. At the same time, new high-performance ways of treatment appeared. This article presents an analytical survey of the irritable bowel syndrome pharmacotherapy. It also shows the role of diet, spasmolysants, psychotherapy, tricyclic antidepressants, serotonin reuptake inhibitors, HT3 antagonists and HT4 agonists.     

抗抑郁药治疗功能性胃肠病的研究进展

功能性胃肠病（FGIDs）包括功能性消化不良（FD）和肠易激综合征（IBS）等。近年来诸多研究显示精神心理因素在FGIDs的发生、发展过程中起重要作用。在临床上抗抑郁药被广泛应用于FGIDs的治疗。与传统剂量相比,小剂量抗抑郁药具有疗效相似、不良反应小、依从性高的特点。本文就抗抑郁药治疗FGIDs的研究进展作一综述。     

Serotonergic modulation of visceral sensation: upper gastrointestinal tract

Agents that modify serotonergic function have therapeutic potential for the treatment of visceral hypersensitivity, either through a direct effect on perception or through modulation of visceral tone or motility. Administration of selective serotonin reuptake inhibitors reduces oesophageal sensitivity to distension but not gastric sensitivity to distension. 5-HT ligands may also influence gastric mechanosensitivity by altering tone. Although the exact role of 5-HT receptors in the control of gastrointestinal functions remains unknown, 5-HT is generally considered to be the main candidate involved in the modulation of motor and sensory function from the gastrointestinal tract. Hence serotonergic modulation of upper gut sensitivity appears to be promising for the development of novel approaches to the treatment of functional disorders of the upper gastrointestinal tract.     

Functional disorders of the gastrointestinal tract: Cost effectiveness review

BackgroundThe project aim was to review current cost-effectiveness research for each functional gastrointestinal disorder, as defined by the Rome III classification system.MethodsBiomedical databases were searched for articles with the functional gastrointestinal disorders and their pseudonyms included in the title, abstract, or medical subject headings, plus the terms benefit, cost, effectiveness, outcomes, test, utility, or utilization in any search field.ResultsHighly prevalent conditions such as dyspepsia and irritable bowel syndrome have advanced cost-effectiveness analyses including cost–utility studies that have helped support current management guidelines. The rarer functional gastrointestinal disorders have few or no published cost-effectiveness analyses, but the Rome III classification system provides a framework for identifying the specific cost data or outcomes measures available or needed for future research.ConclusionsThe Rome process has provided a useful system for defining the functional gastrointestinal disorders and identifying specific clinical questions to be examined using cost-effectiveness analysis techniques.