肠易激综合征感觉异常研究进展

肠易激综合征(IBS)是以腹痛和/或腹部不适伴排便异常为特征性症状的一组肠功能障碍性综合征,近年来的研究表明患者结肠对机械、化学、温度、电刺激等感觉过敏,可能是IBS最重要的致病因素之一.此文综述近年来有关肠易激综合征患者肠神经系统、脊髓及中枢神经系统存在结构或功能的异常.     

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.     

Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome

The last ten years’ wide progress in the gut microbiota phylogenetic and functional characterization has been made evidencing dysbiosis in several gastrointestinal diseases including inflammatory bowel diseases and irritable bowel syndrome (IBS). IBS is a functional gut disease with high prevalence and negative impact on patient’s quality of life characterized mainly by visceral pain and/or discomfort, representing a good paradigm of chronic gut hypersensitivity. The IBS features are strongly regulated by bidirectional gut-brain interactions and there is increasing evidence for the involvement of gut bacteria and/or their metabolites in these features, including visceral pain. Further, gut microbiota modulation by antibiotics or probiotics has been promising in IBS. Mechanistic data provided mainly by animal studies highlight that commensals or probiotics may exert a direct action through bacterial metabolites on sensitive nerve endings in the gut mucosa, or indirect pathways targeting the intestinal epithelial barrier, the mucosal and/or systemic immune activation, and subsequent neuronal sensitization and/or activation.     

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.     

结肠扩张刺激对P2X4受体在IBS大鼠神经中枢中表达的影响

目的观察P2X4受体在结肠扩张刺激引起的IBS大鼠骶髓后连合核（DCN）和骶髓后角中表达的变化，为探讨IBS的神经作用机制提供理论依据。方法采用免疫组织荧光化学的方法，通过对P2X4受体和小胶质细胞的标志物OX42的荧光双标记，观察其在小胶质细胞和神经元上的反应；通过免疫电镜同步观察P2X4受体与小胶质细胞和神经元的相互关系。结果对照组大鼠的DCN和骶髓后角中几乎没有发现P2X4的表达。而在IBS大鼠组，P2X4在DCN和骶髓后角神经元和小胶质细胞中表达明显增高。电镜下，在对照组的DCN和骶髓后角，少数P2X4-LI产物表达在胶质细胞突起上，此突起可与神经元胞体、轴突、树突或另外的胶质细胞突起接触。而在IBS大鼠的DCN和骶髓后角中，P2X4在抑制性突触上的表达明显增加。有的表达在突触复合体上，并且在神经元上也有发现。然而P2X4阳性产物更多的表达在胶质细胞的突起上。结论P2X4是小胶质细胞活化的启动因素，可能是IBS内脏敏感性增高的重要因素。     

Recent advances in pharmacological treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a highly prevalent functional disorder that reduces patients’ quality of life. It is a chronic disorder characterized by abdominal pain or discomfort associated with disordered defecation in the absence of identifiable structural or biochemical abnormalities. IBS imposes a significant economic burden to the healthcare system. Alteration in neurohumoral mechanisms and psychological factors, bacterial overgrowth, genetic factors, gut motility, visceral hypersensitivity, and immune system factors are currently believed to influence the pathogenesis of IBS. It is possible that there is an interaction of one or more of these etiologic factors leading to heterogeneous symptoms of IBS. IBS treatment is predicated upon the patient’s most bothersome symptoms. Despite the wide range of medications and the high prevalence of the disease, to date no completely effective remedy is available. This article reviews the literature from January 2008 to July 2013 on the subject of IBS peripherally acting pharmacological treatment. Drugs are categorized according to their administration for IBS-C, IBS-D or abdominal pain predominant IBS.     

Neurotrophins: Peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity

Brain-derived neurotrophic factor (BDNF) is expressed in nociceptive sensory neurons and transported anterogradely to the dorsal horn of the spinal cord where it is located in dense core vesicles in C-fiber terminals. Peripheral inflammation substantially up-regulates BDNF mRNA and protein in the dorsal root ganglion (DRG) in a nerve growth factor-dependent fashion and results in novel expression of BDNF by DRG neurons with myelinated axons. C-fiber electrical activity also increases BDNF expression in the DRG, and both inflammation and activity increase full-length TrkB receptor levels in the dorsal horn. Sequestration of endogenous BDNF/neurotrophin 4 by intraspinal TrkB-Fc fusion protein administration does not, in noninflamed animals, change basal pain sensitivity nor the mechanical hypersensitivity induced by peripheral capsaicin administration, a measure of C fiber-mediated central sensitization. TrkB-Fc administration also does not modify basal inflammatory pain hypersensitivity, but does block the progressive hypersensitivity elicited by low-intensity tactile stimulation of inflamed tissue. BDNF, by virtue of its nerve growth factor regulation in sensory neurons including novel expression in A fibers, has a role as a central modulator of tactile stimulus-induced inflammatory pain hypersensitivity.     

Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome

BACKGROUND & AIMS: Intestinal mast cell infiltration may participate to abdominal pain in irritable bowel syndrome (IBS) patients. However, the underlying mechanisms remain unknown. We assessed the effect of mast cell mediators released from the colonic mucosa of IBS patients on the activation of rat sensory neurons in vitro. METHODS: Colonic mast cell infiltration and mediator release were assessed with quantitative immunofluorescence and immunoenzymatic assays. The effect of mucosal mediators was tested on mesenteric sensory nerve firing and Ca(2+) mobilization in dorsal root ganglia in rats. RESULTS: Mediators from IBS patients, but not controls, markedly enhanced the firing of mesenteric nerves (14.7 +/- 3.2 imp/sec vs 2.8 +/- 1.5 imp/sec; P < .05) and stimulated mobilization of Ca(2+) in dorsal root ganglia neurons (29% +/- 4% vs 11% +/- 4%; P < .05). On average, 64% of dorsal root ganglia responsive to mediators were capsaicin-sensitive, known to mediate nociception. Histamine and tryptase were mainly localized to mucosal mast cells. IBS-dependent nerve firing and Ca(2+) mobilization were correlated with the area of the colonic lamina propria occupied by mast cells (r = 0.74; P < .01, and r = 0.78; P < .01, respectively). IBS-dependent excitation of dorsal root ganglia was inhibited by histamine H(1) receptor blockade and serine protease inactivation (inhibition of 51.7%; P < .05 and 74.5%; P < .05; respectively). CONCLUSIONS: Mucosal mast cell mediators from IBS patients excite rat nociceptive visceral sensory nerves. These results provide new insights into the mechanism underlying visceral hypersensitivity in IBS.     

Antibiotics,gut microbiota,and irritable bowel syndrome: What are the relations?

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder in which recurrent abdominal pain is associated with defecation or a change in bowel habits (constipation, diarrhea, or both), and it is often accompanied by symptoms of abdominal bloating and distension. IBS is an important health care issue because it negatively affects the quality of life of patients and places a considerable financial burden on health care systems. Despite extensive research, the etiology and underlying pathophysiology of IBS remain incompletely understood. Proposed mechanisms involved in its pathogenesis include increased intestinal permeability, changes in the immune system, visceral hypersensitivity, impaired gut motility, and emotional disorders. Recently, accumulating evidence has highlighted the important role of the gut microbiota in the development of IBS. Microbial dysbiosis within the gut is thought to contribute to all aspects of its multifactorial pathogenesis. The last few decades have also seen an increasing interest in the impact of antibiotics on the gut microbiota. Moreover, antibiotics have been suggested to play a role in the development of IBS. Extensive research has established that antibacterial therapy induces remarkable shifts in the bacterial community composition that are quite similar to those observed in IBS. This suggestion is further supported by data from cohort and case-control studies, indicating that antibiotic treatment is associated with an increased risk of IBS. This paper summarizes the main findings on this issue and contributes to a deeper understanding of the link between antibiotic use and the development of IBS.     

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.     

What activates visceral afferents?

Vagal and spinal afferents represent the information superhighways that convey sensory information from the gut to the central nervous system. These afferents are sensitive to both mechanical and chemical stimuli. Vagal afferents terminate in the muscle layers and in the mucosa. Muscle afferents are activated at physiological levels of distension and during peristalsis. In contrast, spinal afferents encode supraphysiological levels of intestinal pressure. Vagal and spinal afferents also express a wide range of membrane receptors to a variety of chemical mediators generated from both within and outside the gut wall. Some of these receptors are part of a modality specific transduction pathway involved in sensory signalling from the gut lumen to vagal afferent endings in the mucosa. Others, which are activated by substances derived from multiple cellular sources during ischaemia, injury, or inflammation act in a synergistic way to cause acute or chronic sensitisation of the afferent nerves to mechanical and chemical stimuli. Understanding the mechanisms that underlie hypersensitivity may have implications for the pharmaceutical approach to the treatment of functional bowel disorders like irritable bowel syndrome.     

Irritable bowel syndrome:The evolution of multi-dimensional looking and multidisciplinary treatments

Irritable bowel syndrome(IBS)is common in the society.Among the putative pathogeneses,gut dysmotility results in pain and disturbed defecation.The latter is probably caused by the effect of abnormal gut water secretion.The interaction between abnormal gas accumulation,abdominal pain and bloating remains controversial.Visceral hypersensitivity and its modification along with the central transmission are the characteristics of IBS patients.The identification of biologic markers based on genetic polymorphisms is undetermined.Imbalanced gut microbiota may alter epithelial permeability to activate nociceptive sensory pathways which in turn lead to IBS.Certain food constituents may exacerbate bowel symptoms.The impact of adult and childhood abuses on IBS is underestimated.Using the concept of biopsychosocial dysfunction can integrate multidimensional pathogeneses.Antispasmodics plus stool consistency modifiers to treat the major symptoms and defecation are the first-line drug treatment.New drugs targeting receptors governing bowel motility,sensation and secretion can be considered,but clinicians must be aware of their potential serious side effects.Psychiatric drugs and modalities may be the final options for treating intractable subjects.Probiotics of multi-species preparations are safe and worth to be considered for the treatment.Antibiotics are promising but their longterm safety and effectiveness are unknown.Diet therapy including exclusion of certain food constituents is an economic measure.Using relatively safe complementary and alternative medicines(CAMs)may be optional to those patients who failed classical treatment.In conclusion,IBS is a heterogeneous disorder with multidimensional pathogeneses.Personalized medicines with multidisciplinary approaches using different classes of drugs,psychiatric measures,probiotics and antibiotics,dietary therapy,and finally CAMs,can be considered.     

食管内脏高敏感及其相关研究进展

胃食管反流疾病(gastroesophageal reflux disease,GERD)是一种较普遍的疾病,经常伴随各种不适症状,需要利用健康护理资源.在动物实验与人类实验研究中均表明,各种传入神经的受体在暴露于酸的情况下均可以敏感化,以至于使更多的感觉刺激通过传入神经输入到脊髓背角神经元,导致了这些神经元的阈值降低,使得他们的感受范围增大.这种敏感性增高的初级传入神经被形容为外周敏感化,而随之增加敏感性的脊髓背角神经元被描述为中央敏感化.一旦这些机制建立起来,可以使组织对以前原本无害的刺激发生敏感,并且会保持一个长期的过程.此外,心理压力和机械刺激都已经被证实可以使细胞间隙增宽,因此可能促进外围敏感化.目前,外围与中枢敏感化被认为是食管疼痛和高敏感的重要机制,甚至生理量的酸亦可以导致症状的发生.对于这些患者的治疗目的主要是降低神经的敏感性.本文主要围绕食管内脏感觉高敏感作一简要综述.     

Drugs acting on serotonin receptors for the treatment of functional GI disorders

In the gut, serotonin (5-hydroxytryptamine: 5-HT) exerts a variety of effects on intrinsic enteric neurons, extrinsic afferents, enterocytes and smooth muscle cells, which are related to the expression of multiple 5-HT receptor types and subtypes regulating motility, vascular tone, secretion and perception. Agonists and antagonists at 5-HT receptors have gained access to the market for the two major variants of the irritable bowel syndrome (IBS), a functional disorder characterized by abdominal pain associated with diarrhea and/or constipation in the absence of any organic abnormality. Indeed, the 5-HT3 receptor antagonist alosetron is available in the US market for the treatment of women with severe, diarrhea-predominant IBS (D-IBS) refractory to conventional therapy, whereas tegaserod, a partial 5-HT4 receptor agonist, has been approved by the FDA and other regulatory agencies for the treatment of women with constipation-predominant IBS (C-IBS) or functional constipation. This review is mainly intended to discuss the role of non-neuronal (paracrine) and neuronal 5-HT in the pathophysiology of functional gastrointestinal disorders (FGIDs), such as IBS and functional dyspepsia, and the mechanisms through which drugs acting on 5-HT receptors regulate visceral motility, perception and secretion in these two conditions.     

A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development

BACKGROUND & AIMS: The irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain in the setting of altered perception of viscerosensory stimuli. This so-called visceral hyperalgesia occurs in the absence of detectable organic disease in the peripheral organs and may cause normal or physiologic contractions to be perceived as painful. Although the pathogenesis of IBS remains speculative and is probably multifactorial, a prevailing paradigm is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. METHODS: Neonatal male Sprague-Dawley rats received either mechanical or chemical colonic irritation between postnatal days 8 and 21 and were tested when they became adults. The abdominal withdrawal reflex and the responses of viscerosensitive neurons were recorded during colon distention. RESULTS: Colon irritation in neonates, but not in adults, results in chronic visceral hypersensitivity, with characteristics of allodynia and hyperalgesia, associated with central neuronal sensitization in the absence of identifiable peripheral pathology. CONCLUSIONS: These results concur largely with observations in patients with IBS, providing a new animal model to study IBS and validating a neurogenic component of functional abdominal pain that encourages novel approaches to health care and research.     

Sensory dysfunction and the irritable bowel syndrome.

Dysfunction of the sensory system of the gut is now generally believed to be important in the pathophysiology of irritable bowel syndrome (IBS). This disturbance may well account for some of the symptoms of the disorder, such as abdominal pain, by virtue of the fact that intra-lumenal events (e.g. contractions) may be 'sensed' more easily. It can be assessed in the laboratory by a variety of techniques, but usually involves measuring the patient's response to distension of any site of the gut, most commonly the rectum. Hypersensitivity is the most frequent finding, but hyposensitivity can also occur--hypersensitivity does not appear to be specific to any particular pattern of bowel habit, but hyposensitivity does tend to be generally only seen in patients with constipation, especially those with the 'no urge' type. Although there is some evidence to support hypersensitivity being related to enhanced vigilance in some patients, other data suggest that there may be a true alteration in sensory processing. The mechanisms underlying this sensory dysfunction remain to be elucidated, but could involve changes in either the enteric, spinal and/or central nervous systems. Finally, factors such as gender, stress, emotion and infection can all influence the sensitivity of the gut and may therefore play a role in IBS.     

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.     

Mast cells and neuropeptidergic terminals: Experimental studies of the mechanism of visceral hypersensitivity in irritable bowel syndrome

OBJECTIVE: The failure of dysmotility to explain the symptoms of pain in irritable bowel syndrome (IBS) led to studies on visceral hypersensitivity. Mucosal mast cells (MC) may be one factor influencing the response of visceral afferents to mechanical and chemical stimuli because they are found in close proximity to gastrointestinal mucosal sensory nerve terminals containing neuropeptides and a bi‐directional pathway linking the central nervous system, gut and MC has been demonstrated. METHODS: The present study investigated the extent of MC and the neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), in the intestinal mucosa of patients with IBS, as well as the location of the MC. The MC and neuropeptidergic terminals were stained histochemically and immunohistochemically, respectively, neuropeptide concentrations were measured by radioimmunoassay (RIA), and the results were investigated qualitatively and quantitatively by color image analyzer. The structural relation between the MC and neuropeptide terminals was studied by ultramicroscopy using in situ embedding technique. RESULTS: In IBS, the number of MC in the terminal ileum, the ileocecal junction, and the ascending colon was significantly increased (P < 0.01), and the MC had great variations in their extent and size. Significantly increased concentrations of VIP and SP were found in the colon of IBS patients compared with controls. A correlation between mucosal MC and the SP(VIP)‐ergic terminals was found, and the MC were close to these terminals in the lamina propria, which demonstrated SP (VIP)‐ergic terminals. CONCLUSIONS: Mast cells and the neuropeptides of intestinal mucosa may play a central role in gut hypersensitivity, resulting in both the motor response and visceral perceptions that occur with IBS.     

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.     

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.