Post-infectious IBS, tropical sprue and small intestinal bacterial overgrowth: the missing link.
Ghoshal Uday C,Gwee Kok-Ann
Nature reviews. Gastroenterology & hepatology
Evidence is emerging that IBS, a hitherto enigmatic disorder thought to be predominantly related to psychological factors, has a microorganic basis in a subset of patients with the disease. Post-infectious IBS (PI-IBS), commonly of the diarrhoea-predominant subtype (defined as new development of IBS following acute infectious diarrhoea), is one such condition known to occur in up to 10-30% individuals after acute gastroenteritis. However, following acute infectious gastroenteritis, patients can also develop post-infectious malabsorption syndrome (PI-MAS), popularly known as tropical sprue. As no study on PI-IBS has rigorously excluded tropical sprue by appropriate investigations, including small intestinal biopsy, the frequency of tropical sprue among patients with PI-IBS is not known. Small intestinal bacterial overgrowth (SIBO) has been suggested to be associated with IBS in general, and in particular diarrhoea-predominant IBS, including PI-IBS. SIBO is also known to be associated with tropical sprue. As both IBS, particularly the subset probably associated with SIBO, and tropical sprue improve with antibiotic treatment, we provide evidence and an explanatory model to support a link among these disorders.
Dietary and pharmacological treatment of abdominal pain in IBS.
Camilleri Michael,Boeckxstaens Guy
This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT receptor antagonists (alosetron, ondansetron, ramosetron), non-absorbed antibiotic (rifaximin), secretagogues (lubiprostone, linaclotide), μ-opioid receptor (OR) and κ-OR agonist, δ-OR antagonist (eluxadoline), histamine H1 receptor antagonist (ebastine), neurokinin-2 receptor antagonist (ibodutant) and GABAergic agents (gabapentin and pregabalin). Efficacy and safety are discussed based on pivotal trials or published systematic reviews and meta-analysis, expressing ORs or relative risks and their 95% CIs. Potential new approaches may be based on recent insights on mucosal expression of genes, and microRNA and epigenetic markers in human biopsies and in animal models of visceral hypersensitivity.The objectives of this review are to appraise the physiology and anatomy of gut sensation and the efficacy in the relief of visceral pain (typically in IBS) of several classes of therapies. These include fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and different classes of medications (box 1). Box 1Classes of pharmacological agents for visceral painAntidepressants (tricyclic agents, selective serotonin reuptake inhibitors)Peppermint oil5-HT receptor antagonists (alosetron, ondansetron, ramosetron)Non-absorbed antibiotic (rifaximin)Secretagogues (lubiprostone, linaclotide)μ-Opioid receptor (OR) and κ-OR agonist and δ-OR antagonist (eluxadoline)Histamine H1 receptor antagonist (ebastine)Neurokinin-2 receptor antagonist (ibodutant)GABAergic agents (gabapentin and pregabalin).
The influence of the brain-gut axis in inflammatory bowel disease and possible implications for treatment.
Gracie David J,Hamlin P John,Ford Alexander C
The lancet. Gastroenterology & hepatology
Brain-gut interactions affect psychological wellbeing and symptom reporting in functional gastrointestinal disorders; the presence of anxiety or depression is associated with the development of new-onset gastrointestinal symptoms, and the presence of gastrointestinal symptoms is associated with the development of psychological disorders de novo. In inflammatory bowel diseases (IBD), the reporting of irritable bowel syndrome (IBS)-type symptoms by patients with quiescent disease is common, and is associated with psychological disorders, impaired quality of life, and increased health-care use. In IBD, data from observational studies suggest that psychological disorders might be associated with relapse of disease activity, and that inflammatory activity is associated with the development of new psychological disorders, as has been described for functional gastrointestinal disorders such as IBS and functional dyspepsia. The brain-gut axis provides the physiological link between the CNS and gastrointestinal tract that might facilitate these relationships. In IBS, treatments targeting disordered brain-gut axis activity, including psychological therapies and antidepressants, might lead to improved symptoms and quality of life. However, in IBD, the benefit of these treatments is less certain because of a scarcity of interventional studies. Despite the scarcity of trials, observational data suggest that the effect of disordered brain-gut axis activity in IBD is substantial, and scope remains for further well designed trials of psychological therapies and antidepressants, particularly in the subset of patients who have coexistent psychological disorders, or in those who report IBS-type symptoms. Integrating these treatments into a biopsychosocial model of care has the potential to improve both psychological wellbeing and quality of life in some patients with IBD, reducing health-care use and altering the natural history of disease.
IBS and IBD - separate entities or on a spectrum?
Spiller Robin,Major Giles
Nature reviews. Gastroenterology & hepatology
The acute phase of IBD with inflamed gut and often ulcerated mucosa is clearly different from the apparently normal mucosa characteristic of IBS. However, more detailed assessment has detected immune activation, increased gut permeability, increased mucosal serotonin availability, abnormalities of enteric nerve structure and function, and dysbiosis in gut microbiota in IBS - all features seen in IBD. Furthermore, as treatments for inflammation in IBD have become more effective it is now apparent that ∼1 in 3 patients with IBD in remission from inflammation still have persistent abnormalities of sensation, motility and gut microbiota, which might cause IBS-like symptoms. This Perspective explores the overlap between IBS and IBD and their treatments, proposing future directions for research in this stimulating area.
New advances in the treatment of paediatric functional abdominal pain disorders.
Santucci Neha R,Saps Miguel,van Tilburg Miranda A
The lancet. Gastroenterology & hepatology
This Review summarises recent pharmacological and upcoming alternative interventions for children with functional abdominal pain disorders (FAPDs). Pharmacological targets include prokinetics and drugs affecting gastric accommodation to treat postprandial distress and nausea. Similarly, anti-inflammatory agents, junctional protein regulators, analgesics, secretagogues, and serotonin antagonists have a therapeutic role for irritable bowel syndrome. Non-pharmacological treatments include peripheral electrical nerve field stimulation to the external ear, gastric electrical stimulation, dietary interventions such as low fructose and fibre based diets, and nutraceuticals, which include probiotics, prebiotics, and synbiotics. Newer psychological advances such as exposure-based cognitive behavioural therapy, acceptance and commitment therapy, and mindfulness meditation are being investigated for paediatric functional pain. Lastly, alternative therapies such as acupuncture, moxibustion, yoga, and spinal manipulation are also gaining popularity in the treatment of FAPDs.
The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS.
Staudacher Heidi M,Whelan Kevin
There is an intensifying interest in the interaction between diet and the functional GI symptoms experienced in IBS. Recent studies have used MRI to demonstrate that short-chain fermentable carbohydrates increase small intestinal water volume and colonic gas production that, in those with visceral hypersensitivity, induces functional GI symptoms. Dietary restriction of short-chain fermentable carbohydrates (the low fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) diet) is now increasingly used in the clinical setting. Initial research evaluating the efficacy of the low FODMAP diet was limited by retrospective study design and lack of comparator groups, but more recently well-designed clinical trials have been published. There are currently at least 10 randomised controlled trials or randomised comparative trials showing the low FODMAP diet leads to clinical response in 50%-80% of patients with IBS, in particular with improvements in bloating, flatulence, diarrhoea and global symptoms. However, in conjunction with the beneficial clinical impact, recent studies have also demonstrated that the low FODMAP diet leads to profound changes in the microbiota and metabolome, the duration and clinical relevance of which are as yet unknown. This review aims to present recent advances in the understanding of the mechanisms by which the low FODMAP diet impacts on symptoms in IBS, recent evidence for its efficacy, current findings regarding the consequences of the diet on the microbiome and recommendations for areas for future research.
Sensitivity to wheat, gluten and FODMAPs in IBS: facts or fiction?
De Giorgio Roberto,Volta Umberto,Gibson Peter R
IBS is one of the most common types of functional bowel disorder. Increasing attention has been paid to the causative role of food in IBS. Food ingestion precipitates or exacerbates symptoms, such as abdominal pain and bloating in patients with IBS through different hypothesised mechanisms including immune and mast cell activation, mechanoreceptor stimulation and chemosensory activation. Wheat is regarded as one of the most relevant IBS triggers, although which component(s) of this cereal is/are involved remain(s) unknown. Gluten, other wheat proteins, for example, amylase-trypsin inhibitors, and fructans (the latter belonging to fermentable oligo-di-mono-saccharides and polyols (FODMAPs)), have been identified as possible factors for symptom generation/exacerbation. This uncertainty on the true culprit(s) opened a scenario of semantic definitions favoured by the discordant results of double-blind placebo-controlled trials, which have generated various terms ranging from non-coeliac gluten sensitivity to the broader one of non-coeliac wheat or wheat protein sensitivity or, even, FODMAP sensitivity. The role of FODMAPs in eliciting the clinical picture of IBS goes further since these short-chain carbohydrates are found in many other dietary components, including vegetables and fruits. In this review, we assessed current literature in order to unravel whether gluten/wheat/FODMAP sensitivity represent 'facts' and not 'fiction' in IBS symptoms. This knowledge is expected to promote standardisation in dietary strategies (gluten/wheat-free and low FODMAP) as effective measures for the management of IBS symptoms.
The role of mast cells in functional GI disorders.
Wouters Mira M,Vicario Maria,Santos Javier
Functional gastrointestinal disorders (FGIDs) are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. The two most prevalent FGIDs, affecting up to 16-26% of worldwide population, are functional dyspepsia and irritable bowel syndrome. Their etiopathogenic mechanisms remain unclear, however, recent observations reveal low-grade mucosal inflammation and immune activation, in association with impaired epithelial barrier function and aberrant neuronal sensitivity. These findings come to challenge the traditional view of FGIDs as pure functional disorders, and relate the origin to a tangible organic substrate. The mucosal inflammatory infiltrate is dominated by mast cells, eosinophils and intraepithelial lymphocytes in the intestine of FGIDs. It is well established that mast cell activation can generate epithelial and neuro-muscular dysfunction and promote visceral hypersensitivity and altered motility patterns in FGIDs, postoperative ileus, food allergy and inflammatory bowel disease. This review will discuss the role of mucosal mast cells in the gastrointestinal tract with a specific focus on recent advances in disease mechanisms and clinical management in irritable bowel syndrome and functional dyspepsia.
Irritable Bowel Syndrome.
Sultan Shahnaz,Malhotra Ashish
Annals of internal medicine
This issue provides a clinical overview of irritable bowel syndrome, focusing on diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.
Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis.
Klem Fabiane,Wadhwa Akhilesh,Prokop Larry J,Sundt Wendy J,Farrugia Gianrico,Camilleri Michael,Singh Siddharth,Grover Madhusudan
BACKGROUND & AIMS:Foodborne illness affects 15% of the US population each year, and is a risk factor for irritable bowel syndrome (IBS). We evaluated risk of, risk factors for, and outcomes of IBS after infectious enteritis. METHODS:We performed a systematic review of electronic databases from 1994 through August 31, 2015 to identify cohort studies of the prevalence of IBS 3 months or more after infectious enteritis. We used random-effects meta-analysis to calculate the summary point prevalence of IBS after infectious enteritis, as well as relative risk (compared with individuals without infectious enteritis) and host- and enteritis-related risk factors. RESULTS:We identified 45 studies, comprising 21,421 individuals with enteritis, followed for 3 months to 10 years for development of IBS. The pooled prevalence of IBS at 12 months after infectious enteritis was 10.1% (95% confidence interval [CI], 7.2-14.1) and at more than 12 months after infectious enteritis was 14.5% (95% CI, 7.7-25.5). Risk of IBS was 4.2-fold higher in patients who had infectious enteritis in the past 12 months than in those who had not (95% CI, 3.1-5.7); risk of IBS was 2.3-fold higher in individuals who had infectious enteritis more than 12 months ago than in individuals who had not (95% CI, 1.8-3.0). Of patients with enteritis caused by protozoa or parasites, 41.9% developed IBS, and of patients with enteritis caused by bacterial infection, 13.8% developed IBS. Risk of IBS was significantly increased in women (odds ratio [OR], 2.2; 95% CI, 1.6-3.1) and individuals with antibiotic exposure (OR, 1.7; 95% CI, 1.2-2.4), anxiety (OR, 2; 95% CI, 1.3-2.9), depression (OR, 1.5; 95% CI, 1.2-1.9), somatization (OR, 4.1; 95% CI, 2.7-6.0), neuroticism (OR, 3.3; 95% CI, 1.6-6.5), and clinical indicators of enteritis severity. There was a considerable level of heterogeneity among studies. CONCLUSIONS:In a systematic review and meta-analysis, we found >10% of patients with infectious enteritis develop IBS later; risk of IBS was 4-fold higher than in individuals who did not have infectious enteritis, although there was heterogeneity among studies analyzed. Women-particularly those with severe enteritis-are at increased risk for developing IBS, as are individuals with psychological distress and users of antibiotics during the enteritis.
Management of the multiple symptoms of irritable bowel syndrome.
Simrén Magnus,Törnblom Hans,Palsson Olafur S,Whitehead William E
The lancet. Gastroenterology & hepatology
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. A stepwise management approach is advocated for patients with IBS. For a substantial proportion of patients with mild symptoms, general management principles, including making a confident diagnosis and offering explanation, reassurance, and dietary and lifestyle advice, are sufficient. However, many patients continue to have moderate-to-severe symptoms and are not satisfied solely with this approach. In these patients, use of pharmacotherapy on the basis of the predominant symptom (constipation, diarrhoea, pain, or bloating) or combination of symptoms is the next step. For patients with symptoms that are refractory to these initial treatment options and those who have comorbid conditions or psychological symptoms, a combination of therapies should be used, and the use of psychotropic drugs and psychological treatment alternatives is often effective. Finally, the key to successful treatment of patients with IBS is a good physician-patient relationship and use of person-centred care principles.
AGA Technical Review on the Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D).
Carrasco-Labra Alonso,Lytvyn Lyubov,Falck-Ytter Yngve,Surawicz Christina M,Chey William D
BACKGROUND & AIMS:The evaluation of patients with chronic watery diarrhea represents a diagnostic challenge for clinicians because organic causes, including inflammatory bowel disease, microscopic colitis, and chronic infection, must be differentiated from functional diarrhea and diarrhea-predominant irritable bowel syndrome. The purpose of this review is to summarize the available evidence on the usefulness of diagnostic tests in such patients. METHODS:We searched MEDLINE and EMBASE via OVID, from 1978 until April 2017. We included diagnostic test accuracy studies reporting on the use of fecal and blood tests for the evaluation of adult patients with functional diarrhea, including irritable bowel syndrome. We assessed the risk of bias of included studies using a modified version of the Quality Assessment of Diagnostic Accuracy Studies II, and the certainty in the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We calculated pooled sensitivity and specificity, and the proportion of patients with true and false positive and negative results. We evaluated the following tests: erythrocyte sedimentation rate, C-reactive protein, fecal lactoferrin, fecal calprotectin, serologic tests for celiac disease, tests for bile acid diarrhea, the commercially available version of anti-cytolethal distending toxin B and anti-vinculin antibodies, and tests for Giardia infection. We did not evaluate breath tests for small intestinal bacterial overgrowth, as they are not part of a standard diarrhea workup. RESULTS:Thirty-eight studies proved eligible to evaluate 1 or more of these tests. Erythrocyte sedimentation rate and C-reactive protein were similar at discriminating organic from functional disease, with sensitivity and specificity, respectively, of 0.54-0.78 and 0.46-0.95 for erythrocyte sedimentation rate and 0.73 and 0.78 for C-reactive protein. Among fecal tests, fecal calprotectin in a range of 50-60 μg/g (pooled sensitivity 0.81; 95% confidence interval [CI], 0.75-0.86; pooled specificity 0.87; 95% CI, 0.78-0.92) and fecal lactoferrin in a range of 4.0-7.25 μg/g (pooled sensitivity 0.79; 95% CI, 0.73-0.84; pooled specificity 0.93; 95%CI 0.63-0.99) presented the lowest proportion of false-negative results (low certainty in the evidence). Among tests for celiac disease, IgA tissue transglutaminase presented the best diagnostic test accuracy (sensitivity range, 0.79-0.99; specificity range, 0.90-0.99) with moderate certainty in the evidence. Among tests for bile acid diarrhea, the selenium homotaurocholic acid test performed better than serum fibroblast growth factor 19 and 7α-hydroxy-4-cholesten-3-one, but is not available in the United States. There was insufficient evidence to recommend serologic tests for irritable bowel syndrome at this time. There are several good diagnostic tests for Giardia infection. CONCLUSIONS:Moderate to low certainty in the evidence indicates that available fecal and blood tests may play a role in the diagnostic workup of adult patients with functional diarrhea. At the moment, no tests are available to reliably rule in irritable bowel syndrome.
Pathophysiology of irritable bowel syndrome.
Holtmann Gerald J,Ford Alexander C,Talley Nicholas J
The lancet. Gastroenterology & hepatology
Traditionally, irritable bowel syndrome has been considered to be a disorder with no known underlying structural or biochemical explanation, but this concept is likely to be outdated. In this Review we challenge the widely accepted view that irritable bowel syndrome is an unexplained brain-gut disorder. There is epidemiological evidence that, in a major subset of patients, gastrointestinal symptoms arise first and only later do incident mood disorders occur. Additionally, possible mechanisms for gut-brain dysfunction have been identified, suggesting primary gut disturbances might be the underlying cause in a subgroup. Underlying mechanisms that could lead to irritable bowel syndrome include genetic factors (most notably an identified mutation of SCN5A); post-infectious changes, chronic infections and disturbances in the intestinal microbiota; low-grade mucosal inflammation, immune activation, and altered intestinal permeability; disordered bile salt metabolism (in 10-20% of cases with diarrhoea); abnormalities in serotonin metabolism; and alterations in brain function, which could be primary or secondary factors. Identical irritable bowel syndrome symptoms are probably due to different disease processes; grouping patients with this disorder into either diarrhoea-predominant or constipation-predominant subtypes promotes heterogeneity. An approach based on the underlying pathophysiology could help to develop therapies that target causes and ultimately provide a cure for patients with irritable bowel syndrome.