Functional findings in irritable bowel syndrome

The pathophysiology of IBS is complex and still incompletely known. Both central and peripheral factors, including psychosocial factors, abnormal GI motility and secretion, and visceral hypersensitivity, are thought to contribute to the symptoms of IBS. Several studies have demonstrated altered GI motor function in IBS patients and the pattern differs between IBS subgroups based on the predominant bowel pattern. Few studies have so far addressed GI secretion in IBS, but there are some evidence supporting altered secretion in the small intestine of IBS patients. Visceral hypersensitivity is currently considered to be perhaps the most important pathophysiological factor in IBS. Importantly, several external and internal factors can modulate visceral sensitivity, as well as GI motility, and enhanced responsiveness within the GI tract to for instance stress and nutrients has been demonstrated in IBS patients. Today IBS is viewed upon as a disorder of dysregulation of the so-called brain-gut axis, involving abnormal function in the enteric, autonomic and/or central nervous systems, with peripheral alterations probably dominating in some patients and disturbed central processing of signals from the periphery in others.     

Role of stress in functional gastrointestinal disorders. Evidence for stress-induced alterations in gastrointestinal motility and sensitivity.

Psychological stress is widely believed to play a major role in functional gastrointestinal (GI) disorders, especially irritable bowel syndrome (IBS), by precipitating exacerbation of symptoms. The available data clearly demonstrate that inhibition of gastric emptying and stimulation of colonic transit is the most consistent pattern in the motility response of the GI tract to acute or short-term stress. Thus, one might propose that these alterations might play a pathophysiological role in dyspeptic symptoms and alterations in stool frequency and consistency in patients with stress-related functional GI disorders. Taken together, the above-mentioned studies suggest that the colonic motor response to stress is exaggerated in IBS. There is evidence that an increased emotional response is associated with this difference in colonic, and perhaps also gastric motor responses to certain stressors. However, almost no valid data are available so far from human studies addressing the question if differences in motility responses to stress between patients with functional GI disorders and healthy subjects are due to an altered stress response associated with an imbalance of the autonomic nervous system or increased stress susceptibility. We can summarize that in experimental animals the most consistent pattern of GI motor alterations induced by various psychological and physical stressors is that of delaying gastric emptying and accelerating colonic transit. Endogenous corticotropin-releasing factor (CRF) in the brain plays a significant role in the central nervous system mediation of stress-induced inhibition of upper GI and stimulation of lower GI motor function through activation of brain CRF receptors. The inhibition of gastric emptying by CRF may be mediated by interaction with the CRF-2 receptor, while CRF-1 receptors are involved in the colonic and anxiogenic responses to stress. Endogenous serotonin, peripherally released in response to stress, seems to be involved in stress- and central CRF-induced stimulation of colonic motility by acting on 5HT-3 receptors. Taken together, the limited data available from investigations in healthy subjects and patients with functional GI disorders provide some evidence that stress affects visceral sensitivity in humans. Acute psychological stress seems to facilitate increased sensitivity to experimental visceral stimuli, if the stressor induces a significant emotional change. In summary, studies in experimental animals suggest that stress-induced visceral hypersensitivity is centrally mediated by endogenous CRF and involvement of structures of the emotional motor system, e.g. the amygdala. Stress-induced activation or sensitization of mucosal mast cells in the GI tract seem to be involved in stress-associated alterations of visceral sensitivity.     

Motility disorders in the irritable bowel syndrome

Specific abnormalities of colonic and small bowel motility are identifiable and associated with symptoms in IBS. Characteristic abnormalities in colonic motility include a prolonged increase in 3-cycles/min colonic motor activity after a meal, an exaggerated increase in 3-cycles/min motor activity in response to stressors and CCK, and increased visceral sensitivity and motor activity in response to balloon distention. Symptoms in patients with IBS correlate in some cases with the abnormal gastrocolonic response and with pain induced by distention at various sites in the colon. Small bowel motility abnormalities identified reproducibly in IBS include an increase in daytime jejunal DCCs, an increase in daytime ileal PPCs, and more frequent cycling of daytime MMCs (in diarrhea-predominant IBS only). DCCs and PPCs are strongly associated with symptoms in IBS, and PPCs associated with altered ileocecal transit may be an important mechanism of symptoms in some patients with IBS. Esophageal and gastroduodenal motility abnormalities are inconsistently identified in IBS, and most symptoms in IBS appear to be secondary to small bowel or colonic dysfunction. Because of the paroxysmal nature of these motor abnormalities in IBS, prolonged motility recordings are required to better understand the pathophysiology of this syndrome. Patients with IBS may have altered visceral sensation and changes in afferent reflex mechanisms that modulate GI motility. These patients do not have a generalized increase in pain perception, but may have a distinct sensitivity to visceral afferent stimulation in both gastrointestinal and other viscera. Whether the altered "setpoint" to visceral afferent stimulation in IBS is intrinsic to the smooth muscle of viscera or secondary to CNS and ANS modulation is not known. Many of the symptoms and abnormalities of small bowel and colonic motility in IBS probably result from these changes in afferent sensation and reflex mechanisms. These findings support the concept that IBS is an abnormality of intestinal motility in conjunction with a "sensitive" gut.     

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。     

Evolving concepts in functional gastrointestinal disorders: promising directions for novel pharmaceutical treatments

In recent years there has been an increasing appreciation of the complexity of functional gastrointestinal disorders. These represent a spectrum of conditions which may affect any part of the gastrointestinal tract in which there appears to be dysregulation of visceral function and afferent sensation and a strong association with emotional factors and stress. There is a clear psychological dimension, with up to 60% of irritable bowel syndrome (IBS) patients reported to have psychological co-morbidities and altered pain perception is also common in comparison with control populations. The role of the enteric nervous system, the sensory pathways and the brain as well as the influence of the latter on sympathetic and parasympathetic outflow have likewise attracted increasing interest and have led to exciting new methods to study their complex interactions. The concept of low-grade inflammation, such as might occur after infection, acting as a trigger for neuromuscular dysfunction has also led to the broad integrative hypotheses that help to explain the biopsychosocial dimensions seen in functional gastrointestinal disease. The multi-component model places a major emphasis on neurogastroenterology and enteric and neuro-immune interactions where new approaches to pharmacotherapy lie. Drugs may affect motility, visceral sensation and other aspects of gut function such as secretion or absorption. More particularly, however, has been the search for and attempts to influence important mediators of these primary gut functions. Such targets include serotonin and selected 5-HT receptors, which are involved in gut motility, visceral sensation and other aspects of gut function, CCK receptors which are involved in the mediation of pain in the gut and nociception in the CNS, opioid receptors involved in pain in the brain, spinal cord and periphery, muscarinic M3-receptors, substance P and neurokinin A and B receptors which are involved in motor adaptation and pain transmission in association with inflammation, gabba receptors involved in nociception and cannabinoid receptors which are involved in the control of acetyl choline release in the gut. With a better understanding of the structures and pathways involved in visceral perception and hyperalgesia, in the CNS, spinal cord and the gut and new pharmacological tools we will be better able to elucidate the neuropharmacology of visceral perception and its relationship to gut dysfunction. It is likely that there will be multiple therapeutic options based on the spectrum of abnormalities capable of causing the spectrum of symptoms of functional gastrointestinal disorders in any individual patient.     

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.     

Irritable bowel syndrome and chronic constipation: Emerging drugs, devices, and surgical treatments

Irritable bowel syndrome (IBS) and chronic constipation (CC) are two of the most common functional disorders of the gut. CC and IBS are estimated to affect up to 20% and 27% of the North American population respectively. Although not life-threatening, CC and IBS can profoundly and negatively affect quality of life and are associated with a significant economic burden related to direct and indirect annual health-care costs. Possible etiologies for IBS and CC include alterations in visceral sensation and gastrointestinal motility. IBS may be caused by disturbances in brain-gut interactions affecting gastrointestinal motility and visceral sensitivity. Research efforts in CC have begun to identify abnormalities in myenteric neurons, alterations in neurotransmitters and their receptors, and incoordination of the muscles of the pelvic floor or anorectum. Both disorders may be influenced by genetic predisposition, environmental factors, and stress. In this article, the safety and efficacy of traditional and emerging therapies for CC and IBS are examined. In addition, their pathophysiology and symptoms are briefly reviewed.     

Immunomodulation of enteric neural function in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which is characterised by symptoms such as bloating, altered bowel habit and visceral pain. It’s generally accepted that miscommunication between the brain and gut underlies the changes in motility, absorpto-secretory function and pain sensitivity associated with IBS. However, partly due to the lack of disease-defining biomarkers, understanding the aetiology of this complex and multifactorial disease remains elusive. Anecdotally, IBS patients have noted that periods of stress can result in symptom flares and many patients exhibit co-morbid stress-related mood disorders such as anxiety and depression. However, in addition to psychosocial stressors, infection-related stress has also been linked with the initiation, persistence and severity of symptom flares. Indeed, prior gastrointestinal infection is one of the strongest predictors of developing IBS. Despite a lack of overt morphological inflammation, the importance of immune factors in the pathophysiology of IBS is gaining acceptance. Subtle changes in the numbers of mucosal immune cell infiltrates and elevated levels of circulating pro-inflammatory cytokines have been reproducibly demonstrated in IBS populations. Moreover, these immune mediators directly affect neural signalling. An exciting new area of research is the role of luminal microbiota in the modulation of neuro-immune signalling, resulting in local changes in gastrointestinal function and alterations in central neural functioning. Progress in this area has begun to unravel some of the complexities of neuroimmune and neuroendocrine interactions and how these molecular exchanges contribute to GI dysfunction     

Role of the brain and sensory pathways in gastrointestinal sensory disorders in humans

Several features of the irritable bowel syndrome (IBS) suggest involvement of the emotional limbic system in the brain. Abnormalities which upregulate afferent (sensory) signal intensity anywhere in this system, from the gastrointestinal tract to the brain, could induce hypersensitivity, leading to the pain and discomfort that characterise IBS and other functional disorders. Functional gastrointestinal disorders are likely to be heterogeneous given the complexity of the afferent system, and a number of different perturbations are possible. Intestinal hypersensitivity to pain and discomfort and associated reflex alterations in motility might explain the symptoms of functional bowel diseases.     

Pharmacologic and complementary and alternative medicine therapies for irritable bowel syndrome

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by episodic abdominal pain or discomfort in association with altered bowel habits (diarrhea and/or constipation). Other gastrointestinal symptoms, such as bloating and flatulence, are also common. A variety of factors are believed to play a role in the development of IBS symptoms, including altered bowel motility, visceral hypersensitivity, psychosocial stressors, altered brain-gut interactions, immune activation/low grade inflammation, alterations in the gut microbiome, and genetic factors. In the absence of biomarkers that can distinguish between IBS subgroups on the basis of pathophysiology, treatment of this condition is predicated upon a patient's most bothersome symptoms. In clinical trials, effective therapies have only offered a therapeutic gain over placebos of 7-15%. Evidence based therapies for the global symptoms of constipation predominant IBS (IBS-C) include lubiprostone and tegaserod; evidence based therapies for the global symptoms of diarrhea predominant IBS (IBS-D) include the probiotic Bifidobacter infantis, the nonabsorbable antibiotic rifaximin, and alosetron. Additionally, there is persuasive evidence to suggest that selected antispasmodics and antidepressants are of benefit for the treatment of abdominal pain in IBS patients. Finally, several emerging therapies with novel mechanisms of action are in development. Complementary and alternative medicine therapies including probiotics, herbal therapies and acupuncture are gaining popularity among IBS sufferers, although concerns regarding manufacturing standards and the paucity of high quality efficacy and safety data remain.     

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.     

A role for corticotropin-releasing factor in functional gastrointestinal disorders

Functional gastrointestinal disorders (FGIDs), which include irritable bowel syndrome (IBS), encompass a heterogeneous group of diseases identified by chronic or recurrent symptom-based diagnostic criteria. Psychosocial factors are key components in the outcome of clinical manifestations of IBS symptoms. Anxiogenic and endocrine responses to stress are mediated by the corticotropin-releasing factor (CRF)-CRF₁ receptor pathway. Preclinical studies show that activation of the CRF₁ receptor by exogenous CRF or stress recapitulates many functional symptoms of IBS diarrhea-predominant patients as related to anxiogenic/hypervigilant behavior, autonomic nervous system alterations, induction of diarrhea, visceral hyperalgesia, enhanced colonic motility, mucus secretion, increased permeability, bacterial translocation, and mast cell activation, which are all alleviated by selective CRF₁ receptor antagonists. Clinical studies also support that CRF administration can induce IBS-like symptoms in healthy subjects and heighten colonic sensitivity in IBS patients. Yet to be ascertained is whether CRF₁ receptor antagonists hold promise as a new therapy in IBS treatment.     

New insights into the pathogenesis and pathophysiology of irritable bowel syndrome.

The pathogenesis and pathophysiology of irritable bowel syndrome is complex and still incompletely known. Potential pathogenetic factors include genes, infectious events, psychological symptoms and other loosely defined environmental factors. Both alterations at the central and peripheral level are thought to contribute to the symptoms of irritable bowel syndrome, including psychosocial factors, abnormal gastrointestinal motility and secretion, and visceral hypersensitivity. Today irritable bowel syndrome is viewed upon as a disorder of dysregulation of the so-called brain-gut axis, involving abnormal function in the enteric, autonomic and/or central nervous systems, with peripheral abnormalities probably dominating in some patients and disturbed central processing of signals from the periphery in others. Lines of evidence also suggest that inflammation within the gastrointestinal tract may be of great importance in at least subgroups of irritable bowel syndrome patients. To conclude, a complex picture of the pathogenesis and pathophysiology of irritable bowel syndrome is emerging, with interactions between several different alterations resulting in the divergent symptom pattern in these patients.     

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.     

感染后肠易激综合征研究现状

肠易激综合征（IBS）是最常见的功能性胃肠病之一,已有研究证据表明其可能是多种因素共同作用的结果,包括遗传和环境因素、胃肠动力改变、内脏高敏感、肠道感染和炎症、慢性应激、肠道细菌过度生长和脑-肠轴功能紊乱等。部分患者在急性肠道感染恢复后仍存在腹痛、腹部不适、腹泻等症状,即感染后肠易激综合征（PI-IBS）,是近年功能性胃肠病的研究热点。本文就PI-IBS的定义、流行病学、发病机制、动物模型、临床特征、诊断和治疗等研究现状作一概述。     

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.     

Funktionelle Magen- und Darmerkrankungen

Functional gastrointestinal disorders (FGD) are characterized as chronic or recurrent abdominal symptoms that are not explained by structural or biochemical alterations identified in routine diagnostic procedures. Patients suffering from symptoms of functional dyspepsia or irritable bowel syndrome, the two most prevalent FGD, have significantly reduced quality of life but not reduced life expectancy. Current pathogenetic concepts of both disease entities propose central or peripheral alterations that cause disturbed gastrointestinal function (motility, visceral sensitivity). These alterations are possibly related to psychological (neuroendocrine effects of stress) and biological (microinflammation, postinfectious residuals, altered serotonergic mechanism) influences. The most important diagnostic testing in FGD is careful history taking, especially exploration of the presence of alarm symptoms. Depending on the severity and course of the disease, FGD treatment encompasses general lifestyle and dietary recommendations, symptom-directed medical therapy, and psychosocial interventions.     

Psychosocial determinants of irritable bowel syndrome

From a pure motor disorder of the bowel, in the past few years, irritable bowel syndrome (IBS) has become a multifactorial disease that implies visceral hypersensitivity, alterations at the level of nervous and humoral communications between the enteric nervous system and the central nervous system, alteration of the gut microflora, an increased intestinal permeability and minimum intestinal inflammation. Psychological and social factors can interfere with the communication between the central and enteric nervous systems, and there is proof that they are involved in the onset of IBS and influence the response to treatment and outcome. There is evidence that abuse history and stressful life events are involved in the onset of functional gastrointestinal disorders. In order to explain clustering of IBS in families, genetic factors and social learning mechanisms have been proposed. The psychological features, such as anxiety, depression as well as the comorbid psychiatric disorders, health beliefs and coping of patients with IBS are discussed in relation to the symptoms and outcome.     

Symptom overlap and comorbidity of irritable bowel syndrome with other conditions

Irritable bowel syndrome (IBS) is one of several highly prevalent, multi-symptom gastrointestinal motility disorders that have a wide clinical spectrum and are associated with symptoms of gastrointestinal dysmotility and visceral hypersensitivity. Symptom overlap and comorbidity between IBS and other gastrointestinal motility disorders (eg, chronic constipation, functional dyspepsia, gastroesophageal reflux disease), with gastrointestinal disorders that are not related to motility (eg, celiac disease, lactose intolerance), and with somatic conditions (eg, fibromyalgia, chronic fatigue syndrome), are frequent. The clinical associations and pathophysiologic links between IBS and these disorders continue to be explored. This review discusses overlapping symptoms and comorbidity of IBS with select gastrointestinal and non-gastrointestinal disorders and attempts to identify commonalities among these conditions.     

Sex specific alterations in autonomic function among patients with irritable bowel syndrome

BACKGROUND: Irritable bowel syndrome (IBS) is associated with increased psychological symptoms, early life stressors, and alterations in visceral perception and brain responses to noxious visceral stimuli. The autonomic nervous system (ANS) is a likely mediator for these brain-gut interactions. The few studies directly examining ANS measures have been suggestive of alterations in some IBS patients, but no studies to date have examined the potentially critical variables of sex differences or response to visceral stimulation. AIMS: (1) To test differences in ANS function during rest and during a visceral stressor (rectosigmoid balloon distension) between IBS patients and healthy control subjects. (2) To examine the role of sex on the autonomic responses of IBS patients. METHODS: Baseline autonomic measures were evaluated from 130 Rome I positive IBS patients and 55 healthy control subjects. Data were also collected from a subset of 46 IBS patients and 16 healthy control subjects during a sigmoid balloon distension study. Heart rate variability measures of peak power ratio (PPR) and peak power high frequency (PPHF) were analysed to assess sympathetic balance and parasympathetic response, respectively. Peripheral sympathetic response was measured by skin conductance. RESULTS: IBS patients showed a greater skin conductance response to visceral distension than controls. IBS patients had higher PPR and lower PPHF across conditions. Male IBS patients had higher skin conductance and PPR than females and lower PPHF. CONCLUSIONS: IBS patients have altered autonomic responsiveness to a visceral stressor, with increased sympathetic and decreased parasympathetic activity. These differences are predominantly seen in males.