Food hypersensitivity and irritable bowel syndrome

Irritable bowel syndrome is a common condition but its pathophysiology remains poorly understood. Many irritable bowel syndrome patients give a history of food intolerance, but data from dietary elimination and re-challenge studies are inconclusive. Multiple aetio-pathological mechanisms have been postulated. The gut has an extensive immune system but current understanding of processing of food antigens in health and disease is limited. There is no clinically useful marker available to test for food hypersensitivity in irritable bowel syndrome. Researchers have employed both skin tests and serum immunoglobulins (IgG and IgE) as markers of food hypersensitivity in various disorders including irritable bowel syndrome, but published data are equivocal. In this article, the evidence for the role of food hypersensitivity in irritable bowel syndrome is reviewed and, based on the available data, a possible pathophysiological hypothesis has been formulated.     

Review article: visceral hypersensitivity in irritable bowel syndrome: molecular mechanisms and therapeutic agents

Background  Although development of visceral pain is an important defensive mechanism, hypersensitivity results in a significant clinical problem and is likely to be one of the major factors involved in the pathogenesis of abdominal and chest pain in functional bowel disorders (FBDs). Understanding of the molecular mechanisms involved in peripheral sensitization of visceral nociceptors has advanced as a result of the experimental studies, especially in animal models, which have led to knowledge and identification of key mediators and receptors.
Aim  To provide a comprehensive review focused on the peripheral mechanisms believed to be responsible for sensitization and potential molecular targets for a disorder which is common, distressing and has sub-optimal treatment options.
Methods  Literature review using Ovid and Pubmed from 1966.
Results  There is substantial interest in the development of new drugs for treatment of FBDs in the background of advances in understanding the molecular and physiological mechanisms of visceral hypersensitivity. The potential drug targets include TPRV1, ASICs, voltage-gated sodium channels, ATP, PAR-2, cannabinoid, prostaglandin, tachykinin and 5HT₃ receptors.
Conclusion  It is anticipated that with advancing molecular understanding of the basis of visceral hypersensitivity, the next decade will see accelerated development of new molecules for treatment of functional bowel diseases.     

肠易激综合征大鼠内脏高敏感性与脑肠互动的研究

目的研究腹泻型肠易激综合征大鼠模型内脏敏感性的改变与c-fos在结肠及中枢神经系统异常表达的关系。方法采用乙酸灌肠法造成腹泻型肠易激综合征动物模型（A组,n=12）和对照组（B组,n=12）,造模后通过腹部回撤反应评分评价内脏敏感性;用印度墨汁肠道染色法观察小肠蠕动,以墨汁在小肠中移行的距离占整段小肠长度的百分比来观察小肠推进蠕动的变化;应用免疫组织化学染色及计算机图像分析系统半定量分析结肠及中枢神经系统c-fos表达。结果该模型符合腹泻型肠易激综合征特征,A组腹部回撤反应评分、结肠及中枢神经系统c-fos表达高于B组,两组差异有统计学意义（P〈0.05）。结论乙酸灌肠法造成腹泻型肠易激综合征大鼠模型内脏高敏感性,c-fos的高表达参与大鼠内脏高敏感的异常调节。     

Antidepressants in the treatment of irritable bowel syndrome and visceral pain syndromes

Irritable bowel syndrome (IBS) is characterized by abdominal pain associated with disordered defecation, which may include urgency and altered stool frequency. Visceral pain syndromes, including IBS, may be effectively treated by a variety of therapies that modulate the interactions between the central and enteric nervous systems. Clinical observations and preliminary data suggest that antidepressants may be efficacious for the treatment of these syndromes. The tricyclic antidepressants (TCAs) have been utilized most extensively in this area, but there is a need for more rigorous efficacy data. Serotonin, an important neurotransmitter in both the central and enteric nervous systems, modifies both motility and sensation in the gut. Recognition of the importance of serotonin in digestive motility and sensation has sparked interest in the use of agents that modify serotonergic transmission in visceral pain syndromes. Pharmacological therapeutics that modulate the biological amines (serotonin, norepinephrine, dopamine and catecholamines) both peripherally and within the central nervous system may offer more effective therapies for these disorders. The selective serotonin reuptake inhibitors are commonly used in clinical practice, but more rigorous, controlled studies are needed to determine their effects beyond the treatment of psychiatric comorbidity. The newer generation antidepressants may provide additional insight into the pathophysiology of the brain-gut interactions and their relationship to functional bowel disorders, providing new therapeutic interventions.     

Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity is considered an important pathophysiological mechanism in irritable bowel syndrome, yet its relationship to symptoms is unclear. AIM: To detect possible associations between symptoms and the presence of hypersensitivity to rectal distension in patients with irritable bowel syndrome. METHODS: Ninety-two irritable bowel syndrome patients and 17 healthy volunteers underwent a rectal barostat study. The association between specific irritable bowel syndrome symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic curves. RESULTS: Irritable bowel syndrome patients had significantly lower thresholds for discomfort/pain than healthy volunteers: 24 (18-30) and 30 (27-45) mmHg above minimal distending pressure, respectively. Forty-one patients (45%) showed hypersensitivity to rectal distension. Proportions of patients with different predominant bowel habits were similar in hypersensitive and normosensitive subgroups (diarrhoea predominant: 39 and 41%, respectively; alternating type: 27 and 28%, respectively; constipation predominant: 34 and 31%, respectively). Severe abdominal pain was more frequent in hypersensitive, compared with normosensitive patients (88% vs. 67%, P = 0.02), but none of the individual irritable bowel syndrome symptoms could accurately predict the presence of hypersensitivity, as assessed by Area under the Receiver Operating Characteristic curve analysis. CONCLUSIONS: Hypersensitive and normosensitive irritable bowel syndrome patients present with comparable, heterogeneous symptomatology. Therefore, selection based on clinical parameters is unlikely to discriminate individual irritable bowel syndrome patients with visceral hypersensitivity from those with normal visceral sensitivity.     

Pathophysiology in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a distressing condition that impairs quality of life, and it deserves to be treated. It also has a large economic impact on healthcare utilization and absenteeism. IBS is a disorder in which three major mechanisms interact: altered gastrointestinal motility, increased sensory function of the intestine and psychosocial factors. The role of prior infection in the development of IBS is the subject of ongoing study. This article focuses on pathophysiological mechanisms, including the potential roles of mucosal changes and neurobiology in the development of IBS. Novel pharmacological agents are being developed to target neural mediators of IBS; they appear promising, and their role in clinical practice will be clarified with regulatory approval and clinical use.     

Lipid-induced colonic hypersensitivity in irritable bowel syndrome: the role of 5-HT3 receptors

BACKGROUND: Irritable bowel syndrome patients demonstrate colonic hypersensitivity after duodenal lipid infusion. AIM: To investigate the role of 5-hydroxytryptamine-3 (5-HT3) receptors in this sensory component of the gastrocolonic response in irritable bowel syndrome. METHODS: Fifteen female patients with diarrhoea-predominant irritable bowel syndrome completed a trial with the 5-HT3 receptor antagonist alosetron (1 mg b.d.) or placebo (b.d.) over 15 days, followed by the alternative treatment. Each treatment period was followed by a colonic distension trial before and after duodenal lipids. Changes in colonic thresholds, tone and compliance and viscerosomatic referral pattern after lipids were compared between treatments. RESULTS: With placebo, the colonic thresholds after lipids were significantly reduced for all studied sensations, whereas, with alosetron, the thresholds were significantly reduced only for first sensation and discomfort, but not for gas and pain. The reductions in thresholds did not differ significantly between treatments, but the pain threshold after alosetron tended to be less reduced compared with placebo (P = 0.10). The effects of lipids on tone, compliance and viscerosomatic referral pattern were unaffected by alosetron relative to placebo. CONCLUSIONS: 5-HT3 receptor antagonism reduces the lipid-induced colonic hypersensitivity in irritable bowel syndrome. However, 5-HT3 receptors do not seem to be the principal mediator, but may be a cofactor for the exaggerated sensory component of the gastrocolonic response in irritable bowel syndrome.     

Oesophageal hypersensitivity is associated with features of psychiatric disorders and the irritable bowel syndrome

BACKGROUND: Twenty per cent of patients with heartburn do not respond to proton pump inhibitors (PPIs). Many have normal oesophageal acid exposure. We hypothesized that such PPI non-responders have heightened oesophageal sensation, and that oesophageal hypersensitivity is associated with psychiatric features including somatization and anxiety. AIM: To compare oesophageal sensation in subjects with heartburn categorized by response to PPI, and to correlate oesophageal sensation with psychiatric features. METHODS: Twenty-one PPI responders, nine PPI non-responders and 20 healthy volunteers completed questionnaires of psychiatric disorders and gastrointestinal symptoms. Subjects underwent oesophageal sensory testing with acid perfusion and balloon distension. RESULTS: Healthy volunteers displayed higher thresholds for sensation and discomfort from balloon distension than heartburn subjects (sensation P = 0.04, discomfort P = 0.14). Psychiatric disorders were associated with increased intensity of sensation (P = 0.02) and discomfort from acid (P = 0.01). Somatization was associated with increased discomfort from balloon distension (P = 0.006). Features of irritable bowel syndrome were associated with increased sensation and discomfort. CONCLUSIONS: Heartburn subjects tend to have heightened oesophageal sensation, suggesting that oesophageal hypersensitivity may persist despite therapy with PPI. Oesophageal hypersensitivity is associated with features of psychiatric disease and with the irritable bowel syndrome, which might partly explain the aetiology of heartburn symptoms that are refractory to PPI.     

Drug discovery approaches to irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is defined by symptoms of abdominal pain and altered bowel habits without detectable organic disease. Antidepressants and serotonin receptor modulators are used to treat IBS, but rare serious adverse events highlight the safety hurdle. Newer drugs with secretory and motility effects via local gut mechanisms have been successfully approved for IBS, often by registering first in a related, non-IBS condition to optimize dosing, formulation and therapeutic window.

Areas covered: This review looks at approaches for novel IBS drug discovery. The underlying pathologies can be tackled locally from the ‘outside-in’ (intestinal lumen, mucosa and neuromuscular) to identify therapeutic targets. The article discusses the mechanisms associated with bile acid malabsorption, microbial dysbiosis, decreased intestinal barrier function, immune dysregulation, motility and visceral hypersensitivity.

Expert opinion: Challenges for new drug discovery are the unknown mechanisms underlying IBS, making it difficult to predict clinically efficacious molecular targets, limited options for translational research and disease progression biomarkers. Drugs acting locally via multiple targets (e.g., eluxadoline [The U.S. Food and Drug Administration approved Viberzi (eluxadoline) for IBS-D on May 27th 2015], crofelemer) to validated mechanisms are proving successful with tolerable safety margins. Novel mechanisms, identified and optimized based on the emerging role of nutrient signaling, probiotics or microbial products, are promising. Therapeutic treatment earlier in disease progression may improve response and have longer term benefits.     

Milnacipran is active in models of irritable bowel syndrome and abdominal visceral pain in rodents

The role of antidepressants in the treatment of visceral pain has not been extensively examined. Milnacipran, a serotonin/noradrenalin reuptake inhibitor, has recently been approved in the USA for fibromyalgia, a chronic pathology characterized by diffused/chronic musculoskeletal pain, and a high prevalence of irritable bowel syndrome. Here, we determined its antinociceptive efficacy in two visceral pain tests in rodents: the acetic acid-induced writhing model in mice and the butyrate/colonic distension assay in rats, a model of irritable bowel syndrome. Acute milnacipran (5-40 mg/kgi.p.) significantly and dose-dependently reduced writhing (72.2 ± 3.2 versus 17.0 ± 4.1 writhes at 40 mg/kg). Following repeated administration (40 m/kgi.p. for 5 days), milnacipran preserved its ability to significantly reduce writhing (76 ± 8.3 versus 21.1 ± 6.7 writhes). Similarly, in the butyrate model, acute milnacipran (17.5 and 35 mg/kg, i.p.) significantly and dose-dependently increased cramps induction thresholds (from 45.7 ± 5.7 to 66.3 ± 4.8 and 75.6 ± 2.9 mm Hg, for 17.5 and 35 mg/kg, respectively) and reduced the number of cramps (from 3.0 ± 0.8 to 1.2 ± 0.8 and 0.3 ± 0.3 following inflation of an intra-rectal balloon. To summarise, milnacipran was efficacious in the writhing test, after acute and semi-chronic administration. This effect was confirmed after acute administration in a more specific model of colonic hypersensitivity induced by butyrate. This suggests that milnacipran has potential clinical application in the treatment of visceral pain, such as in irritable bowel syndrome, highly co-morbid with fibromyalgia.     

Pioglitazone improves visceral sensation and colonic permeability in a rat model of irritable bowel syndrome

Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-γ activation by pioglitazone may be useful for IBS treatment.     

帕罗西汀治疗肠易激综合征

目的 :观察帕罗西汀治疗肠易激综合征(IBS)的疗效与不良反应。方法 :63例有明显抑郁心理障碍的IBS病人随机分成 2组 ,帕罗西汀组 3 2例 (男性 1 4例 ,女性 1 8例 ;年龄 3 4a±s1 0a) ,对照组 3 1例 ,(男性 1 4例 ,女性 1 7例 ;年龄 3 4a± 1 1a) ,2组均给予硝苯地平 1 0mg、洛哌丁胺 2mg、谷维素 2 0mg ,po,tid;帕罗西汀组同时给予帕罗西汀2 0mg,po,qd;疗程为 4wk ,共 2个疗程。结果 :帕罗西汀组治疗wk 4,8末躯体症状严重度评分 (4 .8± 1 .6,3 .8± 1 .4)、抑郁量表评分 (4 0± 5 ,3 8± 7) ,生活质量评分(5 7± 1 3 ,70± 1 6) ,与对照组 (6.1± 2 .0 ,5 .8±2 .4;5 2± 7,49± 4;49± 1 6,5 1± 1 7)比较差异有非常显著意义 (P <0 .0 1 ) ;帕罗西汀组治疗wk4,8末有效率分别为 75 % ,97% ,对照组为 48% ,5 8% ,(P <0 .0 5 )。帕罗西汀组不良反应轻微。结论 :帕罗西汀治疗伴明显抑郁心理障碍的IBS病人疗效显著 ,且较安全     

Alosetron and irritable bowel syndrome

Alosetron (Lotronex^®, GlaxoSmithKline) is a potent and selective 5-HT₃-receptor antagonist approved by the FDA for the treatment of women with diarrhoea-predominant irritable bowel syndrome (IBS) in whom conventional therapy has failed. Studies involving healthy volunteers and IBS patients have demonstrated a beneficial effect of treatment with alosetron on global IBS symptoms, abdominal pain and discomfort, altered bowel function as well as improvement of quality of life (QOL). Data from animals studies suggest the involvement of 5-HT₃ receptors on intrinsic primary afferent neurons in the mediation of the effect of alosetron on gastrointestinal motility and secretion. While definitive proof of a visceroanalgesic action is not available, an additional central mechanism of action is suggested by findings obtained in animal models, as well as from human brain imaging studies. Alosetron shows a greater effectiveness in women, and the role of genetic factors underlying inter-individual differences in the response to alosetron is currently under investigation. The most frequent adverse event associated with the use of alosetron is constipation and in some rare cases, the development of colonic mucosal ischaemia. In the following review, the most recent reported effects of alosetron on gastrointestinal motility, visceral sensitivity and anxiety, both in terms of preclinical and clinical data will be discussed. The impact of alosetron on QOL in IBS patients and the safety of treatment with alosetron, will also be covered.     

Alosetron and irritable bowel syndrome

Alosetron (Lotronex, GlaxoSmithKline) is a potent and selective 5-HT(3)-receptor antagonist approved by the FDA for the treatment of women with diarrhoea-predominant irritable bowel syndrome (IBS) in whom conventional therapy has failed. Studies involving healthy volunteers and IBS patients have demonstrated a beneficial effect of treatment with alosetron on global IBS symptoms, abdominal pain and discomfort, altered bowel function as well as improvement of quality of life (QOL). Data from animals studies suggest the involvement of 5-HT(3) receptors on intrinsic primary afferent neurons in the mediation of the effect of alosetron on gastrointestinal motility and secretion. While definitive proof of a visceroanalgesic action is not available, an additional central mechanism of action is suggested by findings obtained in animal models, as well as from human brain imaging studies. Alosetron shows a greater effectiveness in women, and the role of genetic factors underlying inter-individual differences in the response to alosetron is currently under investigation. The most frequent adverse event associated with the use of alosetron is constipation and in some rare cases, the development of colonic mucosal ischaemia. In the following review, the most recent reported effects of alosetron on gastrointestinal motility, visceral sensitivity and anxiety, both in terms of preclinical and clinical data will be discussed. The impact of alosetron on QOL in IBS patients and the safety of treatment with alosetron, will also be covered.