Irritable bowel syndrome: new pharmaceutical approaches to treatment.

The irritable bowel syndrome (IBS) is a consortium of symptoms including abdominal pain and alterations in the pattern of defaecation. There is no single pathophysiological marker of IBS although it is generally accepted that some patients do have abnormalities of intestinal motility and/or enhanced visceral sensitivity. There is also an increasing acceptance that the central nervous system, an important component of the brain-gut axis, also plays an important role in symptom production both in the response to stress and when there is an underlying affective disorder. During the past decade new therapeutic targets have been identified that have permitted the development of new drugs with therapeutic potential for IBS. Identification and characterization of 5-hydroxytryptamine (5-HT) receptors in the gastrointestinal tract particularly 5-HT3 and 5-HT4 receptors, which are involved not only in modulating gut motility but in visceral sensory pathways, has led to a number of studies of 5-HT3 (Alosetron, Granisetron and Ondansetron) and 5-HT4 (SB-207266A) antagonists. Both classes of drug appear to reduce visceral sensitivity and have inhibitory effects on motor activity in the distal intestine. Early clinical studies suggest that these agents may have a role in painful, diarrhoea-predominant IBS. 5-HT4 agonists (HTF919, Zelmac) may improve constipation-predominant IBS by normalizing bowel habit and thereby reducing abdominal pain. Alternative approaches to reducing visceral sensation include the use of the opioid kappa agonists, which have no central opioid effects although clinical trials have suggested that these agents are not highly effective in relieving IBS pain. There are in addition, new approaches to modify intestinal motility including the development of gut selective muscarinic M3 receptor antagonists such as zamifenacin and the 5-HT4 partial agonist, HTF919. Preliminary studies suggest that these agents may have therapeutic potential in IBS. Anti-depressants are increasingly used to treat affective disorder in IBS but in addition appear to have added value because of their ability to reduce visceral hypersensitivity and alter gut transit. Therapeutic effects are often obtained at doses below those normally used to treat depression. IBS continues to be a therapeutic challenge because of its diverse symptomatology and lack of a single pathophysiological target for drug intervention.     

Treatment options in irritable bowel syndrome

The irritable bowel syndrome (IBS) is part of the spectrum of functional bowel disorders characterised by a diverse consortium of abdominal symptoms including abdominal pain, altered bowel function (bowel frequency and/or constipation), bloating, abdominal distension, the sensation of incomplete evacuation and the increased passage of mucus. It is not surprising therefore that no single, unifying mechanism has as yet been put forward to explain symptom production in IBS. The currently favoured model includes both central and end-organ components which may be combined to create an integrated hypothesis incorporating psychological factors (stress, distress, affective disorder) with end-organ dysfunction (motility disorder, visceral hypersensitivity) possibly aggravated by sub-clinical inflammation as a residuum of an intestinal infection. There is currently no universally effective therapy for IBS. Standard therapy generally involves a symptom-directed approach; anti-diarrhoeal agents for bowel frequency, soluble fibre or laxatives for constipation and smooth muscle relaxants and anti-spasmodics for pain. New drug development has focused predominantly on agents that modify the effects of 5-hydroxytryptamine (5-HT) in the gut, principally the 5-HT(3) receptor antagonists for painful diarrhoea predominant IBS and 5-HT(4) agonists for constipation predominant IBS. More speculative new therapeutic approaches include anti-inflammatory agents, antibiotics, probiotics, antagonists of CCK1 receptors, tachykinins and other novel neuronal receptors.     

Tegaserod and other serotonergic agents: what is the evidence?

Through effects on gastrointestinal motor and secretory function as well as visceral sensation, serotonin (5-HT) plays a key role in the pathogenesis of irritable bowel syndrome (IBS). In particular, 5-HT3 and 5-HT4 receptors appear to be very important in IBS. This article critically appraises the evidence supporting the use of the 5-HT3 receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS. The safety profile and restricted-use program for alosetron is also reviewed. This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS.     

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.     

Serotonin receptors and their role in the pathophysiology and therapy of irritable bowel syndrome

Background

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterized by abdominal discomfort, pain and changes in bowel habits, often associated with psychological/psychiatric disorders. It has been suggested that the development of IBS may be related to the body’s response to stress, which is one of the main factors that can modulate motility and visceral perception through the interaction between brain and gut (brain–gut axis). The present review will examine and discuss the role of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes in the pathophysiology and therapy of IBS.

Methods

Search of the literature published in English using the PubMed database.

Results

Several lines of evidence indicate that 5-HT and its receptor subtypes are likely to have a central role in the pathophysiology of IBS. 5-HT released from enterochromaffin cells regulates sensory, motor and secretory functions of the digestive system through the interaction with different receptor subtypes. It has been suggested that pain signals originate in intrinsic primary afferent neurons and are transmitted by extrinsic primary afferent neurons. Moreover, IBS is associated with abnormal activation of central stress circuits, which results in altered perception during visceral stimulation.

Conclusions

Altered 5-HT signaling in the central nervous system and in the gut contributes to hypersensitivity in IBS. The therapeutic effects of 5-HT agonists/antagonists in IBS are likely to be due also to the ability to modulate visceral nociception in the central stress circuits. Further studies are needed in order to develop an optimal treatment.     

Patients with constipation-predominant irritable bowel syndrome (IBS) may have elevated serotonin concentrations in colonic mucosa as compared with diarrhea-predominant patients and subjects with normal bowel habits

BACKGROUND: Serotonin (5-HT) may play an important role in the regulation of colonic motility in humans. However, it is not known whether alterations in the colonic 5-HT system are involved in the pathophysiology of irritable bowel syndrome (IBS). METHODS: Colonic mucosal specimens ranging from the ascending colon to the rectum were obtained from patients with diarrhea- or constipation-predominant IBS (n = 7 and n = 8, respectively) and from subjects with normal bowel habits (n = 7) by endoscopic biopsy in order to determine whether patients with different clinical manifestations of IBS have different mucosal disposition of 5-HT. The tissue concentrations of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid, were determined by reversed-phase high-performance liquid chromatography with fluorescence detection. RESULTS: In all study groups, the mean mucosal 5-HT concentrations obtained from the rectum were significantly (p < 0.05) higher than those obtained from more cephalic regions of the colon. In addition, the overall mean mucosal 5-HT concentrations obtained from patients with constipation-predominant IBS were significantly (p < 0.05) higher than those obtained from the control subjects and patients with diarrhea-predominant IBS. No significant differences were observed in 5-hydroxyindoleacetic acid concentrations among the three groups. CONCLUSIONS: The mucosal 5-HT concentrations in the colon showed an ascending cephalocaudal gradient in all study groups. Although the mucosal 5-HT concentrations were elevated in patients with constipation-predominant IBS as compared with those with diarrhea-predominant IBS and the control subjects, further studies are necessary to determine whether the elevated mucosal 5-HT is a cause or a result of abnormal colonic motility.     

5-羟色胺转运体在肠道疾病中的研究进展

5-羟色胺(5-HT)是脑-肠轴中的重要神经递质,参与胃肠动力和感觉的调节过程。5-羟色胺转运体(SERT)可再摄取5-HT,并将其灭活、降解,是调控5-HT表达水平的重要物质。近年来诸多研究表明,SERT表达异常与肠易激综合征(IBS)、炎症性肠病(IBD)、慢传输型便秘等多种肠道疾病密切相关。本文就SERT在肠道疾病中的研究进展作一综述。     

Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome

BACKGROUND & AIMS: Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders. METHODS: Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples. RESULTS: Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls. CONCLUSIONS: These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.     

Altered neuro-endocrine–immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model

The interaction between the brain and the gut as a pathological mechanism of functional gastrointestinal disorders has been recently recognized in the pathophysiology of the irritable bowel syndrome. Communication between central nervous system and enteric nervous system is two-directional: the brain can influence the function of the enteric nervous system and the gut can influence the brain via vagal and sympathetic afferents. In patients with irritable bowel syndrome, symptoms may be caused by alterations either primarily in the central nervous system (top-down model), or in the gut (bottom-up model), or in a combination of both. The brain–gut axis may be stimulated by various stressors either directed to the central nervous system (exteroreceptive stress) or to the gut (interoceptive stress). Particularly, clinical evidence suggest that in complex and multifactorial diseases such as irritable bowel syndrome, psychological disorders represent significant factors in the pathogenesis and course of the syndrome. Neuroimaging techniques have shown functional differences between central process in healthy subjects and patients with irritable bowel syndrome. Moreover, a high prevalence of psychological/psychiatric disorders have been reported in IBS patients compared to controls. Several data also suggest an alteration of neuro-endocrine and autonomic output to the periphery in these patients. This review will examine and discuss the complex interplay of neuro-endocrine–immune pathways, closely associated with neuropsychiatric disorders.     

Regulation of the serotonin transporter in the pathogenesis of irritable bowel syndrome

Serotonin(5-HT) and the serotonin transporter(SERT) have earned a tremendous amount of attention regarding the pathogenesis of irritable bowel syndrome(IBS). Considering that enteric 5-HT is responsible for the secretion, motility and perception of the bowel, the involvement of altered enteric 5-HT metabolism in the pathogenesis of IBS has been elucidated. Higher 5-HT availability is commonly associated with depressed SERT mR NA in patients with IBS compared with healthy controls. The expression difference of SERT between IBS patients and healthy controls might suggest that SERT plays an essential role in IBS pathogenesis, and SERT was expected to be a novel therapeutic target for IBS. Progress in this area has begun to illuminate the complex regulatory mechanisms of SERT in the etiology of IBS. In this article, current insights regarding the regulation of SERT in IBS are provided, including aspects of SERT gene polymorphisms, microR NAs, immunity and inflammation, gut microbiota, growth factors, among others. Potential SERT-directed therapies for IBS are also described. The potential regulators of SERT are of clinical importance and are important for better understanding IBS pathophysiology and therapeutic strategies.     

锌在精神应激致肠易激综合征发生、发展过程中的影响

目的检测锌及相关调节因子在精神应激致肠易激综合征(irritable bowel syndrome,IBS)发生、发展过程中的变化,初步探讨海马锌对精神应激致IBS发生、发展过程的影响。方法60只SD雄性大鼠随机分为正常对照组和慢性避水应激组,每组30只,慢性避水应激组采用慢性避水应激的方法制作IBS动物模型。造模结束后采用腹部收缩反射对大鼠内脏敏感性进行半定量评分;采用荧光定量RT-PCR法检测大鼠海马内5-HT、CREB、BDNF及PKA mRNA的相对表达量,同时用ELISA方法检测各组大鼠海马5-HT、CREB、BDNF及PKA蛋白水平,动态观察各组大鼠的表达变化。结果与正常对照组相比,慢性避水应激组大鼠海马锌离子含量及血清锌离子含量下降,差异有统计学意义(P<0.05);同时慢性避水应激组大鼠5-HT、CREB、BDNF、PKA mRNA及蛋白表达水平均降低,与正常对照组比较,差异有统计学意义(P<0.05)。结论慢性精神应激引起大鼠IBS的发生机制可能是海马内锌离子影响5-HT受体,而后通过cAMP-PKA通路,激活CREB的磷酸化,调节下游的BDNF表达,最终造成内脏高敏感引起IBS的发生。     

Drug therapy for irritable bowel syndrome. What works, what doesn't work and for whom?

The therapy of patients with irritable bowel syndrome (IBS) is often challenging, especially if a broad spectrum of symptoms is present and trigger factors, such as the influence of diet or stress, are lacking. Current pathogenetic concepts propose central or peripheral alterations that cause disturbed gastrointestinal function (motility, visceral sensitivity) and subsequent symptoms. These alterations are possibly related to psychological (stress, depression, anxiety) and biological (post-infectious residuals, micro-inflammation) influences. Since no universally effective medical treatment is available to treat the causes of the disease, standard medical therapy is symptom directed (especially for pain, constipation and diarrhoea). In addition to well established drugs (like spasmolytics, opioids and laxatives), newly developed compounds including those with other primarily indications (e.g. antidepressants) are available for highly differentiated individualized therapies. New medical approaches which are currently undergoing evaluation, promise further progress in the treatment of IBS.     

The role of psychosocial factors in irritable bowel syndrome.

Psychosocial factors, as appreciated within the context of the biopsychosocial model, are necessary for understanding the clinical expression of irritable bowel syndrome (IBS) by virtue of their key roles in the development, precipitation and perpetuation of IBS. Addressing psychosocial factors in assessment and management leads to improvement in the clinical outcome for IBS patients. Pertinent management components include adopting a 'care' approach within an ongoing collaborative treatment relationship; offering any psychological or psychiatric intervention as part of a multi-disciplinary treatment approach; providing education and reassurance; and using mental health professionals when indicated.     

Diet in irritable bowel syndrome: What to recommend,not what to forbid to patients!

A substantial proportion of patients with irritable bowel syndrome(IBS) associate their symptoms with the ingestion of specific foods. Therefore, in recent years, scientific research has increasingly focused on the role of diet in IBS and dietary management is now considered an important tool in IBS treatment. This article reviews the main dietary approaches in IBS emphasizing evidence from experimental and observational studies and summarizing the main diet and lifestyle recommendations provided by dietary guidelines and scientific literature. Despite the limited evidence for a beneficial role, general advice on healthy eating and lifestyle is recommended as the first-line approach in the dietary management of IBS. Standard recommendations include adhering to a regular meal pattern, reducing intake of insoluble fibers, alcohol, caffeine, spicy foods, and fat, as well as performing regular physical activity and ensuring a good hydration. Second-line dietary approach should be considered where IBS symptoms persist and recommendations include following a low FODMAP diet, to be delivered only by a healthcare professional with expertise in dietary management. The efficacy of this diet is supported by a growing body of evidence. In contrast, the role of lactose or gluten dietary restriction in the treatment of IBS remains subject to ongoing research with a lack of high-quality evidence. Likewise, further clinical trials are needed to conclude the efficacy of probiotics on IBS symptoms.     

5-羟色胺信号系统在炎症性肠病发病机制中的地位

炎症性肠病(IBD)患者较易出现功能性肠道症状,这些症状往往与肠道活动性炎症关系不大,却与肠功能紊乱有关,说明IBD的发病在某些方面与肠易激综合征(IBS)相似。5-羟色胺(5-HT)信号系统异常可致胃肠动力、分泌功能异常和内脏高敏感性,与多种功能性胃肠病密切相关。而IBD的发病机制中亦存在功能性因素,提示IBD与IBS可能存在某些分子水平的联系,有必要对5-HT信号系统在IBD发病机制中的作用进行研究。     

行为心理学疗法治疗肠易激综合征的研究进展

精神心理因素在肠易激综合征（IBS）发病机制中的作用越来越引起广大临床医师的重视。随着社会竞争压力的增大,仅靠药物治疗已无法完全改善IBS患者的临床症状,行为心理学疗法的疗效目前已得到认可。行为心理学疗法的目的并不是为了完全治愈疾病,而是为了缓解临床症状,节省医疗开支,提高患者生活质量。本文就行为心理学疗法治疗IBS的研究进展作一综述。     

Sex hormones in the modulation of irritable bowel syndrome

Compelling evidence indicates sex and gender differences in epidemiology,symptomatology,pathophysiology,and treatment outcome in irritable bowel syndrome(IBS).Based on the female predominance as well as the correlation between IBS symptoms and hormonal status,several models have been proposed to examine the role of sex hormones in gastrointestinal(GI)function including differences in GI symptoms expression in distinct phases of the menstrual cycle,in pre-and post-menopausal women,during pregnancy,hormonal treatment or after oophorectomy.Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity,motility,intestinal barrier function,and immune activation of intestinal mucosa.Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system,neuroimmune interac-tions triggered by stress,as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized.A concept of"microgenderome"related to the potential role of sex hormone modulation of the gut microbiota is also emerging.Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders,together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.     

肠黏膜肥大细胞参与感染后肠易激综合征内脏高敏感机制的研究进展

感染后肠易激综合征（PI—IBS）是肠易激综合征（IBS）的常见临床类型。内脏高敏感是PI-IBS的核心机制之一．其形成可能是源于胃肠道传人神经通路的敏感化和抑制性调控内脏痛反应的神经通路功能减退。肠黏膜肥大细胞可通过其脱颗粒产物如5．羟色胺（5-HT）等参与调节内脏高敏感,目前相关制剂已用于IBS的治疗,但疗效尚不确定。因此,深入了解肠黏膜肥大细胞功能改变在PI-IBS内脏高敏感发生机制中的作用,将为阐明PI-IBS的病理生理机制及其临床治疗提供新的思路。     

Meditation over Medication for Irritable Bowel Syndrome? On Exercise and Alternative Treatments for Irritable Bowel Syndrome

Complimentary alternative treatment regimens are widely used in irritable bowel syndrome (IBS), but the evidence supporting their use varies. For psychological treatment options, such as cognitive behavioral therapy, mindfulness, gut-directed hypnotherapy, and psychodynamic therapy, the evidence supporting their use in IBS patients is strong, but the availability limits their use in clinical practice. Dietary interventions are commonly included in the management of IBS patients, but these are primarily based on studies assessing physiological function in relation to dietary components, and to a lesser degree upon research examining the role of dietary components in the therapeutic management of IBS. Several probiotic products improve a range of symptoms in IBS patients. Physical activity is of benefit for health in general and recent data implicates its usefulness also for IBS patients. Acupuncture does not seem to have an effect beyond placebo in IBS. A beneficial effect of some herbal treatments has been reported.     

肠道微生态与肠易激综合征

微生物群与宿主、环境之间的相互作用、相互协调对于维持宿主正常的生理功能起着十分重要的作用,三者关系失衡则直接或间接参与了众多疾病的发生、发展。肠易激综合征(IBS)是一种复杂的多因素功能性疾病,流行病学研究表明IBS患者多存在肠道菌群失调,益生菌的治疗也取得部分疗效,通过对正常人和IBS患者肠道菌群的比较,从小肠细菌过度生长、感染、抗生素、应激、肠道酵解异常五个方面,将近年肠道微生态与IBS关系做一综述。