P- Reviewer: Chiba T, O’Mahony SM S- Editor: Qi Y L- Editor: A E- Editor: Ma S
Published online Sep 14, 2014. doi: 10.3748/wjg.v20.i34.12144
Revised: February 9, 2014
Accepted: May 19, 2014
Published online: September 14, 2014
Irritable bowel syndrome (IBS) remains a clinical challenge in the 21st century. It’s the most commonly diagnosed gastrointestinal condition and also the most common reason for referral to gastroenterology clinics. Its can affect up to one in five people at some point in their lives, and has a significantly impact of life quality and health care utilization. The prevalence varies according to country and criteria used to define IBS. Various mechanisms and theories have been proposed about its etiology, but the biopsychosocial model is the most currently accepted for IBS. The complex of symptoms would be the result of the interaction between psychological, behavioral, psychosocial and environmental factors. The diagnosis of IBS is not confirmed by a specific test or structural abnormality. It is made using criteria based on clinical symptoms such as Rome criteria, unless the symptoms are thought to be atypical. Today the Rome Criteria III is the current gold-standard for the diagnoses of IBS. Secure positive evidence of IBS by means of specific disease marker is currently not possible and cannot be currently recommended for routine diagnosis. There is still no clinical evidence to recommend the use of biomarkers in blood to diagnose IBS. However, a number of different changes in IBS patients were demonstrated in recent years, some of which can be used in the future as a diagnostic support. IBS has no definitive treatment but could be controlled by non-pharmacologic management eliminating of some exacerbating factors such certain drugs, stressor conditions and changes in dietary habits.The traditional pharmacologic management of IBS has been symptom based and several drugs have been used. However, the cornerstone of its therapy is a solid patient physician relationship. This review will provide a summary of pathophysiology, diagnostic criteria and current and emerging therapies for IBS.
Core tip: Irritable bowel syndrome (IBS) remains a clinical challenge in the 21st century. Various mechanisms and theories have been proposed about its etiology, but the biopsychosocial model is the most currently accepted. Today the Rome Criteria are the current gold-standard for the diagnoses of IBS. Traditional management of IBS has been symptom based and several drugs have been used. However, the cornerstone of its therapy is a solid patient physician relationship. This review will provide a summary of pathophysiology, diagnostic criteria and current and emerging therapies for IBS.
Citation: Soares RL. Irritable bowel syndrome: A clinical review. World J Gastroenterol 2014; 20(34): 12144-12160
The functional gastrointestinal disorders (FGIDs) are a heterogeneous group of chronic conditions that are considered important to public health because they are remarkably common, can be disabling, and induce a major social and economic burden. Irritable bowel syndrome (IBS) is the most prevalent FGID noted in the general population worldwide and also the most common reason for referral to gastroenterology clinics[1-4]. Even though it was described to 150 years ago, IBS remains a clinical challenge in the 21st century[5,6]. Its can affect up to one in five people at some point in their lives, and has a significantly impact of life quality and health care utilization[7,8]. The prevalence varies according to country and criteria used to define IBS[9-21]. Various mechanisms and theories have been proposed about its etiology, but the biopsychosocial model is the most currently accepted for IBS. The complex of symptoms would be the result of the interaction between psychological, behavioral, psychosocial and environmental factors[23-27]. The diagnosis of IBS is not confirmed by a specific test or structural abnormality. It is made using criteria based on clinical symptoms such as Rome criteria, unless the symptoms are thought to be atypical. There is still no clinical evidence to recommend the use of biomarkers in blood to diagnose IBS. Today the Rome Criteria are the current gold-standard for the diagnoses of IBS[26,28,29]. There is no definitive treatment for IBS and the traditional management has been symptom based but recent developments in the understanding of complex interaction between the gut, immune system and nerve system have led to an expanded arsenal of therapeutic options for relief of both bowel movement-related symptoms and pain[30-34]. However, a strong doctor-patient relationship is the key for effective treatment of patients and realistic expectations.
In despite its high prevalence, the pathophysiology of IBS is not yet completely understood and seems to be multifactorial[22-25]. Various mechanisms [gastrointestinal (GI) dismotility[40,41] visceral hypersensitivity[42,43] intestinal mucosa activation[44-48], Increased intestinal permeability[49-54], have been proposed about the IBS pathophysiology. Studies suggest interplay between luminal factors (e.g., foods and bacteria residing in the intestine], the epithelial barrier, and the mucosal immune system. However, the biopsychosocial model[22,25,26,36] is the most currently theory accepted for IBS. The complex of symptoms would be the result of the interaction between psychological, behavioral, psychosocial and environmental factors Since fifty years ago, several theories have proposed regarding the etiology of IBS of which the most important are as follows.
IBS is a complex disorder that is associated with altered GI motility, secretion and sensation[55,56]. In some patients with IBS motor abnormalities of the GI are detectable, e.g., increased frequency and irregularity of luminal contractions, prolonged transit time in constipation-predominant IBS and an exaggerated motor response to cholecystokinin and meal ingestion in diarrhea-predominant IBS. Despite this no predominant pattern of motor activity has emerged as a marker for IBS[57-60] and the relevance of these motor function alterations to symptoms has yet to be established. However, pharmacological stimulation of gut motility in IBS patients appears to reduce gas retention and improve symptoms. These data suggest that a motility disorder could be associated with this complaint in some patients[61,62].Role of serotonin in the pathophysiology of IBS. Serotonin (5-HT) plays a critical role in the regulation of GI motility, secretion and sensation. It is an important signaling molecule in the gut targeting enterocytes, smooth muscles and enteric neurons. Most of the body serotonin is present in enterochromaffin cells. Serotonin activates both intrinsic and extrinsic primary afferent neurons to, respectively initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin activates both intrinsic and extrinsic primary afferent neurons to, respectively initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. It is inactivated by the serotonin reuptake transporter (SERT) in the enterocytes or neurons[22,24,30,32]. There are lines of evidence that FGIDs, as IBS, are associated with defective enteric serotonergic signaling. Altered serotonin signaling could lead to intestinal and extra intestinal symptoms in IBS. These results support the concept that diarrhea-predominant (IBS-D) IBS is characterized by reduced 5-HT reuptake, whereas impaired release may be a feature of constipation predominant IBS (IBS-C). However, exogenous serotonin application evokes so many responses that it is difficult to determine which is physiologically relevant. Therapeutic agents targeting altered serotonin signaling may provide new effective treatment for patients with IBS[62-65].
Visceral hypersensitivity is considered to be one of the main factors that cause symptoms in IBS patients and increased sensation in response to stimuli is a frequent finding in IBS patients[42,43,65-68]. This selective hypersensitization results from stimulation of various receptors in the gut wall of visceral afferent nerves in the gut[69-71], triggered by bowel distention or bloating, as a possible explanation for IBS symptoms[72-77]. Rectal distension in patients with IBS also increased cerebral cortical activity more than in controls. The increased sensitivity of the colon could be influenced by a psychological tendency to report pain and urgency, rather than increased neurosensory sensitivity. About half of patients with IBS (mainly those with constipation) have a measurable increase in abdominal girth associated with bloating (sensation of abdominal fullness), although this may not be related to the volume of intestinal gas[72,74,79]. In addition, other factors may contribute to visceral hyperalgesia, such as specific GI mediators (serotonin, linins), or increases in spinal cord excitability due to activation of an N-methyl-D-aspartate (NMDA) receptor. In addition, IBS patients show an increased secretion in the duodenum and jejunum. Larsson et al proposed that the enhanced secretion may reflect disturbed enteric network behavior in some patients with IBS.
Some authors reported an increase in permeability of the intestinal mucosa and disruption of tight junctions in sub-groups of patients with IBS often triggered by some factors[45-50]. The possible mechanisms underlying these changes could be associated with the interaction between mucosa permeability, visceral hypersensitivity and inflammation mucous[48-54,82,83]. Studies suggest that an interaction between luminal factors (for example, food and bacteria that reside in the gut), the epithelial barrier and mucosal immune system could result in pain through the inflammatory stimulation of afferent nerves[45-48,51,82,83]. Some factors were described as triggers for intestinal permeability alterations. They are stress, food, bile, infection and dysbioses[48,49].
Role of stress: The association between IBS and psychological factors, especially anxiety and stress, has been described for many years[22-25,36]. In rats chronically stressed the consequently increased corticosterone release leads to intestinal inflammation with consequent mucosal barrier dysfunction[84-88]. However, the direct association between intestinal barrier dysfunction and stress in patients with IBS still needs confirmation.
Role of food and bile: Some patients with IBS report worsening of symptoms after eating and perceive food intolerance to certain foods[89-93]. Multiple factors have been considered to contribute to food sensitivity in patients with IBS. Investigations have centered on food specific antibodies, carbohydrate malabsorption, and gluten sensitivity. Although some IBS patients related relief of symptoms on a gluten-free diet the specific relationship between gluten and increased intestinal permeability in IBS have not yet confirmed[93-96]. We reported that IBS patients have difficulties with food in general and specific foods may not be involved in IBS pathogenesis.
It is reasonable to assume that IBS causes food sensitivity, rather than vice versa[97,98]. Certain bile acids could increase intestinal permeability through the phosphorylation of epidermoid growth factor receptor, which induces occludin desphosphorylation or via dysfunction of the enteric neurons.
Role of infection-IBS post-infectious: Gastroenteritis is a common trigger for IBS. The IBS symptoms can be triggered by an enteric infection and can persist for weeks, months and years[52,101-104]. Two meta-analyses demonstrated an increased risk of IBS in patients who experienced an episode of acute gastroenteritis. Risk factors for post infectious IBS included young age, prolonged fever, anxiety, and depression. A longer duration of the initial infection has also been associated with increased risk for IBS. One of the largest prospective studies included a total of 2069 individuals who had been exposed to contaminated drinking water after heavy rainfall[105,106]. The cause of the intestinal symptoms after PI-IBS is not yet defined. The likely increase in intestinal permeability during the episode of acute gastroenterite could cause inflammation and intestinal microbiota change, leading to intestinal barrier dysfunction and infection-induced dysbiosis[107,108]. Development of idiopathic malabsorption bile acids and increase in serotonin-containing enteroendocrine cells and T lymphocytes[108-111]. The use of antibiotics for GI or other infections was observed to be a risk factor for developing functional bowel symptoms.
Small intestinal bacterial overgrowth (SIBO) is associated with an increased number and/or type of bacteria in the upper GI tract. However, data reporting an association between IBS and SIBO have been conflicting. In support of an association between SIBO and IBS are studies demonstrating abnormal breath hydrogen levels in IBS patients after receiving a test dose of a carbohydrate, as well as improvement in symptoms after eradication of the overgrowth[114,115]. In addition, increased methane production, a gas by product of intestinal bacteria, has been associated with constipation predominant IBS[116,117]. Other studies have failed to support an association between SIBO and IBS The improvement of symptoms with antibiotics described in some patients with IBS may be due to improved intestinal motility or a change in the flora of the colon, rather than SIBO[118-121].
The relationship between stress and microbiota goes back many decades, when Tannack and Savage reported that stressed mice showed dramatic reductions in these populations of lactobacilli. Recent studies demonstrated that the intestinal microbiota can influence the gut-brain communication in health and disease, and consequently altering brain chemistry and behavior. However, it’s perhaps premature to extrapolate the current preclinical work to the clinic. The complex ecology of the fecal microflora has led to speculation that changes in its composition could be associated with diseases including IBS. Emerging data suggest that the fecal microbiota in individuals with IBS differ from healthy controls and varies with the predominant symptom[122-124]. However, not all studies have found disturbances in the microbiota composition of IBS patients and his currently unclear whether the alteration that have been reported are primary or secondary in nature. The contribution of altered intestinal composition or function in IBS remains controversial and additional studies are needed to validate these observations[125-129].
Increased numbers of lymphocytes have been reported in the colon and small intestine in a subset of patients with IBS[130,131]. These cells release mediators (nitric oxide, histamine and proteases) capable of stimulating the enteric nervous system, leading to abnormal motor and visceral responses within the intestine[132-134]. Studies have demonstrated a correlation between abdominal pain in IBS and the presence of activated mast cells in proximity to colonic nerves. In addition, peripheral blood mononuclear cells of IBS patients produce higher amounts of tumor necrosis factor than healthy controls. Changes in mucosal barrier function and a consequent increase in intestinal permeability could be the basis for the increased inflammation in IBS[45-49]. The interaction between the increased intestinal permeability, low levels of inflammation and hypersensitivity could be the key to the pathophysiology of IBS[48,136-138].
The pathogenesis of IBS has traditionally been based on the biopsychosocial model that emphasizes that the symptom manifestations of IBS and consulting behavior are influenced at least in part by psychological processes. However, there has been increasing interest in trying to identify potential molecular mechanisms in IBS, and this endeavor has been driven by some evidence that there is a true genetic contribution to IBS[138-140]. IBS does aggregate in families, and the concordance of IBS is twice as great in monozygotic compared with dizygotic twins in most, but not all studies[141-144]. A number of genetic polymorphisms have been associated with IBS but most remain to be independently confirmed, and unknown gene-environment interactions probably remain essential for the disorder to manifest[144-146]. A future direction of investigation includes genome-wide approaches and further delineation of the role of epigenetic factors in IBS. By studying the genetic associations between candidate genes and intermediate phenotypes that are associated with manifestations of the clinical phenotype, one can also evaluate the role of the candidate mechanism in IBS. The intermediate phenotypes most commonly used in IBS are colonic transit, colonic motility and compliance, and sensation thresholds and ratings[147,148].
Psychosocial factors may influence the expression of IBS[149-153]. Though the role of the BGA is not fully understood, there is strong evidence of a crucial involvement of the BGA in the development of IBS and IBS like symptoms[22-24,36]. In patients with IBS the dysregulation of the BGA, a bidirectional and integrated system modified by psychosocial processes and environmental influences, could induce dysmotility or visceral sensitivity. The importance of the knowledge of concepts related brain-gut interactions improves patient physician relationship and identifies what level pharmacological treatment can be beneficial for patients with IBS[154-159].
Although it is among the most common disorders in gastroenterology and primary care practices IBS continues as a substantial diagnostic challenge[1,3,4,20,22,24,27,160]. Frequently, the IBS diagnosis is missed or delayed. There are several medical conceptions concerning the SII. While a large number of doctors consider that IBS would be a mixture of different organic diseases and others believe IBS does not exist and in your point of view these symptoms are normal and these patients are not medical priority, only a few doctors consider IBS as a functional bowel disease well defined by the byopsychosocial model[22,25,26,36]. This fact is an important obstacle to making IBS diagnosis. However millions of IBS patients around the world are still looking for responses and relief of symptoms. For these reasons is so important to make a diagnosis of IBS. The key issues is to diagnose IBS safely through minimal risks and reasonable costs[9,26,27,29,36,161-164]. To standardize clinical research protocols, was published a definition of consensus for the diagnosis of IBS in 1992 called Rome criteria, which was recently revised in 2005 and named as Rome III criteria. The diagnosis must be based on clinical data, using symptoms based on criteria of Rome, unless the symptoms are atypical[165,166]. When the criteria are filled in IBS diagnosis and alarm features are absent, the number of diagnostic tests should be minimal.Reports and guidelines emphasize that IBS is not a diagnosis of exclusion and encourage clinicians to make a positive diagnostic using the Rome Criteria alone[9,26-29,36,167-171].
IBS is the most commonly diagnosed GI condition and also the most common reason for referral to gastroenterology clinics (up to 50% of all offices visits to gastroenterologists). Its can affect up to one in five people at some point in their lives, and has a significantly impact of life quality and health care utilization. The prevalence varies according to country and criteria used to define IBS. IBS is more frequent in women than in men, and its prevalence is less for individuals over 50 years, when compared with those of less than 50 years. Are considered typical clinical manifestations in IBS discomfort or abdominal pain relieved by defecation, associated with a change in stool form[172-176].
Patients with IBS can present with a variety of symptoms which include both GI and extraintestinal complaints. However, the symptom complex of chronic abdominal pain and altered bowel habits remains the nonspecific primary characteristic of IBS. It’s chronic nature, signs and symptoms which vary periodically from mild to severe have many negative effects on the quality of life for the suffers. Many factors, for example. emotional stress and eating may exacerbate the pain. In contrast defecation usually provides some relief[28,164,168,177-180].
Patients with IBS complain of altered bowel habit, ranging from diarrhea (IBS-D), constipation (IBS-C), or alternating diarrhea and constipation (IBS-M). One half of patients with IBS-D complain of mucus discharge. Large volume diarrhea, bloody stools, nocturnal diarrhea, and greasy stools are not associated with IBS and suggest organic disease. Another sub-group of patients with IBS-D describe an acute viral or bacterial GI before the onset of symptoms compatible with IBS. This clinical entity is called post-infectious IBS. It’s important to remember that the most bowel movements are preceded by lower abdominal cramps. 8-Patients with IBS-C may experience a sensation of incomplete evacuation and periods of constipation can last from days to months alternating with diarrhea or normal bowel function[28,164,168,180].
Bloating or feeling of abdominal distension are very frequent complaints in IBS and may be included in the diagnostic criteria for IBS in the future. Other digestive symptoms as dysphagia, early satiety, intermittent dyspepsia, nausea and non-cardiac chest pain patients with are also often associated with IBS. Comorbidity with other FGIDs is high and can be caused by shared as visceral hypersensitivity pathophysiological mechanisms. Comorbidity with other FGIDs is high and may be caused by shared pathophysiological mechanisms such as visceral hipersensivity[180-185].
Psychiatric disorders, especially major depression, anxiety, and somatoform disorders occur frequently[158,186,187]. The nonGI nonpschiatric disorders with the best documented association are fibromyalgia, chronic fatigue syndrome, temporal mandibular joint disorder and chronic pelvic pain[188-190]. In addition, IBS is often accompanied by other extra-intestinal symptoms as asthma and cerebral pain symptoms as primary headache[191-193]. The high prevalence of co morbidities in IBS patients has led investigators to develop hypothesis regarding underlying pathophysiologic mechanisms linking these disorders[194,195]. The comorbidities are correlated with enhanced medical help seeking, worse prognosis, and higher rates of anxiety and depression all resulting in a reduced quality of life. The identification of this clinical problem could improve the therapeutic options and the prevention strategies[196-198].
The concept of utilization of the clinical criteria for IBS diagnosis was formulated at first time for Manning in 1978. Other criteria have also been proposed[200-202]. Today the Rome Criteria III are the current gold-standard for the diagnoses of IBS. IBS was defined as recurrent abdominal pain or discomfort associated with altered defecation and IBS patients are grouped into different subtypes based on the predominant stool consistency. Formally, the Rome III Criteria require recurrent abdominal pain or discomfort ≥ 3 d/mo in the last 3 mo associated with ≥ 2 of the following: 1- improvement with defecation; 2- onset associated with a change in form (appearance) of the stool. Supportive symptoms that are not part of the Rome III Criteria include: abnormal stool frequency, abnormal stool form, defecation straining, urgency or a feeling of incomplete bowel movement, passing mucus and bloating.
The basic diagnosis should include a careful and thorough medical history. This complaint data should be quantified as precisely as possible (e.g., by symptom diaries). The aim is the most accurate detection of symptom constellation and dynamics, as well as the active queries alarm symptoms. There is evidence that the (patient and doctor alike convincing) exclusion of relevant other causes can contribute for the mutual improved trust and due to also to the success of the treatment[205,206]. The substantial human and economic costs associated with IBS needs to development of efficient diagnostic and management strategies[6,27]. Patients are first identified as having a symptom complex compatible with IBS based upon Rome III Criteria. If the patient who have IBS suggestive symptoms, and no alarm symptoms or no family history of IBD or colorectal cancer are present, a limited number of diagnostic studies is required to exclude organic disease in most patients and a considerable number do not require any tests at all. This limited diagnostic approach excludes organic disease in more than 95 percent of patients[201,205,206]. Routine laboratory studies (complete blood count, chemistries) are normal in IBS[22,26,201,207-210]. The rates of prevalence of IBD, colorectal cancer and thyroid disease are different in patients with IBS when compared with the general population. Lactose intolerance seems to be more prevalent in patients with IBS symptoms when compared with controls other carbohydrates such fructose and sucrose can also cause or exacerbate IBS symptoms. However, there is no evidence of cause and effect between lactose intolerance and IBS[211-213]. Stool examination for ova and parasites would be indicated only in patients who live in developing countries or were there recently. There is insufficient evidence to recommend routinely test for SIBO in patients with IBS[26,168,215-222]. The utility of abdominal imaging tests in patients with suspected IBS and no alarm features is scarce. In absence of alarm signals characteristic IBS patients aged less than 50 years need not be submitted to colonoscopy. The image of the colon would not be useful in obtaining colonic imaging that could explain the symptoms of patients with IBS.
In the presence of alarm features or atypical symptoms which are not compatible with IBS, it’s important to exclude other causes. The alarm symptoms (e.g., anemia and weight loss) have a high specificity for the presence of inflammatory or malignant diseases. Rectal bleeding, nocturnal or progressive abdominal pain, weight loss, anemia and another laboratory abnormalities such as elevated inflammatory markers, or electrolyte disturbances, a family history of colorectal cancer, IBD or celiac disease are often associated with IBS-like symptoms[216-218]. Faced with a patient with IBS symptoms and alarm signals the colonoscopy should be performed to exclude organic disease[22,26,168,219,224]. We suggest performing screening tests based upon the patient’s clinical history in patients with IBS-M, and in IBS with refractory symptoms (change of progression of symptoms or absence in response to general therapeutic measures)[26,225,226]. further evaluation depends upon the predominate symptoms. In IBS C the evaluation is similar to other patients with chronic constipation and in patients with predominant diarrhea is similar to other with chronic diarrhea[26,168,226].
Secure positive evidence of IBS by means of specific disease marker is currently not possible and cannot be currently recommended for routine diagnosis. However, a number of different changes in IBS patients were demonstrated in recent years, some of which can be used in the future as a diagnostic support. Several non-invasive approaches were investigated for their ability to discriminate IBS from non-IBS disorders. Although a larger number of data are necessary these tests show potential as adjuncts to traditional diagnosis methods in IBS and may reduce unnecessary testing in clinical practice[227-231]. They are examination of stools forms, fecal markers, and serological markers. A blood screening test approved in the United States for the IBS (“Prometheus® IBS diagnostics”) tests a constellation from a total of 10 “IBS blood biomarkers” and can thus supposedly secure diagnosis “IBS” in combination with the other clinical parameters. The practical value of this test currently (still) cannot clearly be evaluated, because the published evidence is insufficient. Secure positive evidence of IBS by means of specific “disease marker” is currently not possible and cannot be currently recommended for routine diagnosis.
Over the past 2 decades very few agents have achieved regulatory approval for the treatment of IBS. IBS has no definitive treatment but could be controlled by eliminating of some exacerbating factors such certain drugs, stressor conditions and changes in dietary habits. Traditional management of IBS has been symptom based. Because of the abnormalities in bowel states associated with each IBS subtype, it is not likely that one agent would successfully treat all three subtypes. As a result, clinical trials have focused, for the most part, on one IBS subtype[2,25,22,29,32,36,168,229].
Many patients with IBS have bounced around the field of medicine for many years with different diagnoses, due to lack of interest or deep frustration of the doctor in the treatment of IBS. The absence of biological markers for the diagnosis of IBS or even its characterisation as a mental illness. The absence of biological markers for the diagnosis of IBS or even its characterisation as a mental illness could lead to inadequate interpretation. Patients should be informed that the nature of the disease is chronic, benign, and educated on how to deal with and control symptoms of the disease, which vary periodically from mild to severe and have many negative effects on quality of life. Patients should be also informed that their diagnosis is not like being altered, but that it is possible to have a normal life. A detailed medical history and physical examination physician should pay particular attention to their patient’s concerns. The treatment goal in patients suffering with IBS is to try eliminating or decreasing the patient’s primary symptoms which should be addressed on first encounter with the patient.
It should be noted that the intake of foods does not cause IBS. However, many IBS patients have non-specific intolerance to foods. The dietary restriction of fermentable carbohydrates popularly termed the low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet has received considerable attention is now accepted as an effective strategy for managing symptoms of IBS. However, limitations still exist with this approach in part due to the fundamental difficulty of placebo control in dietary trials. In essence, IBS patients should avoid foods that trigger an onset of their symptoms, consume a minimum of high fat foods and take part in regular physical activity[168,229,231].
In patients with IBS, psychological factors (such as stress factors in career, family, etc.) such anxiety and depression, as well as the tendency towards summarization should be evaluated in interdisciplinary collaboration. Trauma and abuse should be considered and carefully be explored. As a result, the treatment success can be positively influenced. The evidence suggests that IBS patients who alternate the intestinal habits more often, are more affected by its symptoms, exhibit a greater tendency towards somatization and have a higher prevalence of psychiatric comorbidities[31,37,232-234].
The treatment of IBS, with forms of alternative therapy cannot be recommended on the basis of insufficient evidence. However, in IBS patients who did not respond to conventional treatment, complementary therapy could be effective. More recent studies are related to hypnotherapy[168,235-242].
Due to the heterogeneity of IBS, there is no standard treatment. The chronic use of drugs should be minimized as much as possible or even avoided. Different time periods may apply for not pharmacotherapy treatment approaches. However a medical therapy attempt without response should be terminated at the latest 3 months and the duration of therapy should be discussed with the patient[30-34,168].
Visceral hypersensitivity is felt to be a major contributing factor in abdominal pain experienced by IBS patients. Managing abdominal pain in IBS has changed very little over the past few decades. The antispasmodics remain a cornerstone of therapy. The antispasmodic are the most prescribed pharmacological agents for IBS, and their effect in reducing abdominal pain would be related to direct action in the contractility of muscle wall. As its use may lead to constipation should be used with caution in patients with IBS. Anxiolitc agents such benzodiazepines are of limited use in IBS. However, they can reduce acute anxiety that may contribute to the symptoms. Their use may be indicated for short-term (less than two weeks)[168,243-245].
Antidepressants have analgesic properties. The postulated mechanisms of pain modulation with tricyclic antidepressants (TCAs) and possibly selective serotonin reuptake inhibitors (SSRIs) in IBS are facilitation of endogenous endorphin release, blockade of norepinephrine reuptake leading to enhancement of descending inhibitory pain pathways, and blockade of the pain neuromodulator serotonin[32,168]. Beside imipramine, nortriptilina and desipramine, amitryptline are of the tricycle antidepressant drugs commonly used in the treatment of IBS patients at low doses. TCAs and SSRIS appear to be more effective than placebo in the overall reduction of symptoms associated with IBS. However, the degree of tolerability and safety of use of these patients is not well defined[246-250].
Dietary modifications and lifestyle should be the initial tools of the treatment of patients with constipation predominant IBS who have mild to moderate symptoms. The consumption of fiber-enriched foods and the increased fluid intake to prevent stool dehydration should be stimulated by the physician in this sub-group of IBS patients. Some improvement has been demonstrated in primary complains. However some patients may experience increased bloating. There is no evidence for the use of laxatives in patients with IBS. In refractory cases polyethylene glycol can be used to improve only the frequency of bowel movements and gaseousness due to colonic metabolism of non-digestible[251,252].
Lubiprostone is a locally acting chloride channel activator that enhances chloride chloride-rich intestinal fluid secretion[32,253]. In a first step it was approved by the Food and Administration (FDA) for use in chronic idiopathic constipation and for women with IBS-C. However, its use is currently only suitable for women with IBS and severe constipation that has been refractory to other forms of treatment. Serious adverse events were similar to placebo. However, the long-term security remains to be established. been refractory to other treatments[168,254-256].
Tegaserode, a first of the agonists of the 5-hydroxityptamine (5-HT4) receptor class of drugs that stimulate the release of neurotransmitters and increase colonic motility, was approved for IBS and constipation but removed from the market in 2007 because of cardiovascular side effects[32,255-258]. It’s a 5-HT4 receptor agonist that in clinical trials has been reported to reduce the general symptoms of IBS patients in comparison to attested placebo. The Linaclotide, a guanylate cyclase agonist stimulates intestinal fluid secretion and transit, has been approved by the United States FDA for treatment of IBS with constipation in 2012. Their approval was two randomized controlled trials in phase III. The patients initially randomized to placebo had significant improvement in abdominal pain and complete and spontaneous bowel movements. Diarrhea was the most common side effect. However, the long term risks of linaclotide are unknown and therefore its role on the treatment of IBS with constipation remains to be determined[260,261].
In this group of patients the anti-diarrheal agents are generally effective. There is evidence which suggests that the use of regular low doses of anti-diarrheal agents could be effective in such patients. Among the most commonly used anti of diarrhea agents loperamide is one that has been more studied in patients with diarrhea predominant IBS. Constipation is the major side effect of Loperamide[262,263]. It should not be used in patients with constipation and in patients with IBS diarrhea constipation alternating with diarrhea should be used with caution. In patients with diarrhea predominant IBS reports of stressors (e.g., eating, stressful encounters, travel) that lead to symptoms are frequent. When the predictors of crises are known the physician may start a first line of treatment, using antidiarrhea agents. The use of cholestyramine could be beneficial in patients with IBS-D. However, there are still no definitive evidence for its use in IBS treatment.
Alosetron (such as cilansetron, ondasetron and granisetron) is a 5-hydroxitriptamine (serotonin) 3-receptor antagonist. Its modulates visceral afferent activity from GI tract and in IBS patients could act favorably on colonic motility and secretion and afferent neural systems Constipation was reported in approximately one third of patients using alosetron. It was recertified by the FDA (after the withdrawal from the market) with restrictive guidelines and is prescribed under a specific Protocol. Its benefits are more favorable in women with severe IBS and diarrhea that are refractory to conventional therapies[168,264-268].
Abdominal bloating, a symptom commonly witnessed in IBS patients, is unfortunately very subjective and often observed in constipation predominant IBS patients. Probable mechanisms of bloating include: psychosocial, weak abdominal muscles, paradoxal relaxation of abdominal muscles and changes in visceral sensitivity. The role of prokinetic agents, simethicone and activated charcoal need to be better assessed with further well-designed studies. Dietary fiber supplementation and no absorbable sugars like lactulose can worse bloating and gaseous food, beans, carbonated beverages can lead to aerophagia symptoms. Some patients with IBS have shown improvement in symptoms of bloating, abdominal pain, or altered bowel habits. when treated with antibiotics[266-268]. The mechanism responsible for the improvement of the symptoms of these patients could be the suppression of gas produced by colonic bacteria or by alteration of colonic flora or by decreasing of the small bacterial overgrowth. It’s a question to be answered[269-271]. However, the benefit from the treatment appears to be transient. Currently is not recommended breath testing for intestinal bacterial overgrowth neither. It is not recommended to use antibiotics routinely for all patients with IBS and there are no data available to justify the prolonged use of of nonabsorbable antibiotics in these patients. In patients with moderate to severe IBS without constipation (particularly those with bloating) who failed to respond to all other therapies it’s reasonable to try a 2 wk trial (not long term) of a nonabsorbable antibiotic such rifamixin.
The rationale for the use of probiotics in IBS is its association with infectious diarrhea. It’s accepted that IBS-like symptoms are highly prevalent in the months after cure from infectious enteritis. About 7%-30% of patients with infectious diarrhea can develop IBS, in particular associated after travel to tropical countries. Among the possible mechanisms of probiotic therapy is the promotion of the endogenous defense barrier of the gut. These include the normalization of intestinal permeability and increase intestinal microecology changed, as well as improvement of gut immune barrier through the downregulation of a proinflammatory State. The Bifidobacteria, Saccharomyces boulardii and other combinations of probiotics demonstrate some efficacy in IBS. The Bifidobacteria (especially Bifidobacterium infantis 35624), Saccharomyces boulardii and other combinations of probiotics demonstrate some efficacy in IBS Trials to date remain conflicting and no clear benefit has yet to be established for lactobacilli. However, due to the number of clinical studies available, the role of probiotics in the relief of symptoms of IBS remains uncertain.
IBS affects up to one in five people at some point in their lives. However its remains a clinical challenge in the 21st century. The pathogenesis of IBS is likely multifactorial, including disorders the intestinal barrier, motility, secretion, visceral sensitivity and interactions between psycho logic and psychosocial factors. The biopsychosocial model is the most currently accepted for IBS. It’s not confirmed by a specific biomarker. Guidelines emphasize that IBS is not a diagnosis of exclusion and encourage clinicians to make a positive diagnostic using the Rome Criteria alone Today the Rome Criteria III are the current gold-standard for the diagnoses of IBS.
IBS has no definitive treatment but could be controlled by eliminating of some exacerbating factors such certain drugs, stressor conditions and changes in dietary habits. Traditional management of IBS has been symptom based. Because of the abnormalities in bowel states associated with each IBS subtype, it is not likely that one agent would successfully treat all three subtypes. As a result, clinical trials have focused, for the most part, on one IBS subtype. The modulation of the brain-gut axis is being seen as an attractive target for the development of novel treatments for a wide variety of disorder. However, the cornerstone of its therapy is a solid patient physician relationship. There are no recommendations for prevention for IBS.
|1.||Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012;10:712-721.e4. [PubMed] [DOI]|
|2.||Harvey RF, Mauad EC, Brown AM. Prognosis in the irritable bowel syndrome: a 5-year prospective study. Lancet. 1987;1:963-965. [PubMed]|
|3.||Jones R, Lydeard S. Irritable bowel syndrome in the general population. BMJ. 1992;304:87-90. [PubMed]|
|4.||Locke GR. The epidemiology of functional gastrointestinal disorders in North America. Gastroenterol Clin North Am. 1996;25:1-19. [PubMed]|
|5.||Cumming W. Electrogalvinism in a particular affliction of mucous membrane of the bowels. London Med Gaz. 1948;59:969-973.|
|6.||Horwitz BJ, Fisher RS. The irritable bowel syndrome. N Engl J Med. 2001;344:1846-1850. [PubMed]|
|7.||Longstreth GF, Wilson A, Knight K, Wong J, Chiou CF, Barghout V, Frech F, Ofman JJ. Irritable bowel syndrome, health care use, and costs: a U.S. managed care perspective. Am J Gastroenterol. 2003;98:600-607. [PubMed]|
|8.||Occhipinti K, Smith JW. Irritable bowel syndrome: a review and update. Clin Colon Rectal Surg. 2012;25:46-52. [PubMed]|
|9.||Hammer J, Talley NJ. Value of different diagnostic criteria for the irritable bowel syndrome among men and women. J Clin Gastroenterol. 2008;42:160-166. [PubMed] [DOI]|
|10.||Soares RL, dos Santos JM, Rocha VR. Prevalence of irritable bowel syndrome in a Brazilian Amazon community. Neurogastroenterol Motil. 2005;17:883. [PubMed]|
|11.||Husain N, Chaudhry IB, Jafri F, Niaz SK, Tomenson B, Creed F. A population-based study of irritable bowel syndrome in a non-Western population. Neurogastroenterol Motil. 2008;20:1022-1029. [PubMed] [DOI]|
|12.||Osterberg E, Blomquist L, Krakau I, Weinryb RM, Asberg M, Hultcrantz R. A population study on irritable bowel syndrome and mental health. Scand J Gastroenterol. 2000;35:264-268. [PubMed]|
|13.||Pan G, Lu S, Ke M, Han S, Guo H, Fang X. Epidemiologic study of the irritable bowel syndrome in Beijing: stratified randomized study by cluster sampling. Chin Med J (Engl). 2000;113:35-39. [PubMed]|
|14.||Rajendra S, Alahuddin S. Prevalence of irritable bowel syndrome in a multi-ethnic Asian population. Aliment Pharmacol Ther. 2004;19:704-706. [PubMed]|
|15.||Hongo M. Epidemiology of FGID symptoms in Japanese general population with reference to life style. J Gastroenterol Hepatol. 2011;26 Suppl 3:19-22. [PubMed] [DOI]|
|16.||Jeong JJ, Choi MG, Cho YS, Lee SG, Oh JH, Park JM, Cho YK, Lee IS, Kim SW, Han SW. Chronic gastrointestinal symptoms and quality of life in the Korean population. World J Gastroenterol. 2008;14:6388-6394. [PubMed]|
|17.||Li FX, Patten SB, Hilsden RJ, Sutherland LR. Irritable bowel syndrome and health-related quality of life: a population-based study in Calgary, Alberta. Can J Gastroenterol. 2003;17:259-263. [PubMed]|
|18.||Talley NJ, Boyce PM, Owen BK, Newman P, Paterson KJ. Initial validation of a bowel symptom questionnaire and measurement of chronic gastrointestinal symptoms in Australians. Aust N Z J Med. 1995;25:302-308. [PubMed]|
|19.||Wilson S, Roberts L, Roalfe A, Bridge P, Singh S. Prevalence of irritable bowel syndrome: a community survey. Br J Gen Pract. 2004;54:495-502. [PubMed]|
|20.||Breckan RK, Asfeldt AM, Straume B, Florholmen J, Paulssen EJ. Prevalence, comorbidity, and risk factors for functional bowel symptoms: a population-based survey in Northern Norway. Scand J Gastroenterol. 2012;47:1274-1282. [PubMed] [DOI]|
|21.||Kang JY. Systematic review: the influence of geography and ethnicity in irritable bowel syndrome. Aliment Pharmacol Ther. 2005;21:663-676. [PubMed]|
|22.||Chang JY, Talley NJ. An update on irritable bowel syndrome: from diagnosis to emerging therapies. Curr Opin Gastroenterol. 2011;27:72-78. [PubMed] [DOI]|
|23.||Mayer EA, Naliboff BD, Chang L. Basic pathophysiologic mechanisms in irritable bowel syndrome. Dig Dis. 2001;19:212-218. [PubMed]|
|24.||Saito YA, Talley NJ. Irritable Bowel Syndrome. GI Epidemiology. 1st ed. United States: Blackwell Publishing Press; 2007;pp. 176-183.|
|25.||Tanaka Y, Kanazawa M, Fukudo S, Drossman DA. Biopsychosocial model of irritable bowel syndrome. J Neurogastroenterol Motil. 2011;17:131-139. [PubMed] [DOI]|
|26.||Mearin F, Lacy BE. Diagnostic criteria in IBS: useful or not? Neurogastroenterol Motil. 2012;24:791-801. [PubMed] [DOI]|
|27.||Drossman DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Thompson WG, Whitehead WE, Janssens J, Funch-Jensen P, Corazziari E. U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci. 1993;38:1569-1580. [PubMed]|
|28.||Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130:1377-1390. [PubMed]|
|29.||Spiegel BM, Farid M, Esrailian E, Talley J, Chang L. Is irritable bowel syndrome a diagnosis of exclusion?: a survey of primary care providers, gastroenterologists, and IBS experts. Am J Gastroenterol. 2010;105:848-858. [PubMed] [DOI]|
|30.||Talley NJ. Pharmacologic therapy for the irritable bowel syndrome. Am J Gastroenterol. 2003;98:750-758. [PubMed]|
|31.||Dorn SD, Kaptchuk TJ, Park JB, Nguyen LT, Canenguez K, Nam BH, Woods KB, Conboy LA, Stason WB, Lembo AJ. A meta-analysis of the placebo response in complementary and alternative medicine trials of irritable bowel syndrome. Neurogastroenterol Motil. 2007;19:630-637. [PubMed]|
|32.||Lesbros-Pantoflickova D, Michetti P, Fried M, Beglinger C, Blum AL. Meta-analysis: The treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2004;20:1253-1269. [PubMed]|
|33.||Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med. 2000;133:136-147. [PubMed]|
|34.||Akehurst R, Kaltenthaler E. Treatment of irritable bowel syndrome: a review of randomised controlled trials. Gut. 2001;48:272-282. [PubMed]|
|35.||Drossman DA, Thompson WG. The irritable bowel syndrome: review and a graduated multicomponent treatment approach. Ann Intern Med. 1992;116:1009-1016. [PubMed]|
|36.||Sperber AD, Drossman DA. Irritable bowel syndrome: a multidimensional disorder cannot be understood or treated from a unidimensional perspective. Therap Adv Gastroenterol. 2012;5:387-393. [PubMed] [DOI]|
|37.||Zijdenbos IL, de Wit NJ, van der Heijden GJ, Rubin G, Quartero AO. Psychological treatments for the management of irritable bowel syndrome. Cochrane Database Syst Rev. 2009;CD006442. [PubMed] [DOI]|
|38.||Robinson A, Lee V, Kennedy A, Middleton L, Rogers A, Thompson DG, Reeves D. A randomised controlled trial of self-help interventions in patients with a primary care diagnosis of irritable bowel syndrome. Gut. 2006;55:643-648. [PubMed]|
|39.||Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011;12:453-466. [PubMed] [DOI]|
|40.||Stanghellini V, Tosetti C, Barbara G, De Giorgio R, Cogliandro L, Cogliandro R, Corinaldesi R. Dyspeptic symptoms and gastric emptying in the irritable bowel syndrome. Am J Gastroenterol. 2002;97:2738-2743. [PubMed]|
|41.||Cann PA, Read NW, Brown C, Hobson N, Holdsworth CD. Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut. 1983;24:405-411. [PubMed]|
|42.||Tillisch K, Labus JS. Advances in imaging the brain-gut axis: functional gastrointestinal disorders. Gastroenterology. 2011;140:407-411.e1. [PubMed] [DOI]|
|43.||Tillisch K, Mayer EA, Labus JS. Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology. 2011;140:91-100. [PubMed] [DOI]|
|44.||Mearin F, Perelló A, Balboa A. [Irritable bowel syndrome and inflammatory bowel disease: Is there a connection?]. Gastroenterol Hepatol. 2009;32:364-372. [PubMed] [DOI]|
|45.||Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology. 2002;122:1778-1783. [PubMed]|
|46.||Cremon C, Gargano L, Morselli-Labate AM, Santini D, Cogliandro RF, De Giorgio R, Stanghellini V, Corinaldesi R, Barbara G. Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol. 2009;104:392-400. [PubMed] [DOI]|
|47.||Barbara G. Mucosal barrier defects in irritable bowel syndrome. Who left the door open? Am J Gastroenterol. 2006;101:1295-1298. [PubMed]|
|48.||Camilleri M, Lasch K, Zhou W. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;303:G775-G785. [PubMed] [DOI]|
|49.||Barbara G, Zecchi L, Barbaro R, Cremon C, Bellacosa L, Marcellini M, De Giorgio R, Corinaldesi R, Stanghellini V. Mucosal permeability and immune activation as potential therapeutic targets of probiotics in irritable bowel syndrome. J Clin Gastroenterol. 2012;46 Suppl:S52-S55. [PubMed]|
|50.||Barbara G, De Giorgio R, Stanghellini V, Cremon C, Corinaldesi R. A role for inflammation in irritable bowel syndrome? Gut. 2002;51 Suppl 1:i41-i44. [PubMed]|
|51.||Soares RL, Figueiredo HN, Santos JM, Oliveira RF, Godoy RL, Mendonca FA. Discrepancies between the responses to skin prick test to food and respiratory antigens in two subtypes of patients with irritable bowel syndrome. World J Gastroenterol. 2008;14:3044-3048. [PubMed]|
|52.||Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, Neal KR. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804-811. [PubMed]|
|53.||Camilleri M, Gorman H. Intestinal permeability and irritable bowel syndrome. Neurogastroenterol Motil. 2007;19:545-552. [PubMed]|
|54.||Dunlop SP, Hebden J, Campbell E, Naesdal J, Olbe L, Perkins AC, Spiller RC. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol. 2006;101:1288-1294. [PubMed]|
|55.||Simrén M, Castedal M, Svedlund J, Abrahamsson H, Björnsson E. Abnormal propagation pattern of duodenal pressure waves in the irritable bowel syndrome (IBS) [correction of (IBD)]. Dig Dis Sci. 2000;45:2151-2161. [PubMed]|
|56.||Schmidt T, Hackelsberger N, Widmer R, Meisel C, Pfeiffer A, Kaess H. Ambulatory 24-hour jejunal motility in diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol. 1996;31:581-589. [PubMed]|
|57.||Chey WY, Jin HO, Lee MH, Sun SW, Lee KY. Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea. Am J Gastroenterol. 2001;96:1499-1506. [PubMed]|
|58.||McKee DP, Quigley EM. Intestinal motility in irritable bowel syndrome: is IBS a motility disorder? Part 1. Definition of IBS and colonic motility. Dig Dis Sci. 1993;38:1761-1772. [PubMed]|
|59.||Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology. 1995;109:40-52. [PubMed]|
|60.||Houghton LA, Lea R, Agrawal A, Reilly B, Whorwell PJ. Relationship of abdominal bloating to distention in irritable bowel syndrome and effect of bowel habit. Gastroenterology. 2006;131:1003-1010. [PubMed]|
|61.||Caldarella MP, Serra J, Azpiroz F, Malagelada JR. Prokinetic effects in patients with intestinal gas retention. Gastroenterology. 2002;122:1748-1755. [PubMed]|
|62.||Agrawal A, Houghton LA, Reilly B, Morris J, Whorwell PJ. Bloating and distension in irritable bowel syndrome: the role of gastrointestinal transit. Am J Gastroenterol. 2009;104:1998-2004. [PubMed] [DOI]|
|63.||Cremon C, Carini G, Wang B, Vasina V, Cogliandro RF, De Giorgio R, Stanghellini V, Grundy D, Tonini M, De Ponti F. Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am J Gastroenterol. 2011;106:1290-1298. [PubMed] [DOI]|
|64.||Spiller R. Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders: alterations in 5-HT signalling and metabolism in human disease. Neurogastroenterol Motil. 2007;19 Suppl 2:25-31. [PubMed]|
|65.||Faure C, Patey N, Gauthier C, Brooks EM, Mawe GM. Serotonin signaling is altered in irritable bowel syndrome with diarrhea but not in functional dyspepsia in pediatric age patients. Gastroenterology. 2010;139:249-258. [PubMed] [DOI]|
|66.||Whitehead WE, Holtkotter B, Enck P, Hoelzl R, Holmes KD, Anthony J, Shabsin HS, Schuster MM. Tolerance for rectosigmoid distention in irritable bowel syndrome. Gastroenterology. 1990;98:1187-1192. [PubMed]|
|67.||Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganière M, Verrier P, Poitras P. Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology. 2002;122:1771-1777. [PubMed]|
|68.||Zuo XL, Li YQ, Shi L, Lv GP, Kuang RG, Lu XF, Li JM, Desmond PV. Visceral hypersensitivity following cold water intake in subjects with irritable bowel syndrome. J Gastroenterol. 2006;41:311-317. [PubMed]|
|69.||Nozu T, Kudaira M, Kitamori S, Uehara A. Repetitive rectal painful distention induces rectal hypersensitivity in patients with irritable bowel syndrome. J Gastroenterol. 2006;41:217-222. [PubMed]|
|70.||Wilder-Smith CH, Robert-Yap J. Abnormal endogenous pain modulation and somatic and visceral hypersensitivity in female patients with irritable bowel syndrome. World J Gastroenterol. 2007;13:3699-3704. [PubMed]|
|71.||Dorn SD, Palsson OS, Thiwan SI, Kanazawa M, Clark WC, van Tilburg MA, Drossman DA, Scarlett Y, Levy RL, Ringel Y. Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity. Gut. 2007;56:1202-1209. [PubMed]|
|72.||Lasser RB, Bond JH, Levitt MD. The role of intestinal gas in functional abdominal pain. N Engl J Med. 1975;293:524-526. [PubMed]|
|73.||Serra J, Azpiroz F, Malagelada JR. Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. Gut. 2001;48:14-19. [PubMed]|
|74.||Serra J, Salvioli B, Azpiroz F, Malagelada JR. Lipid-induced intestinal gas retention in irritable bowel syndrome. Gastroenterology. 2002;123:700-706. [PubMed]|
|75.||Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology. 2000;118:842-848. [PubMed]|
|76.||Song GH, Venkatraman V, Ho KY, Chee MW, Yeoh KG, Wilder-Smith CH. Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls. Pain. 2006;126:79-90. [PubMed]|
|77.||Aizawa E, Sato Y, Kochiyama T, Saito N, Izumiyama M, Morishita J, Kanazawa M, Shima K, Mushiake H, Hongo M. Altered cognitive function of prefrontal cortex during error feedback in patients with irritable bowel syndrome, based on FMRI and dynamic causal modeling. Gastroenterology. 2012;143:1188-1198. [PubMed] [DOI]|
|78.||Valdez-Morales EE, Overington J, Guerrero-Alba R, Ochoa-Cortes F, Ibeakanma CO, Spreadbury I, Bunnett NW, Beyak M, Vanner SJ. Sensitization of peripheral sensory nerves by mediators from colonic biopsies of diarrhea-predominant irritable bowel syndrome patients: a role for PAR2. Am J Gastroenterol. 2013;108:1634-1643. [PubMed] [DOI]|
|79.||Buéno L, Fioramonti J, Garcia-Villar R. Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. III. Visceral afferent pathways: a source of new therapeutic targets for abdominal pain. Am J Physiol Gastrointest Liver Physiol. 2000;278:G670-G676. [PubMed]|
|80.||Willert RP, Woolf CJ, Hobson AR, Delaney C, Thompson DG, Aziz Q. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor. Gastroenterology. 2004;126:683-692. [PubMed]|
|81.||Larsson MH, Simrén M, Thomas EA, Bornstein JC, Lindström E, Sjövall H. Elevated motility-related transmucosal potential difference in the upper small intestine in the irritable bowel syndrome. Neurogastroenterol Motil. 2007;19:812-820. [PubMed]|
|82.||Piche T, Barbara G, Aubert P, Bruley des Varannes S, Dainese R, Nano JL, Cremon C, Stanghellini V, De Giorgio R, Galmiche JP. Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut. 2009;58:196-201. [PubMed] [DOI]|
|83.||Martínez C, Vicario M, Ramos L, Lobo B, Mosquera JL, Alonso C, Sánchez A, Guilarte M, Antolín M, de Torres I. The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations. Am J Gastroenterol. 2012;107:736-746. [PubMed] [DOI]|
|84.||Barreau F, Cartier C, Leveque M, Ferrier L, Moriez R, Laroute V, Rosztoczy A, Fioramonti J, Bueno L. Pathways involved in gut mucosal barrier dysfunction induced in adult rats by maternal deprivation: corticotrophin-releasing factor and nerve growth factor interplay. J Physiol. 2007;580:347-356. [PubMed]|
|85.||Saunders PR, Santos J, Hanssen NP, Yates D, Groot JA, Perdue MH. Physical and psychological stress in rats enhances colonic epithelial permeability via peripheral CRH. Dig Dis Sci. 2002;47:208-215. [PubMed]|
|86.||Demaude J, Salvador-Cartier C, Fioramonti J, Ferrier L, Bueno L. Phenotypic changes in colonocytes following acute stress or activation of mast cells in mice: implications for delayed epithelial barrier dysfunction. Gut. 2006;55:655-661. [PubMed]|
|87.||Gareau MG, Jury J, Perdue MH. Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability. Am J Physiol Gastrointest Liver Physiol. 2007;293:G198-G203. [PubMed]|
|88.||Larauche M, Gourcerol G, Wang L, Pambukchian K, Brunnhuber S, Adelson DW, Rivier J, Million M, Taché Y. Cortagine, a CRF1 agonist, induces stresslike alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways. Am J Physiol Gastrointest Liver Physiol. 2009;297:G215-G227. [PubMed] [DOI]|
|89.||Petitpierre M, Gumowski P, Girard JP. Irritable bowel syndrome and hypersensitivity to food. Ann Allergy. 1985;54:538-540. [PubMed]|
|90.||Crowe SE, Perdue MH. Gastrointestinal food hypersensitivity: basic mechanisms of pathophysiology. Gastroenterology. 1992;103:1075-1095. [PubMed]|
|91.||Brandtzaeg PE. Current understanding of gastrointestinal immunoregulation and its relation to food allergy. Ann N Y Acad Sci. 2002;964:13-45. [PubMed]|
|92.||Simrén M, Månsson A, Langkilde AM, Svedlund J, Abrahamsson H, Bengtsson U, Björnsson ES. Food-related gastrointestinal symptoms in the irritable bowel syndrome. Digestion. 2001;63:108-115. [PubMed]|
|93.||Monsbakken KW, Vandvik PO, Farup PG. Perceived food intolerance in subjects with irritable bowel syndrome-- etiology, prevalence and consequences. Eur J Clin Nutr. 2006;60:667-672. [PubMed]|
|94.||Zar S, Mincher L, Benson MJ, Kumar D. Food-specific IgG4 antibody-guided exclusion diet improves symptoms and rectal compliance in irritable bowel syndrome. Scand J Gastroenterol. 2005;40:800-807. [PubMed]|
|95.||Jun DW, Lee OY, Yoon HJ, Lee SH, Lee HL, Choi HS, Yoon BC, Lee MH, Lee DH, Cho SH. Food intolerance and skin prick test in treated and untreated irritable bowel syndrome. World J Gastroenterol. 2006;12:2382-2387. [PubMed]|
|96.||Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004;53:1459-1464. [PubMed]|
|97.||Soares RL, Figueiredo HN, Maneschy CP, Rocha VR, Santos JM. Correlation between symptoms of the irritable bowel syndrome and the response to the food extract skin prick test. Braz J Med Biol Res. 2004;37:659-662. [PubMed]|
|98.||Soares RL, Figueiredo HN, Moreira Filho PF, Oliveira RF, Gonçalves CD, Micuci AJQR, Parada BA, Brandão IB, Rodrigues CC. The prevalence and clinical characteristics of atopic manifestations in patients with irritable bowel syndrome in a Brazilian urban community. Gastroenterol Ins. 2010;2:p. e11. [DOI]|
|99.||Wedlake L, A’Hern R, Russell D, Thomas K, Walters JR, Andreyev HJ. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2009;30:707-717. [PubMed] [DOI]|
|100.||Bertiaux-Vandaële N, Youmba SB, Belmonte L, Lecleire S, Antonietti M, Gourcerol G, Leroi AM, Déchelotte P, Ménard JF, Ducrotté P. The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype. Am J Gastroenterol. 2011;106:2165-2173. [PubMed] [DOI]|
|101.||Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut. 2004;53:1096-1101. [PubMed]|
|102.||Marshall JK, Thabane M, Garg AX, Clark WF, Salvadori M, Collins SM. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology. 2006;131:445-50; quiz 660. [PubMed]|
|103.||Zanini B, Ricci C, Bandera F, Caselani F, Magni A, Laronga AM, Lanzini A. Incidence of post-infectious irritable bowel syndrome and functional intestinal disorders following a water-borne viral gastroenteritis outbreak. Am J Gastroenterol. 2012;107:891-899. [PubMed] [DOI]|
|104.||Dizdar V, Gilja OH, Hausken T. Increased visceral sensitivity in Giardia-induced postinfectious irritable bowel syndrome and functional dyspepsia. Effect of the 5HT3-antagonist ondansetron. Neurogastroenterol Motil. 2007;19:977-982. [PubMed]|
|105.||Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome--a meta-analysis. Am J Gastroenterol. 2006;101:1894-189; quiz 1942. [PubMed]|
|106.||Thabane M, Kottachchi DT, Marshall JK. Systematic review and meta-analysis: The incidence and prognosis of post-infectious irritable bowel syndrome. Aliment Pharmacol Ther. 2007;26:535-544. [PubMed]|
|107.||Niaz SK, Sandrasegaran K, Renny FH, Jones BJ. Postinfective diarrhoea and bile acid malabsorption. J R Coll Physicians Lond. 1997;31:53-56. [PubMed]|
|108.||Sinha L, Liston R, Testa HJ, Moriarty KJ. Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. Aliment Pharmacol Ther. 1998;12:839-844. [PubMed]|
|109.||Dunlop SP, Jenkins D, Neal KR, Naesdal J, Borgaonker M, Collins SM, Spiller RC. Randomized, double-blind, placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome. Aliment Pharmacol Ther. 2003;18:77-84. [PubMed]|
|110.||Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology. 2003;125:1651-1659. [PubMed]|
|111.||Törnblom H, Holmvall P, Svenungsson B, Lindberg G. Gastrointestinal symptoms after infectious diarrhea: a five-year follow-up in a Swedish cohort of adults. Clin Gastroenterol Hepatol. 2007;5:461-464. [PubMed]|
|112.||Maxwell PR, Rink E, Kumar D, Mendall MA. Antibiotics increase functional abdominal symptoms. Am J Gastroenterol. 2002;97:104-108. [PubMed]|
|113.||Lupascu A, Gabrielli M, Lauritano EC, Scarpellini E, Santoliquido A, Cammarota G, Flore R, Tondi P, Pola P, Gasbarrini G. Hydrogen glucose breath test to detect small intestinal bacterial overgrowth: a prevalence case-control study in irritable bowel syndrome. Aliment Pharmacol Ther. 2005;22:1157-1160. [PubMed]|
|114.||Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98:412-419. [PubMed]|
|115.||Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503-3506. [PubMed]|
|116.||Chatterjee S, Park S, Low K, Kong Y, Pimentel M. The degree of breath methane production in IBS correlates with the severity of constipation. Am J Gastroenterol. 2007;102:837-841. [PubMed]|
|117.||Pimentel M, Lin HC, Enayati P, van den Burg B, Lee HR, Chen JH, Park S, Kong Y, Conklin J. Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1089-G1095. [PubMed]|
|118.||Walters B, Vanner SJ. Detection of bacterial overgrowth in IBS using the lactulose H2 breath test: comparison with 14C-D-xylose and healthy controls. Am J Gastroenterol. 2005;100:1566-1570. [PubMed]|
|119.||Posserud I, Stotzer PO, Björnsson ES, Abrahamsson H, Simrén M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007;56:802-808. [PubMed]|
|120.||Yu D, Cheeseman F, Vanner S. Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS. Gut. 2011;60:334-340. [PubMed] [DOI]|
|121.||Spiegel BM. Questioning the bacterial overgrowth hypothesis of irritable bowel syndrome: an epidemiologic and evolutionary perspective. Clin Gastroenterol Hepatol. 2011;9:461-49; quiz e59. [PubMed] [DOI]|
|122.||Tannock GW, Savage DC. Influences of dietary and environmental stress on microbial populations in the murine gastrointestinal tract. Infect Immun. 1974;9:591-598. [PubMed]|
|123.||Parkes GC, Brostoff J, Whelan K, Sanderson JD. Gastrointestinal microbiota in irritable bowel syndrome: their role in its pathogenesis and treatment. Am J Gastroenterol. 2008;103:1557-1567. [PubMed] [DOI]|
|124.||Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007;133:24-33. [PubMed]|
|125.||Malinen E, Rinttilä T, Kajander K, Mättö J, Kassinen A, Krogius L, Saarela M, Korpela R, Palva A. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol. 2005;100:373-382. [PubMed]|
|126.||Rajilić-Stojanović M, Biagi E, Heilig HG, Kajander K, Kekkonen RA, Tims S, de Vos WM. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. 2011;141:1792-1801. [PubMed] [DOI]|
|127.||Saulnier DM, Riehle K, Mistretta TA, Diaz MA, Mandal D, Raza S, Weidler EM, Qin X, Coarfa C, Milosavljevic A. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology. 2011;141:1782-1791. [PubMed] [DOI]|
|128.||Jeffery IB, O’Toole PW, Öhman L, Claesson MJ, Deane J, Quigley EM, Simrén M. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut. 2012;61:997-1006. [PubMed] [DOI]|
|129.||Crouzet L, Gaultier E, Del’Homme C, Cartier C, Delmas E, Dapoigny M, Fioramonti J, Bernalier-Donadille A. The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. Neurogastroenterol Motil. 2013;25:e272-e282. [PubMed] [DOI]|
|130.||O’Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, O’Morain CA. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil. 2000;12:449-457. [PubMed]|
|131.||Törnblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology. 2002;123:1972-1979. [PubMed]|
|132.||Bueno L. Protease activated receptor 2: a new target for IBS treatment. Eur Rev Med Pharmacol Sci. 2008;12 Suppl 1:95-102. [PubMed]|
|133.||Gecse K, Róka R, Ferrier L, Leveque M, Eutamene H, Cartier C, Ait-Belgnaoui A, Rosztóczy A, Izbéki F, Fioramonti J. Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity. Gut. 2008;57:591-599. [PubMed] [DOI]|
|134.||Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Martínez C, Casellas F, Saperas E, Malagelada JR. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut. 2007;56:203-209. [PubMed]|
|135.||Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126:693-702. [PubMed]|
|136.||Dinan TG, Quigley EM, Ahmed SM, Scully P, O’Brien S, O’Mahony L, O’Mahony S, Shanahan F, Keeling PW. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology. 2006;130:304-311. [PubMed]|
|137.||Barreau F, Salvador-Cartier C, Houdeau E, Bueno L, Fioramonti J. Long-term alterations of colonic nerve-mast cell interactions induced by neonatal maternal deprivation in rats. Gut. 2008;57:582-590. [PubMed]|
|138.||Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G. Evidence of a genetic contribution to functional bowel disorder. Am J Gastroenterol. 1998;93:1311-1317. [PubMed]|
|139.||Saito YA, Petersen GM, Locke GR, Talley NJ. The genetics of irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:1057-1065. [PubMed]|
|140.||Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ. Genetic influences in irritable bowel syndrome: a twin study. Am J Gastroenterol. 2005;100:1340-1344. [PubMed]|
|141.||Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology. 2001;121:799-804. [PubMed]|
|142.||Lembo A, Zaman M, Jones M, Talley NJ. Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study. Aliment Pharmacol Ther. 2007;25:1343-1350. [PubMed]|
|143.||Bengtson MB, Rønning T, Vatn MH, Harris JR. Irritable bowel syndrome in twins: genes and environment. Gut. 2006;55:1754-1759. [PubMed]|
|144.||Park MI, Camilleri M. Genetics and genotypes in irritable bowel syndrome: implications for diagnosis and treatment. Gastroenterol Clin North Am. 2005;34:305-317. [PubMed]|
|145.||Kim HJ, Camilleri M, Carlson PJ, Cremonini F, Ferber I, Stephens D, McKinzie S, Zinsmeister AR, Urrutia R. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders. Gut. 2004;53:829-837. [PubMed]|
|146.||Pata C, Erdal ME, Derici E, Yazar A, Kanik A, Ulu O. Serotonin transporter gene polymorphism in irritable bowel syndrome. Am J Gastroenterol. 2002;97:1780-1784. [PubMed]|
|147.||Huang GH, Hsieh CC, Chen CH, Chen WJ. Statistical validation of endophenotypes using a surrogate endpoint analytic analogue. Genet Epidemiol. 2009;33:549-558. [PubMed] [DOI]|
|148.||Zinsmeister AR, Burton D, Camilleri M. Pharmacodynamic and clinical endpoints for functional colonic disorders: statistical considerations. Dig Dis Sci. 2013;58:509-518. [PubMed] [DOI]|
|149.||Drossman DA, Leserman J, Nachman G, Li ZM, Gluck H, Toomey TC, Mitchell CM. Sexual and physical abuse in women with functional or organic gastrointestinal disorders. Ann Intern Med. 1990;113:828-833. [PubMed]|
|150.||Talley NJ, Boyce PM, Jones M. Is the association between irritable bowel syndrome and abuse explained by neuroticism? A population based study. Gut. 1998;42:47-53. [PubMed]|
|151.||Koloski NA, Talley NJ, Boyce PM. A history of abuse in community subjects with irritable bowel syndrome and functional dyspepsia: the role of other psychosocial variables. Digestion. 2005;72:86-96. [PubMed]|
|152.||Perona M, Benasayag R, Perelló A, Santos J, Zárate N, Zárate P, Mearin F. Prevalence of functional gastrointestinal disorders in women who report domestic violence to the police. Clin Gastroenterol Hepatol. 2005;3:436-441. [PubMed]|
|153.||Hobbis IC, Turpin G, Read NW. A re-examination of the relationship between abuse experience and functional bowel disorders. Scand J Gastroenterol. 2002;37:423-430. [PubMed]|
|154.||Locke GR, Weaver AL, Melton LJ, Talley NJ. Psychosocial factors are linked to functional gastrointestinal disorders: a population based nested case-control study. Am J Gastroenterol. 2004;99:350-357. [PubMed]|
|155.||Solmaz M, Kavuk I, Sayar K. Psychological factors in the irritable bowel syndrome. Eur J Med Res. 2003;8:549-556. [PubMed]|
|157.||Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 2009;136:2003-2014. [PubMed] [DOI]|
|158.||Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, Underwood JE, Read NW. The role of psychological and biological factors in postinfective gut dysfunction. Gut. 1999;44:400-406. [PubMed]|
|159.||Bueno L, Fioramonti J. Visceral perception: inflammatory and non-inflammatory mediators. Gut. 2002;51 Suppl 1:i19-i23. [PubMed]|
|160.||Choung RS, Locke GR. Epidemiology of IBS. Gastroenterol Clin North Am. 2011;40:1-10. [PubMed] [DOI]|
|161.||Martin BC, Ganguly R, Pannicker S, Frech F, Barghout V. Utilization patterns and net direct medical cost to Medicaid of irritable bowel syndrome. Curr Med Res Opin. 2003;19:771-780. [PubMed]|
|162.||Hungin AP, Whorwell PJ, Tack J, Mearin F. The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40,000 subjects. Aliment Pharmacol Ther. 2003;17:643-650. [PubMed]|
|163.||Vincent C, Young M, Phillips A. Why do people sue doctors? A study of patients and relatives taking legal action. Lancet. 1994;343:1609-1613. [PubMed]|
|164.||Pimentel M, Talley NJ, Quigley EM, Hani A, Sharara A, Mahachai V. Report from the multinational irritable bowel syndrome initiative 2012. Gastroenterology. 2013;144:e1-e5. [PubMed] [DOI]|
|165.||Costanza CD, Longstreth GF, Liu AL. Chronic abdominal wall pain: clinical features, health care costs, and long-term outcome. Clin Gastroenterol Hepatol. 2004;2:395-399. [PubMed]|
|166.||Owens DM, Nelson DK, Talley NJ. The irritable bowel syndrome: long-term prognosis and the physician-patient interaction. Ann Intern Med. 1995;122:107-112. [PubMed]|
|167.||Frigerio G, Beretta A, Orsenigo G, Tadeo G, Imperiali G, Minoli G. Irritable bowel syndrome. Still far from a positive diagnosis. Dig Dis Sci. 1992;37:164-167. [PubMed]|
|168.||Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, Talley NJ, Quigley EM. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104 Suppl 1:S1-35. [PubMed] [DOI]|
|169.||Olafsdottir LB, Gudjonsson H, Jonsdottir HH, Jonsson JS, Bjornsson E, Thjodleifsson B. Irritable bowel syndrome: physicians’ awareness and patients’ experience. World J Gastroenterol. 2012;18:3715-3720. [PubMed] [DOI]|
|170.||Moayyedi P, Ford AC. Symptom-based diagnostic criteria for irritable bowel syndrome: the more things change, the more they stay the same. Gastroenterol Clin North Am. 2011;40:87-103. [PubMed] [DOI]|
|171.||Jellema P, van der Windt DA, Schellevis FG, van der Horst HE. Systematic review: accuracy of symptom-based criteria for diagnosis of irritable bowel syndrome in primary care. Aliment Pharmacol Ther. 2009;30:695-706. [PubMed] [DOI]|
|172.||Minocha A, Johnson WD, Abell TL, Wigington WC. Prevalence, sociodemography, and quality of life of older versus younger patients with irritable bowel syndrome: a population-based study. Dig Dis Sci. 2006;51:446-453. [PubMed]|
|173.||Quigley EM, Bytzer P, Jones R, Mearin F. Irritable bowel syndrome: the burden and unmet needs in Europe. Dig Liver Dis. 2006;38:717-723. [PubMed]|
|174.||Saito YA, Locke GR, Talley NJ, Zinsmeister AR, Fett SL, Melton LJ. A comparison of the Rome and Manning criteria for case identification in epidemiological investigations of irritable bowel syndrome. Am J Gastroenterol. 2000;95:2816-2824. [PubMed]|
|175.||Longstreth GF, Yao JF. Irritable bowel syndrome and surgery: a multivariable analysis. Gastroenterology. 2004;126:1665-1673. [PubMed]|
|176.||Boyce PM, Koloski NA, Talley NJ. Irritable bowel syndrome according to varying diagnostic criteria: are the new Rome II criteria unnecessarily restrictive for research and practice? Am J Gastroenterol. 2000;95:3176-3183. [PubMed]|
|177.||Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480-1491. [PubMed]|
|178.||Heaton KW, O’Donnell LJ, Braddon FE, Mountford RA, Hughes AO, Cripps PJ. Symptoms of irritable bowel syndrome in a British urban community: consulters and nonconsulters. Gastroenterology. 1992;102:1962-1967. [PubMed]|
|179.||Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P. Irritable bowel syndrome: a 10-yr natural history of symptoms and factors that influence consultation behavior. Am J Gastroenterol. 2008;103:1229-139; quiz 1240. [PubMed] [DOI]|
|180.||Halder SL, Locke GR, Schleck CD, Zinsmeister AR, Melton LJ, Talley NJ. Natural history of functional gastrointestinal disorders: a 12-year longitudinal population-based study. Gastroenterology. 2007;133:799-807. [PubMed]|
|181.||Sperber AD, Dekel R. Irritable Bowel Syndrome and Co-morbid Gastrointestinal and Extra-gastrointestinal Functional Syndromes. J Neurogastroenterol Motil. 2010;16:113-119. [PubMed] [DOI]|
|182.||Choung RS, Locke GR, Schleck CD, Zinsmeister AR, Talley NJ. Associations between medication use and functional gastrointestinal disorders: a population-based study. Neurogastroenterol Motil. 2013;25:413-49, e298. [PubMed] [DOI]|
|183.||Lovell RM, Ford AC. Prevalence of gastro-esophageal reflux-type symptoms in individuals with irritable bowel syndrome in the community: a meta-analysis. Am J Gastroenterol. 2012;107:1793-801; quiz 1802. [PubMed] [DOI]|
|184.||Sandler RS, Stewart WF, Liberman JN, Ricci JA, Zorich NL. Abdominal pain, bloating, and diarrhea in the United States: prevalence and impact. Dig Dis Sci. 2000;45:1166-1171. [PubMed]|
|185.||Ringel Y, Williams RE, Kalilani L, Cook SF. Prevalence, characteristics, and impact of bloating symptoms in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2009;7:68-72; quiz 3. [PubMed] [DOI]|
|186.||Bonavita V, De Simone R. Towards a definition of comorbidity in the light of clinical complexity. Neurol Sci. 2008;29 Suppl 1:S99-102. [PubMed]|
|187.||Drossman DA. Presidential address: Gastrointestinal illness and the biopsychosocial model. Psychosom Med. 1998;60:258-267. [PubMed]|
|188.||Hershfield NB. Nongastrointestinal symptoms of irritable bowel syndrome: an office-based clinical survey. Can J Gastroenterol. 2005;19:231-234. [PubMed]|
|189.||Johansson PA, Farup PG, Bracco A, Vandvik PO. How does comorbidity affect cost of health care in patients with irritable bowel syndrome? A cohort study in general practice. BMC Gastroenterol. 2010;10:31. [PubMed] [DOI]|
|190.||Riedl A, Schmidtmann M, Stengel A, Goebel M, Wisser AS, Klapp BF, Mönnikes H. Somatic comorbidities of irritable bowel syndrome: a systematic analysis. J Psychosom Res. 2008;64:573-582. [PubMed] [DOI]|
|191.||Soares RL, Moreira-Filho PF, Maneschy CP, Breijão JF, Schmidte NM. The prevalence and clinical characteristics of primary headache in irritable bowel syndrome: a subgroup of the functional somatic syndromes. Arq Gastroenterol. 2013;50:281-284. [PubMed] [DOI]|
|192.||Yunus MB. The prevalence of fibromyalgia in other chronic pain conditions. Pain Res Treat. 2012;2012:584573. [PubMed] [DOI]|
|193.||Jun DW, Lee OY, Yoon HJ, Lee HL, Yoon BC, Choi HS, Lee MH, Lee DH, Kee CS. Bronchial hyperresponsiveness in irritable bowel syndrome. Dig Dis Sci. 2005;50:1688-1691. [PubMed]|
|194.||Roussos A, Koursarakos P, Patsopoulos D, Gerogianni I, Philippou N. Increased prevalence of irritable bowel syndrome in patients with bronchial asthma. Respir Med. 2003;97:75-79. [PubMed]|
|195.||Sperber AD, Atzmon Y, Neumann L, Weisberg I, Shalit Y, Abu-Shakrah M, Fich A, Buskila D. Fibromyalgia in the irritable bowel syndrome: studies of prevalence and clinical implications. Am J Gastroenterol. 1999;94:3541-3546. [PubMed]|
|196.||Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of irritable bowel syndrome on health-related quality of life. Gastroenterology. 2000;119:654-660. [PubMed]|
|197.||Camilleri M. Treating irritable bowel syndrome: overview, perspective and future therapies. Br J Pharmacol. 2004;141:1237-1248. [PubMed]|
|198.||Drossman DA, Chang L, Bellamy N, Gallo-Torres HE, Lembo A, Mearin F, Norton NJ, Whorwell P. Severity in irritable bowel syndrome: a Rome Foundation Working Team report. Am J Gastroenterol. 2011;106:1749-159; quiz 1760. [PubMed] [DOI]|
|199.||Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J. 1978;2:653-654. [PubMed]|
|200.||Drossman DA, Corazziari E, Talley NJ. Rome II: The Functional Gastrointestinal Disorders: Diagnosis. Pathophysiology, and Treatment: A multinational Consensus. 2nd ed. McLean,Va: Degnon Associates; 2000;.|
|201.||Doğan UB, Unal S. Kruis scoring system and Manning’s criteria in diagnosis of irritable bowel syndrome: is it better to use combined? Acta Gastroenterol Belg. 1996;59:225-228. [PubMed]|
|202.||Pimentel M, Hwang L, Melmed GY, Low K, Vasiliauskas E, Ippoliti A, Yang J, Lezcano S, Conklin JL, Sahakian A. New clinical method for distinguishing D-IBS from other gastrointestinal conditions causing diarrhea: the LA/IBS diagnostic strategy. Dig Dis Sci. 2010;55:145-149. [PubMed]|
|203.||Tytgat G. Foreword II. The Functional Gastrointestinal Disorders. 2nd ed. McLean, VA: Degnon Associates, Inc; 2006;pp. xxiii-xxv.|
|204.||Halpert AD. Importance of early diagnosis in patients with irritable bowel syndrome. Postgrad Med. 2010;122:102-111. [PubMed] [DOI]|
|205.||Ilnyckyj A, Graff LA, Blanchard JF, Bernstein CN. Therapeutic value of a gastroenterology consultation in irritable bowel syndrome. Aliment Pharmacol Ther. 2003;17:871-880. [PubMed]|
|206.||Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE, Kirsch I, Schyner RN, Nam BH, Nguyen LT. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008;336:999-1003. [PubMed] [DOI]|
|207.||Spiegel BM, Gralnek IM, Bolus R, Chang L, Dulai GS, Naliboff B, Mayer EA. Is a negative colonoscopy associated with reassurance or improved health-related quality of life in irritable bowel syndrome? Gastrointest Endosc. 2005;62:892-899. [PubMed]|
|208.||Goff BA, Mandel LS, Melancon CH, Muntz HG. Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA. 2004;291:2705-2712. [PubMed]|
|209.||Minderhoud IM, Oldenburg B, Wismeijer JA, van Berge Henegouwen GP, Smout AJ. IBS-like symptoms in patients with inflammatory bowel disease in remission; relationships with quality of life and coping behavior. Dig Dis Sci. 2004;49:469-474. [PubMed]|
|210.||Farrokhyar F, Marshall JK, Easterbrook B, Irvine EJ. Functional gastrointestinal disorders and mood disorders in patients with inactive inflammatory bowel disease: prevalence and impact on health. Inflamm Bowel Dis. 2006;12:38-46. [PubMed]|
|211.||Fernández-Bañares F, Rosinach M, Esteve M, Forné M, Espinós JC, Maria Viver J. Sugar malabsorption in functional abdominal bloating: a pilot study on the long-term effect of dietary treatment. Clin Nutr. 2006;25:824-831. [PubMed]|
|212.||Cash BD, Schoenfeld P, Chey WD. The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review. Am J Gastroenterol. 2002;97:2812-2819. [PubMed]|
|213.||Spiegel BM, DeRosa VP, Gralnek IM, Wang V, Dulai GS. Testing for celiac sprue in irritable bowel syndrome with predominant diarrhea: a cost-effectiveness analysis. Gastroenterology. 2004;126:1721-1732. [PubMed]|
|214.||Grazioli B, Matera G, Laratta C, Schipani G, Guarnieri G, Spiniello E, Imeneo M, Amorosi A, Focà A, Luzza F. Giardia lamblia infection in patients with irritable bowel syndrome and dyspepsia: a prospective study. World J Gastroenterol. 2006;12:1941-1944. [PubMed]|
|215.||Habba SF. Chronic diarrhea: identifying a new syndrome. Am J Gastroenterol. 2000;95:2140-2141. [PubMed]|
|216.||Cash BD, Rubenstein JH, Young PE, Gentry A, Nojkov B, Lee D, Andrews AH, Dobhan R, Chey WD. The prevalence of celiac disease among patients with nonconstipated irritable bowel syndrome is similar to controls. Gastroenterology. 2011;141:1187-1193. [PubMed] [DOI]|
|217.||Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Ward AM, McAlindon ME, Lobo AJ. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet. 2001;358:1504-1508. [PubMed]|
|218.||Zipser RD, Patel S, Yahya KZ, Baisch DW, Monarch E. Presentations of adult celiac disease in a nationwide patient support group. Dig Dis Sci. 2003;48:761-764. [PubMed]|
|219.||Whitehead WE, Palsson OS, Feld AD, Levy RL, VON Korff M, Turner MJ, Drossman DA. Utility of red flag symptom exclusions in the diagnosis of irritable bowel syndrome. Aliment Pharmacol Ther. 2006;24:137-146. [PubMed]|
|220.||Quigley EM, Abu-Shanab A. Small intestinal bacterial overgrowth. Infect Dis Clin North Am. 2010;24:943-59, viii-ix. [PubMed] [DOI]|
|221.||Bratten JR, Spanier J, Jones MP. Lactulose breath testing does not discriminate patients with irritable bowel syndrome from healthy controls. Am J Gastroenterol. 2008;103:958-963. [PubMed] [DOI]|
|222.||Rana SV, Sharma S, Kaur J, Sinha SK, Singh K. Comparison of lactulose and glucose breath test for diagnosis of small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Digestion. 2012;85:243-247. [PubMed] [DOI]|
|223.||O’Connor OJ, McSweeney SE, McWilliams S, O’Neill S, Shanahan F, Quigley EM, Maher MM. Role of radiologic imaging in irritable bowel syndrome: evidence-based review. Radiology. 2012;262:485-494. [PubMed] [DOI]|
|224.||Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:1582-191; quiz 1581, 1592. [PubMed] [DOI]|
|225.||Limsui D, Pardi DS, Camilleri M, Loftus EV, Kammer PP, Tremaine WJ, Sandborn WJ. Symptomatic overlap between irritable bowel syndrome and microscopic colitis. Inflamm Bowel Dis. 2007;13:175-181. [PubMed]|
|226.||Tillisch K, Labus JS, Naliboff BD, Bolus R, Shetzline M, Mayer EA, Chang L. Characterization of the alternating bowel habit subtype in patients with irritable bowel syndrome. Am J Gastroenterol. 2005;100:896-904. [PubMed]|
|227.||Camilleri M. Scintigraphic biomarkers for colonic dysmotility. Clin Pharmacol Ther. 2010;87:748-753. [PubMed] [DOI]|
|228.||El-Salhy M. Irritable bowel syndrome: diagnosis and pathogenesis. World J Gastroenterol. 2012;18:5151-5163. [PubMed] [DOI]|
|229.||Langhorst J, Elsenbruch S, Koelzer J, Rueffer A, Michalsen A, Dobos GJ. Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices. Am J Gastroenterol. 2008;103:162-169. [PubMed]|
|230.||Sidhu R, Wilson P, Wright A, Yau CW, D’Cruz FA, Foye L, Morley S, Lobo AJ, McAlindon ME, Sanders DS. Faecal lactoferrin--a novel test to differentiate between the irritable and inflamed bowel? Aliment Pharmacol Ther. 2010;31:1365-1370. [PubMed] [DOI]|
|231.||Fine KD, Ogunji F, George J, Niehaus MD, Guerrant RL. Utility of a rapid fecal latex agglutination test detecting the neutrophil protein, lactoferrin, for diagnosing inflammatory causes of chronic diarrhea. Am J Gastroenterol. 1998;93:1300-1305. [PubMed]|
|232.||Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636-645. [PubMed]|
|233.||Reme SE, Kennedy T, Jones R, Darnley S, Chalder T. Predictors of treatment outcome after cognitive behavior therapy and antispasmodic treatment for patients with irritable bowel syndrome in primary care. J Psychosom Res. 2010;68:385-388. [PubMed] [DOI]|
|234.||Robinson A, O’Neill S, Kiernan A, O’Donoghue N, Moran N. Bacitracin reveals a role for multiple thiol isomerases in platelet function. Br J Haematol. 2006;132:339-348. [PubMed]|
|235.||Kennedy T, Jones R, Darnley S, Seed P, Wessely S, Chalder T. Cognitive behaviour therapy in addition to antispasmodic treatment for irritable bowel syndrome in primary care: randomised controlled trial. BMJ. 2005;331:435. [PubMed]|
|236.||Talley NJ, Owen BK, Boyce P, Paterson K. Psychological treatments for irritable bowel syndrome: a critique of controlled treatment trials. Am J Gastroenterol. 1996;91:277-283. [PubMed]|
|237.||Moser G, Trägner S, Gajowniczek EE, Mikulits A, Michalski M, Kazemi-Shirazi L, Kulnigg-Dabsch S, Führer M, Ponocny-Seliger E, Dejaco C. Long-term success of GUT-directed group hypnosis for patients with refractory irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol. 2013;108:602-609. [PubMed] [DOI]|
|238.||Taneja I, Deepak KK, Poojary G, Acharya IN, Pandey RM, Sharma MP. Yogic versus conventional treatment in diarrhea-predominant irritable bowel syndrome: a randomized control study. Appl Psychophysiol Biofeedback. 2004;29:19-33. [PubMed]|
|239.||Tovey P. A single-blind trial of reflexology for irritable bowel syndrome. Br J Gen Pract. 2002;52:19-23. [PubMed]|
|240.||Spanier JA, Howden CW, Jones MP. A systematic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med. 2003;163:265-274. [PubMed]|
|241.||Hundscheid HW, Pepels MJ, Engels LG, Loffeld RJ. Treatment of irritable bowel syndrome with osteopathy: results of a randomized controlled pilot study. J Gastroenterol Hepatol. 2007;22:1394-1398. [PubMed]|
|242.||Manheimer E, Cheng K, Wieland LS, Min LS, Shen X, Berman BM, Lao L. Acupuncture for treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2012;5:CD005111. [PubMed] [DOI]|
|243.||Patel SM, Stason WB, Legedza A, Ock SM, Kaptchuk TJ, Conboy L, Canenguez K, Park JK, Kelly E, Jacobson E. The placebo effect in irritable bowel syndrome trials: a meta-analysis. Neurogastroenterol Motil. 2005;17:332-340. [PubMed]|
|244.||Pitz M, Cheang M, Bernstein CN. Defining the predictors of the placebo response in irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:237-247. [PubMed]|
|245.||Poynard T, Regimbeau C, Benhamou Y. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2001;15:355-361. [PubMed]|
|246.||Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi P. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58:367-378. [PubMed] [DOI]|
|247.||Ladabaum U, Sharabidze A, Levin TR, Zhao WK, Chung E, Bacchetti P, Jin C, Grimes B, Pepin CJ. Citalopram provides little or no benefit in nondepressed patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2010;8:42-48.e1. [PubMed] [DOI]|
|248.||Rahimi R, Nikfar S, Rezaie A, Abdollahi M. Efficacy of tricyclic antidepressants in irritable bowel syndrome: a meta-analysis. World J Gastroenterol. 2009;15:1548-1553. [PubMed]|
|249.||Bahar RJ, Collins BS, Steinmetz B, Ament ME. Double-blind placebo-controlled trial of amitriptyline for the treatment of irritable bowel syndrome in adolescents. J Pediatr. 2008;152:685-689. [PubMed] [DOI]|
|250.||Brandt LJ, Bjorkman D, Fennerty MB, Locke GR, Olden K, Peterson W, Quigley E, Schoenfeld P, Schuster M, Talley N. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002;97:S7-26. [PubMed]|
|251.||Zuckerman MJ. The role of fiber in the treatment of irritable bowel syndrome: therapeutic recommendations. J Clin Gastroenterol. 2006;40:104-108. [PubMed]|
|252.||Ford AC, Talley NJ, Spiegel BM, Foxx-Orenstein AE, Schiller L, Quigley EM, Moayyedi P. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ. 2008;337:a2313. [PubMed] [DOI]|
|253.||Drossman DA, Chey WD, Johanson JF, Fass R, Scott C, Panas R, Ueno R. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome--results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther. 2009;29:329-341. [PubMed] [DOI]|
|254.||Ford AC, Brandt LJ, Young C, Chey WD, Foxx-Orenstein AE, Moayyedi P. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2009;104:1831-143; quiz 1844. [PubMed] [DOI]|
|255.||Andresen V, Montori VM, Keller J, West CP, Layer P, Camilleri M. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2008;6:545-555. [PubMed] [DOI]|
|256.||Tack J, van Outryve M, Beyens G, Kerstens R, Vandeplassche L. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut. 2009;58:357-365. [PubMed] [DOI]|
|257.||Tack J, Talley NJ. Functional dyspepsia--symptoms, definitions and validity of the Rome III criteria. Nat Rev Gastroenterol Hepatol. 2013;10:134-141. [PubMed] [DOI]|
|258.||Quigley EM, Vandeplassche L, Kerstens R, Ausma J. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation--a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2009;29:315-328. [PubMed] [DOI]|
|259.||Jones BW, Moore DJ, Robinson SM, Song F. A systematic review of tegaserod for the treatment of irritable bowel syndrome. J Clin Pharm Ther. 2002;27:343-352. [PubMed]|
|260.||Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, Shi K, MacDougall JE, Shao JZ, Eng P. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107:1714-124; quiz p.1725. [PubMed]|
|261.||Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, MacDougall JE, Jia XD, Shao JZ, Fitch DA. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107:1702-1712. [PubMed]|
|262.||Efskind PS, Bernklev T, Vatn MH. A double-blind placebo-controlled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol. 1996;31:463-468. [PubMed]|
|263.||Lavö B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel syndrome--a double-blind placebo controlled study. Scand J Gastroenterol Suppl. 1987;130:77-80. [PubMed]|
|264.||Zighelboim J, Talley NJ, Phillips SF, Harmsen WS, Zinsmeister AR. Visceral perception in irritable bowel syndrome. Rectal and gastric responses to distension and serotonin type 3 antagonism. Dig Dis Sci. 1995;40:819-827. [PubMed]|
|265.||Andresen V, Pise-Masison CA, Sinha-Datta U, Bellon M, Valeri V, Washington Parks R, Cecchinato V, Fukumoto R, Nicot C, Franchini G. Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles. Blood. 2011;118:1549-1559. [PubMed] [DOI]|
|266.||Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131. [PubMed]|
|267.||Brandt LJ. Ismar Boas: father of gastroenterology and founder of the oldest surviving publication in digestive diseases. Am J Gastroenterol. 2011;106:171-172. [PubMed] [DOI]|
|268.||Francis CY, Whorwell PJ. Bran and irritable bowel syndrome: time for reappraisal. Lancet. 1994;344:39-40. [PubMed]|
|269.||Sharara AI, Aoun E, Abdul-Baki H, Mounzer R, Sidani S, Elhajj I. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol. 2006;101:326-333. [PubMed]|
|270.||Menees SB, Maneerattannaporn M, Kim HM, Chey WD. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2012;107:28-35; quiz 36. [PubMed]|
|271.||Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364:22-32. [PubMed] [DOI]|
|272.||Dinan TG, Cryan JF. Melancholic microbes: a link between gut microbiota and depression? Neurogastroenterol Motil. 2013;25:713-719. [PubMed] [DOI]|