New insights into visceral hypersensitivity--clinical implications in IBS

A subset of patients with IBS have visceral hypersensitivity and/or somatic hypersensitivity. Visceral hypersensitivity might have use as a clinical marker of IBS and could account for symptoms of urgency for bowel movements, bloating and abdominal pain. The mechanisms that lead to chronic visceral hypersensitivity in patients who have IBS are unclear. However, several working models may be considered, including: nociceptive input from the colon that leads to hypersensitivity; increased intestinal permeability that induces a visceral nociceptive drive; and alterations in the expression of microRNAs in gastrointestinal tissue that might be delivered via blood microvesicles to other target organs, such as the peripheral and/or central nervous system. As such, the chronic visceral hypersensitivity that is present in a subset of patients with IBS might be maintained by both peripheral and central phenomena. The theories underlying the development of chronic visceral hypersensitivity in patients with IBS are supported by findings from new animal models in which hypersensitivity follows transient inflammation of the colon. The presence of somatic hypersensitivity and an alteration in the neuroendocrine system in some patients who have IBS suggests that multisystemic factors are involved in the overall disorder. Thus, IBS is similar to other chronic pain disorders, such as fibromyalgia, chronic regional pain disorder and temporomandibular joint disorder, as chronic nociceptive mechanisms are activated in all of these disorders.     

Novel techniques to study visceral hypersensitivity in irritable bowel syndrome

Visceral hypersensitivity has emerged as a key hypothesis in explaining the painful symptoms of irritable bowel syndrome (IBS), and it has been proposed as a “biologic marker” for the condition. Visceral hypersensitivity can be influenced by peripheral and central mechanisms affecting pain perception. The optimal method for its assessment in humans has not been determined. Current techniques include stimulation via the computerized barostat and electrical stimulation, response measures including the lower limb reflex, and brain imaging modalities such as functional MRI and positron emission tomography. It has been shown that IBS patients have decreased sensory thresholds to colonic and rectal balloon distention by barostat. Studies using electrical stimulation and the RIII lower limb reflex have further confirmed enhanced visceral perception in IBS. Evidence from more recent neuroimaging studies suggests that IBS patients have abnormal activation of brain circuits involved in emotional and cognitive modulation of sensory information, resulting in ineffective pain modulation; these circuits may have a pathophysiologic role in enhancing visceral perception. There are few effective pharmacologic treatments that relieve IBS symptoms, and improved understanding of brain-gut interactions and factors relating to enhanced visceral perception may guide us in developing more efficacious treatments.     

Sensitivity disturbances in patients with irritable bowel syndrome and fibromyalgia

BACKGROUND: Although visceral hypersensitivity is a common feature among patients with irritable bowel syndrome (IBS), studies on somatic sensitivity have given controversial results. AIM: To assess visceral sensitivity in response to isotonic rectal distensions and somatic sensitivity at different layers of the body wall (skin, subcutis, and muscle) in patients with IBS and fibromyalgia (FM), within and outside the area of abdominal pain referral. MATERIALS AND METHODS: We studied 10 patients with IBS, 5 patients with FM, 9 patients with IBS+FM, and 9 healthy controls. Rectal distensions were performed by increasing tension at 4 g steps up to 64 g or discomfort. Pain thresholds to electrical stimulation were measured within and outside the areas of abdominal pain referral. RESULTS: Patients with IBS and IBS+FM demonstrated rectal hypersensitivity in comparison to controls. The threshold of discomfort was 44 +/- 5 g in IBS and 36 +/- 5 in IBS+FM patients, while patients with FM and healthy controls tolerated all distensions without discomfort. In the areas of pain referral, pain thresholds of all three tissues of the body wall were lower than normal in all patients groups (p < 0.001). In control areas, the pain thresholds were normal in skin, and lower than normal in subcutis and muscle in IBS (p < 0.001). FM and IBS+FM demonstrated somatic hypersensitivity at all sites (p < 0.001 vs healthy). CONCLUSION: Our observations seem to indicate that, although sharing a common hypersensitivity background, multiple mechanisms may modulate perceptual somatic and visceral responses in patients with IBS and FM.     

Visceral hypersensitivity in irritable bowel syndrome

Altered central processing, abnormal gastrointestinal motility and visceral hypersensitivity may be possible major pathophysiology of irritable bowel syndrome (IBS). These factors affect each other and are probably associated with development of IBS symptoms. It has been confirmed that lower pain threshold to colonic distention was observed in most of patients with IBS than healthy subjects. We have investigated pain perception of the descending colon among different subtypes of IBS. There was no difference in pain threshold to colonic distention between IBS with diarrhea and constipation. Some brain regions such as the anterior cingulate cortex (ACC) may play a major role for generating pain and/or pain-related emotion in humans. IBS patients showed greater activation in the perigenual ACC during painful rectal distention compared with healthy subjects. Inflammation, stress and the combination of both stimuli can induce significant increase in visceral sensitivity in animal models. Serotonin (5-HT) can modulate visceral perception. It has been thought that 5-HT(3) receptors may play an important role for conveying visceral sensation from the gut. Corticotropin-releasing hormone (CRH) may also modulate visceral pain hypersensitivity in IBS. CRH receptor-1 antagonist significantly prevented an increase in gut sensitivity in rats. It has been demonstrated that non-specific CRH receptor antagonist α-helical CRH significantly reduced abdominal pain score during gut stimulus in patients with IBS. In conclusion, visceral hypersensitivity is common in IBS patients and probably plays a major role in development of the symptoms and both central and peripheral factors may enhance the pain sensitivity.     

Abnormal endogenous pain modulation and somatic and visceral hypersensitivity in female patients with irritable bowel syndrome

AIM： To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome （IBS）. Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function.
METHODS： Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities （visual analogue scale, VAS 0-100） during suprathreshold rectal distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously （heterotopic stimulation） were recorded in 40 female patients with IBS and 20 female healthy controls.
RESULTS： Rectal hypersensitivity （defined by 95% Cl of controls） was seen in 21 （53%）, somatic hypersensitivity in 22 （55%） and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 （-11 to -1） in controls, but increased rectal pain by 2 （-3 to ＋6） in all IBS patients （P 〈 0.05） and by 8 （-2 to ＋19） in IBS patients with somatic and visceral hypersensitivity （P 〈 0.02）.
CONCLUSION： A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.     

Role of visceral sensitivity in the pathophysiology of irritable bowel syndrome

Visceral hypersensitivity has been recognised as a characteristic of patients with irritable bowel syndrome (IBS). It may be involved in the pathogenesis of abdominal pain/discomfort, and seems to result from the sensitisation of nerve afferent pathways originating from the gastrointestinal tract. From a clinical point of view, hypersensitivity, although frequent, is not a constant finding among patients with IBS and cannot therefore be considered as a diagnostic marker of the condition. The advances made in understanding visceral hypersensitivity in patients with IBS are reviewed: the factors that influence abdominal distension are defined and different therapeutic perspectives are examined.     

肠易激综合征内脏高敏感的研究进展

肠易激综合征(IBS)是以腹痛或腹部不适并伴有排便习惯改变但无器质性病变的功能性胃肠疾病,其发病与多种因素有关。近年来,内脏高敏感(包括内脏痛觉过敏和痛觉异常)作为IBS的生物学标记受到广泛关注。本文就IBS内脏高敏感的的研究进展作一综述。     

肠易激综合征患者结肠黏膜辣椒素受体、P物质和肥大细胞变化的研究

背景:腹痛是一般人群中最常见的肠道症状,肠易激综合征(IBS)患者的腹痛症状更为严重、频繁,然而其发生机制尚不明确。目的:分析IBS患者结肠黏膜中与痛觉和内脏高敏感相关的辣椒素受体VR1、P物质(SP)和肥大细胞(MC)的变化,探讨IBS患者内脏高敏感和腹痛的发生机制。方法:39例IBS患者[腹泻型IBS(IBS-D)21例,便秘型IBS(IBS-C)18例]和18名健康人纳入研究。受检者于结肠镜检查时在回盲部和乙状结肠取活检,行VR1、SP免疫组化染色和MC改良甲苯胺蓝染色。结肠镜检查前采用视觉模拟评分法行疼痛评分。结果:IBS患者乙状结肠VR1、回盲部和乙状结肠SP免疫反应阳性细胞以及回盲部MC数量显著多于正常对照组(P0.01),IBS-D与IBS-C组间则无明显差异。IBS-D和IBS-C患者的腹痛评分均与VR1呈正相关(r=0.553,P=0.009;r=0.592,P=0.010)。结论:IBS患者结肠黏膜中VR1、SP免疫反应阳性细胞和MC数量显著增多,VR1与腹痛评分呈正相关,三者可能参与了IBS患者内脏高敏感和腹痛的发生机制。     

Evidence for autonomic dysregulation in the irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain and visceral hypersensitivity. In this study, resting blood pressure and heart rate were recorded in 20 IBS patients and 23 controls. We assessed pain intensity and unpleasantness to visceral and cutaneous stimuli using rectal distension and immersion of the foot in hot water. Mean resting heart rate was higher in IBS patients compared to controls. IBS patients rated pain intensity and unpleasantness to visceral and cutaneous stimuli significantly higher than controls. In IBS patients, blood pressure was significantly inversely associated with visceral pain and only weakly and positively associated with cutaneous pain; there were no relationships in controls. Sex and anxiety did not explain these relationships. In conclusion, we found evidence suggestive of central autonomic dysregulation in IBS patients.     

Psychosocial factors and visceral hypersensitivity in irritable bowel syndrome]

Most studies provide strong support for an etiologic role of stressful life events in irritable bowel syndrome (IBS). Consistent with the observations in both patients and doctors that psychosocial disturbances seem to precede the onset or exacerbation of gut symptoms, researches have consistently found high levels of emotional distress in a proportion of patients with IBS and other functional gastrointestinal disorders. Moreover, a variety of other potentially psychiatric diseases such as anxiety, depression, and sleep disorder also coexist frequently with IBS. In recent literatures, some studies have shown altered mechanoelastic properties such as colonic tone, compliance, and accommodation. The demonstrated differences in colonic compliance and accommodation suggest peripheral neuromuscular substrate contributing to the pathogenesis of IBS. However, until now, attention has focused on the disturbances of visceral hypersensitivity rather than on gastrointestinal motor function as a hallmark of IBS pathophysiology. But not all IBS patients show decreased rectosigmoid pain thresholds. Recent advances in brain imaging have allowed investigators to measure changes in regional cerebral blood flow during stimulation. Those methods have extended our understanding of brain function and brain-gut interaction. IBS is characterized by hypersensitivity to visceral sensation and augmented response to stress. Studies on the disorders of sensori-motor function have also contributed to understand the knowledge of neurotransmitters involved in the function of the enteric nervous system and to identify targets for the development of new treatments for IBS.     

脑源性神经营养因子在肠道高敏感中的研究进展

内脏敏感性增高是肠易激综合征(IBS)重要的病理生理学机制之一。近年研究显示,脑源性神经营养因子(BDNF)过表达与IBS内脏高敏感密切相关。BDNF作为神经营养因子参与了神经元的存活、生长、发育、分化、再生过程。肠道组织中大量表达BDNF及其受体,对肠神经系统(ENS)的形成和功能具有调节作用,提示BDNF可能在肠道高敏感的发生机制中发挥重要作用。本文就BDNF在肠道高敏感中的研究进展作一综述。     

5-羟色胺与肠易激综合征的内脏高敏感性

肠易激综合征（IBS）是一种常见的功能性胃肠病，由于缺少明确的结构和生化改变，其临床诊断和治疗均有～定难度。目前认为内脏高敏感性和胃肠道动力异常是IBS的病理生理基础，近年来探索内脏高敏感性的形成机制成为IBS研究的热点。研究显示5-羟色胺（5-HT）可能与内脏高敏感性相关。5-HT相关制剂用于IBS的治疗已取得一定疗效。5-HT在内脏高敏感性形成机制中作用的研究将有助于IBS病理生理机制的阐明和临床新药的开发。     

The pathophysiology of irritable bowel syndrome: inflammation and motor disorder]

Irritable bowel syndrome (IBS) is one of the most common disorders and a heterogeneous condition in view of symptoms and underlying mechanisms. Though underlying causes of pathophysiologic changes remain unclear, low grade mucosal inflammation and abnormal intestinal motility are accepted mechanisms which alter gut function and generate symptoms of IBS. First, before 1980s, abnormal colonic and rectal motor functions were regarded as the main pathophysiology of IBS, but only 25-75% of IBS patients have apparent motor abnormalities which differ from the motor functions in normal controls. So, various gastrointestinal motility tests were not indicated for the diagnosis of IBS. The high-amplitude propagating contractions of colon in IBS patients may be related to the visceral pain perception. Second, the low grade mucosal inflammation may be involved in the pathophysiology of visceral hypersensitivity. Post infectious IBS (PI-IBS) occupied 6-17% of the total IBS and some previous prospective studies reported that 7-33% of acute bacterial enteritis patients developed IBS after 6-12 months of infection. The relative risk of IBS in the gastroenteritis cohort was 11.9 and the strongest risk factor is the duration of diarrhea. After enteritis event, the increased number of immunocytes, mast cells and large amount of lymphocytes infiltration were revealed in mucosa and enteric nervous system of the gut. Beside the inflammatory cells, enterochromaffin cells, cytokines and inducible nitric oxide may be related to the pathophysiologic mechanism of PI-IBS. Lastly, the abnormalities in the gastrointestinal autonomic nervous system can induce constipation or motor disorders, but further research should elucidate it.     

New concepts of irritable bowel syndrome

Significant recent advances in basic and clinical science have improved our understanding of irritable bowel syndrome (IBS). Sensory abnormalities, particularly visceral hypersensitivity after sensitizing stimulation, indicate neural dysfunction in patients with IBS. This dysfunction could be mediated by N-methyl-D-aspartate or calcium gene-related peptide receptors in the spinal cord. The stress response in the gut is augmented in IBS, which may be related to hypothalamic release of corticotropin-releasing factor. Postinfectious IBS may be related to psychologic factors that allow persistent inflammation. Finally, functional brain imaging has shown augmented central nervous system responses to visceral pain in IBS, particularly in the prefrontal cortex. Low-dose tricyclic antidepressants are useful to control symptoms, and the new serotonin type 3 (5-HT3) receptor antagonists show promise for symptom control.     

Role of antispasmodics in the treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a long-lasting, relapsing disorder characterized by abdominal pain/discomfort and altered bowel habits. Intestinal motility impairment and visceral hypersensitivity are the key factors among its multifactorial pathogenesis, both of which require effective treatment. Voltage-gated calcium channels mediate smooth muscle contraction and endocrine secretion and play important roles in neuronal transmission. Antispasmodics are a group of drugs that have been used in the treatment of IBS for decades. Alverine citrate, a spasmolytic, decreases the sensitivity of smooth muscle contractile proteins to calcium, and it is a selective 5-HT_1A receptor antagonist. Alverine, in combination with simethicone, has been demonstrated to effectively reduce abdominal pain and discomfort in a large placebo-controlled trial. Mebeverine is a musculotropic agent that potently blocks intestinal peristalsis. Non-placebo-controlled trials have shown positive effects of mebeverine in IBS regarding symptom control; nevertheless, in recent placebo-controlled studies, mebeverine did not exhibit superiority over placebo. Otilonium bromide is poorly absorbed from the GI tract, where it acts locally as an L-type calcium channel blocker, an antimuscarinic and a tachykinin NK2 receptor antagonist. Otilonium has effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients. Pinaverium bromide is also an L-type calcium channel blocker that acts locally in the GI tract. Pinaverium improves motility disorders and consequently reduces stool problems in IBS patients. Phloroglucinol and trimethylphloroglucinol are non-specific antispasmodics that reduced pain in IBS patients in a placebo-controlled trial. Antispasmodics have excellent safety profiles. T-type calcium channel blockers can abolish visceral hypersensitivity in animal models, which makes them potential candidates for the development of novel therapeutic agents in the treatment of IBS.     

肠易激综合征动物模型研制现状和进展

肠易激综合征(IBS)是一种常见的肠功能紊乱性疾病,特点是慢性反复发作的腹痛、腹部不适及排便习惯的改变。发病机制目前尚未阐明。研究显示IBS可能与肠道动力、内脏感觉过敏和肠道感染等因素有关。此文对IBS动物模型研制现状及展望作一综述。     

Electroacupuncture Reduces Rectal Distension-Induced Blood Pressure Changes in Conscious Dogs

It has been shown that acupuncture relieves symptoms of abdominal pain and bloating in patients with irritable bowel syndrome (IBS). However, the mechanism of beneficial effects of acupuncture still remains unproven. The aim of the present study was to investigate the mechanisms of the antinociceptive effects of acupuncture in conscious dogs. We evaluated the increase in mean arterial blood pressure (MAP) caused by rectal distension as an index of visceral pain. Electroacupuncture (EA; 10 Hz) at ST-36 (lower leg), but not at BL-21 (back), significantly reduced the increase in MAP in response to rectal distension (30 and 40 cm³). The antinociceptive effect of EA at ST-36 was abolished by pretreatment with naloxone (a central and peripheral opioid receptor antagonist) but not by naloxone methiodide (a peripheral opioid receptor antagonist). These results suggest that EA at ST-36 may reduce visceral pain via central opioid pathway. Acupuncture may be useful to treat visceral hypersensitivity in IBS patients.     

Rifaximin for the treatment of diarrhea-predominant irritable bowel syndrome

Irritable bowel syndrome (IBS) is a chronic, functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habit. The pathophysiology is unclear, but may include altered gut motility, visceral hypersensitivity, abnormal central pain processing, chronic low-grade intestinal inflammation, or disturbances in the gut microbiome. These etiological mechanisms, alongside environmental factors such as stress and anxiety, vary between individuals and represent potential targets for treatment. Rifaximin is a poorly absorbed oral antibiotic proposed to act on the gut microenvironment, used in the treatment of travelers’ diarrhea and hepatic encephalopathy. Clinical trials suggest the drug can reduce global IBS symptoms and improve bloating, abdominal pain, and stool consistency in some patients with non-constipated IBS, leading to Food and Drug Administration approval in the United States. This article considers the pharmacology of rifaximin, the evidence for its use in IBS, and the safety and tolerability of the drug.     

Is it diverticular disease or is it irritable bowel syndrome?

Symptomatic diverticular disease (SYMP-DD) and irritable bowel syndrome (IBS) share many features. Both are characterised by recurrent episodes of abdominal pain which may be slightly more frequent in IBS than SYMP-DD. They may also both exhibit an erratic bowel habit with diarrhoea, constipation and alternating types. It is important to assess anxiety, depression and somatisation since this can be increased in both types of patients and may be associated with visceral hypersensitivity. There are also significant differences between IBS and SYMP-DD. In particular, SYMP-DD patients are older, lack the female predominance seen in IBS and may often have fever with prolonged episodes of pain. For them, abnormalities of the gut are probably more important than cerebral factors, while for IBS the reverse is true. Treatments should be directed at the predominant abnormality which will vary in every patient.     

Repetitive rectal painful distention induces rectal hypersensitivity in patients with irritable bowel syndrome

Background A reduced rectal perceptual threshold has been reported in patients with irritable bowel syndrome (IBS), but this phenomenon may be induced by a comorbid psychological state. We evaluated the rectal pain threshold at baseline and after conditioning (repetitive rectal painful distention: RRD) in patients with IBS or functional abdominal pain syndrome (FAPS), which is an abdominal pain disorder, and in healthy controls, and determined whether rectal hypersensitivity is a reliable marker for IBS. Methods The rectal sensory threshold was assessed by a barostat. First, a ramp distention of 40 ml/min was induced, and the threshold of pain and the maximum tolerable pressure (mmHg) were measured. Next, RRD (phasic distentions of 60-s duration separated by 30-s intervals) was given with a tracking method until the subjects had complained of pain six times. Finally, ramp distention was induced again, and the same parameters were measured. The normal value was defined by calculating the 95% confidence intervals of controls. Results Five or six of the seven IBS patients showed a reduced rectal pain threshold or maximum tolerable pressure, respectively, at baseline. In all patients with IBS, both thresholds were reduced after RRD load, but they were reduced in none of the patients with FAPS. RRD significantly reduced both thresholds in the IBS group (P < 0.05), but it had no effect in the control or FAPS groups. Conclusions Rectal hypersensitivity induced by RRD may be a reliable marker for IBS. Conditioning-induced visceral hypersensitivity may play a pathophysiologic role in IBS.