Novel Irritable Bowel Syndrome Subgroups are Reproducible in the Global Adult Population.

BACKGROUND & AIMS: Current classification systems for irritable bowel syndrome (IBS) based on bowel habit do not consider psychological impact. We validated a classification model in a UK population with confirmed IBS, using latent class analysis, incorporating psychological factors. We applied this model in the Rome Foundation Global Epidemiological Survey (RFGES), assessing impact of IBS on the individual and the healthcare system, as well as examining reproducibility. METHODS: We applied our model to 2195 individuals in the RFGES with Rome IV-defined IBS. As described previously, we identified seven clusters, based on gastrointestinal symptom severity and psychological burden. We assessed demographics, healthcare-seeking, symptom severity, and quality of life in each. We also used the RFGES to derive a new model, examining whether the broader concepts of our original model were replicated, in terms of breakdown and characteristics of identified clusters. RESULTS: All seven clusters were identified. Those in clusters with highest psychological burden, and particularly cluster 6 with high overall gastrointestinal symptom severity, were more often female, exhibited higher levels of healthcare-seeking, were more likely to have undergone previous abdominal surgeries, and had higher symptom severity and lower quality of life (p<0.001 for trend for all). When deriving a new model, the best solution consisted of 10 clusters, although at least two appeared to be duplicates, and almost all mapped on to the previous clusters. CONCLUSIONS: Even in the community, our original clusters derived from patients with physician-confirmed IBS identified groups of individuals with significantly higher rates of healthcare-seeking and abdominal surgery, more severe symptoms, and impairments in quality of life.

British Society of Gastroenterology guidelines on the management of functional dyspepsia.

Functional dyspepsia (FD) is a common disorder of gut-brain interaction, affecting approximately 7% of individuals in the community, with most patients managed in primary care. The last British Society of Gastroenterology (BSG) guideline for the management of dyspepsia was published in 1996. In the interim, substantial advances have been made in understanding the complex pathophysiology of FD, and there has been a considerable amount of new evidence published concerning its diagnosis and classification, with the advent of the Rome IV criteria, and management. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based diagnosis and treatment of patients. The approach to investigating the patient presenting with dyspepsia is discussed, and efficacy of drugs in FD summarised based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of pairwise and network meta-analyses. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system. These provide both the strength of the recommendations and the overall quality of evidence. Finally, in this guideline, we consider novel treatments that are in development, as well as highlighting areas of unmet need and priorities for future research.

Natural History and Disease Impact of Rome IV Vs Rome III Irritable Bowel Syndrome: A Longitudinal Follow-Up Study.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a chronic functional bowel disorder diagnosed using the Rome criteria, which have evolved since their original description 30 years ago. Little is known about the effects on the natural history of IBS of moving to the latest iteration, Rome IV, from the previous Rome III criteria. We conducted a 12-month longitudinal follow-up study to examine this. METHODS: We collected complete demographic, symptom, mood, and psychological health data at baseline from 1097 adults who self-identified as having IBS and met either Rome IV or Rome III criteria. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, treatments commenced, and psychological health. We examined whether subsequent disease behavior in Rome IV- or Rome III-defined IBS differed. RESULTS: At 12 months, 638 (58.2%) of the 1097 participants were followed up successfully. Of these, 452 met Rome IV criteria and 186 met Rome III criteria at baseline. During the 12-month study period, individuals with Rome IV IBS were significantly more likely to have seen a primary care physician (44.7% vs 28.5%; P < .001) or a gastroenterologist (26.3% vs 12.4%; P < .001) for their IBS symptoms, were significantly more likely to have commenced a new treatment (73.0% vs 60.2%; P = .001), and cycled through significantly more treatments (P = .007), for their IBS compared with those with Rome III IBS. At follow-up evaluation, individuals with Rome IV IBS had more severe symptoms, which had a significantly greater impact on activities of daily living, were more likely to report continuous abdominal pain, and a higher proportion showed poor psychological health, compared with those with Rome III IBS (P < .001 for all analyses). CONCLUSIONS: The natural history of IBS defined according to Rome IV criteria is more severe than that of Rome III-defined IBS. This has important implications for future treatment trials in IBS.

Overlap of Rome IV Irritable Bowel Syndrome and Functional Dyspepsia and Effect on Natural History: A Longitudinal Follow-Up Study.

OBJECTIVES: Disorders of gut-brain interaction, such as irritable bowel syndrome (IBS) and functional dyspepsia (FD), frequently overlap, but the impact of this on the natural history is unknown. We examined this issue in a longitudinal follow-up study conducted in a large cohort of individuals. METHODS: We collected complete demographic, symptom, mood, and psychological health data from 1374 adults who self-identified as having IBS. We applied the Rome IV criteria to examine what proportion met criteria for IBS and FD, as well as the degree of overlap between them. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, treatments commenced, and psychological health according to degree of overlap between IBS and FD. RESULTS: Overall, 807 individuals met the Rome IV criteria for IBS at baseline and provided complete data. At study entry, overlap of FD occurred in 446 (55.3%) people who met Rome IV criteria for IBS. At 12 months, 451 (55.9%) individuals were successfully followed up. The proportion of individuals consulting their primary care physician (P = .001) or a gastroenterologist (P < .001) because of their IBS was significantly higher in those with overlap of IBS and FD, and the number of new IBS treatments commenced was significantly higher (P = .007). Those with overlap of IBS and FD reported significantly more severe IBS symptoms (P < .001), continuous abdominal pain, and that their IBS symptoms limited normal daily activities ≥50% of the time. Finally, those with overlap were more likely to report abnormal anxiety and depression scores at 12 months compared with those with IBS alone, and to have higher levels of somatization (P < .001 for all analyses). CONCLUSIONS: The natural history of people with IBS with overlap FD defined according to Rome IV criteria is more severe than those with IBS alone. This has important implications for future treatment trials in IBS.

High-Dimensional Clustering of 4000 Irritable Bowel Syndrome Patients Reveals Seven Distinct Disease Subsets.

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is a pain disorder classified by bowel habits, disregarding other factors that may influence the clinical course. The aim of this study was to determine if IBS patients can be clustered based on clinical, dietary, lifestyle, and psychosocial factors. METHODS: Between 2013 and 2020, the Mayo Clinic Biobank surveyed and received 40,291 responses to a questionnaire incorporating Rome III criteria. Factors associated with IBS were determined and latent class analysis, a model-based clustering, was performed on IBS cases. RESULTS: We identified 4021 IBS patients (mean 64 years; 75% women) and 12,063 controls. Using 26 variables separating cases from controls, the optimal clustering revealed 7 latent clusters. These were characterized by perceived health impairment (moderate or severe), psychoneurological factors, and bowel dysfunction (diarrhea or constipation predominance). Health impairment clusters demonstrated more pain, with the severe cluster also having more psychiatric comorbidities. The next 3 clusters had unique enrichment of psychiatric, neurological, or both comorbidities. The bowel dysfunction clusters demonstrated less abdominal pain, with diarrhea cluster most likely to report pain improvement with defecation. The constipation cluster had the highest exercise score and consumption of fruits, vegetables, and alcohol. The distribution of clusters remained similar when Rome IV criteria were applied. Physiologic tests were available on a limited subset (6%), and there were no significant differences between clusters. CONCLUSIONS: In this cohort of older IBS patients, 7 distinct clusters were identified demonstrating varying degrees of gastrointestinal symptoms, comorbidities, dietary, and lifestyle factors. Further research is required to assess whether these unique clusters could be used to direct clinical trials and individualize patient management.

British Society of Gastroenterology guidelines on the management of irritable bowel syndrome.

Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

Symptom Stability in Rome IV vs Rome III Irritable Bowel Syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS) is a chronic functional bowel disorder, which follows a relapsing and remitting course. Little is known about how evolving definitions of IBS or treatment for the condition affect symptom stability. We conducted a 12-month longitudinal follow-up study of individuals who self-identified as having IBS to examine these issues. METHODS: We collected demographic, gastrointestinal symptom, mood, and psychological health data at baseline, and gastrointestinal symptom data at 12 months, from adults who self-identified as having IBS, registered with 3 organizations providing services to people with IBS. We applied the Rome III and Rome IV criteria simultaneously at baseline and 12 months and subtyped participants according to predominant stool form or frequency. We examined stability of a diagnosis of IBS, and stability of IBS subtype, for the Rome IV and III criteria separately and examined the effect of commencing new therapy on fluctuation of symptoms. RESULTS: Of 1,375 individuals recruited at baseline, 784 (57.0%) provided data at 12 months. Of these, 452 met the Rome IV criteria for IBS at baseline, of whom 133 (29.4%) fluctuated to another functional bowel disorder at 12 months. In the remaining 319 (70.6%) who still met the Rome IV criteria for IBS, IBS subtype changed in 101 (31.7%) subjects, with IBS with mixed bowel habit (IBS-M) the least stable. Commencing a new treatment for IBS did not affect symptom stability. Among 631 who met the Rome III criteria at baseline responding at 12 months, 104 (16.5%) fluctuated to another functional bowel disorder. In the 527 (83.5%) who still met the Rome III criteria for IBS, IBS subtype fluctuated in 129 (24.5%), with IBS-M the most stable subtype. Again, commencing a new treatment for IBS did not affect symptom stability. DISCUSSION: Fluctuation between functional bowel disorders and predominant stool subtype is common in people with IBS and does not appear to be influenced solely by treatment. Rome IV IBS appears less stable than Rome III IBS.

A Novel Method to Classify and Subgroup Patients With IBS Based on Gastrointestinal Symptoms and Psychological Profiles.

INTRODUCTION: Conventionally, patients with irritable bowel syndrome (IBS) are subgrouped based on their predominant bowel habit. Given the relevance of psychological comorbidity to IBS symptoms, our aim was to explore an alternative approach to subgrouping by incorporating factors beyond stool form and frequency. METHODS: We collected demographic, symptom, and psychological health data from 1,375 adult subjects in the community who self-identified as having IBS, identifying 2 cohorts meeting either Rome III or Rome IV criteria. In each cohort, we performed latent class analysis, a method of model-based clustering, to identify specific subgroups (clusters). For each cluster, we drew a radar plot and compared these by visual inspection, describing cluster characteristics. RESULTS: In total, 1,080 individuals met the Rome III criteria for IBS, and 811 met the Rome IV criteria. In both cohorts, a 7-cluster model was the optimum solution, and the characteristics of the clusters were almost identical between Rome III and IV. Four clusters were defined by the pattern of gastrointestinal symptoms (loose stools and urgency or hard stools and bloating), further differentiated by the presence of abdominal pain not relieved by defecation, and by the extent of psychological comorbidity. Two clusters had below-average gastrointestinal symptoms, differentiated by the extent of psychological comorbidity. The final cluster had well-above-average gastrointestinal symptoms and high levels of psychological comorbidity. The proportion of subjects with severe IBS symptom scores, high levels of perceived stress, and high levels of gastrointestinal symptom-specific anxiety was significantly higher in clusters with high psychological comorbidity (P < 0.001). DISCUSSION: Latent class analysis identified 7 distinct IBS subgroups characterized by varying degrees of gastrointestinal symptoms, extraintestinal symptoms, and psychological comorbidity. Further research is needed to assess whether they might be used to direct treatment.

Impact of Psychological Comorbidity on the Prognosis of Irritable Bowel Syndrome.

INTRODUCTION: Psychological comorbidities are associated with irritable bowel syndrome (IBS), but little is known about their cumulative effect on its prognosis. We examined this issue in a longitudinal 12-month follow-up study. METHODS: We collected complete demographic, symptom, and psychological comorbidity data (anxiety, depression, somatic symptom disorder, perceived stress, and gastrointestinal symptom-specific anxiety) at baseline from 807 adults who met Rome IV criteria for IBS. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, and treatments commenced from 452 individuals successfully followed up. We examined the cumulative effects of psychological comorbidities at baseline on subsequent IBS disease behavior. RESULTS: At baseline, among the 807 participants, 177 (21.9%) had 1, 139 (17.2%) 2, 103 (12.8%) 3, 89 (11.0%) 4, and 54 (6.7%) 5 psychological comorbidities. IBS symptom severity at baseline increased significantly with the number of psychological comorbidities (72.2% of those with 5 psychological comorbidities reported severe symptoms, vs 29.1% of those with none, P < 0.001). Among 452 (56.0%) participants followed up at 12 months, those with a higher number of psychological comorbidities at baseline were significantly more likely to have seen a gastroenterologist (33.3% of those with 5 psychological comorbidities, vs 21.4% of those with none, P = 0.001), cycle through more treatments (P < 0.0001), to report more severe IBS symptoms (66.7% with 5, vs 24.4% with none, P < 0.001) and continuous abdominal pain (22.1% with none, vs 61.9% with 5, P < 0.001), and to report that symptoms impacted on daily activities ≥50% of the time (90.5% with 5, vs 41.2% with none, P < 0.001). DISCUSSION: The prognosis of individuals with Rome IV-defined IBS worsens according to incremental increases in psychological comorbidity. This has important clinical and research implications.

The Perils and Pitfalls of Esophageal Dysmotility in Idiopathic Pulmonary Fibrosis.

INTRODUCTION: Gastroesophageal reflux plays a significant role in idiopathic pulmonary fibrosis (IPF). Given the morbidity and mortality associated with IPF, understanding the mechanisms responsible for reflux is essential if patients are to receive optimal treatment and management, especially given the lack of clear benefit of antireflux therapies. Our aim was to understand the inter-relationships between esophageal motility, lung mechanics and reflux (particularly proximal reflux-a prerequisite of aspiration), and pulmonary function in patients with IPF. METHODS: We prospectively recruited 35 patients with IPF (aged 53-75 years; 27 men) who underwent high-resolution impedance manometry and 24-hour pH-impedance, together with pulmonary function assessment. RESULTS: Twenty-two patients (63%) exhibited dysmotility, 16 (73%) exhibited ineffective esophageal motility (IEM), and 6 (27%) exhibited esophagogastric junction outflow obstruction. Patients with IEM had more severe pulmonary disease (% forced vital capacity: P = 0.032) and more proximal reflux (P = 0.074) than patients with normal motility. In patients with IEM, intrathoracic pressure inversely correlated with the number of proximal events (r = -0.429; P = 0.098). Surprisingly, inspiratory lower esophageal sphincter pressure (LESP) positively correlated with the percentage of reflux events reaching the proximal esophagus (r = 0.583; P = 0.018), whereas in patients with normal motility, it inversely correlated with the bolus exposure time (r = -0.478; P = 0.098) and number of proximal events (r = -0.542; P = 0.056). % forced vital capacity in patients with IEM inversely correlated with the percentage of reflux events reaching the proximal esophagus (r = -0.520; P = 0.039) and inspiratory LESP (r = -0.477; P = 0.062) and positively correlated with intrathoracic pressure (r = 0.633; P = 0.008). DISCUSSION: We have shown that pulmonary function is worse in patients with IEM which is associated with more proximal reflux events, the latter correlating with lower intrathoracic pressures and higher LESPs.

Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis.

OBJECTIVES: National guidelines for the management of irritable bowel syndrome (IBS) recommend that psychological therapies should be considered, but their relative efficacy is unknown, because there have been few head-to-head trials. We performed a systematic review and network meta-analysis to try to resolve this uncertainty. DESIGN: We searched the medical literature through January 2020 for randomised controlled trials (RCTs) assessing efficacy of psychological therapies for adults with IBS, compared with each other, or a control intervention. Trials reported a dichotomous assessment of symptom status after completion of therapy. We pooled data using a random effects model. Efficacy was reported as a pooled relative risk (RR) of remaining symptomatic, with a 95% CI to summarise efficacy of each comparison tested, and ranked by therapy according to P score. RESULTS: We identified 41 eligible RCTs, containing 4072 participants. After completion of therapy, the psychological interventions with the largest numbers of trials, and patients recruited, demonstrating efficacy included self-administered or minimal contact cognitive behavioural therapy (CBT) (RR 0.61; 95% CI 0.45 to 0.83, P score 0.66), face-to-face CBT (RR 0.62; 95% CI 0.48 to 0.80, P score 0.65) and gut-directed hypnotherapy (RR 0.67; 95% CI 0.49 to 0.91, P score 0.57). After completion of therapy, among trials recruiting only patients with refractory symptoms, group CBT and gut-directed hypnotherapy were more efficacious than either education and/or support or routine care, and CBT via the telephone, contingency management, CBT via the internet and dynamic psychotherapy were all superior to routine care. Risk of bias of trials was high, with evidence of funnel plot asymmetry; the efficacy of psychological therapies is therefore likely to have been overestimated. CONCLUSIONS: Several psychological therapies are efficacious for IBS, although none were superior to another. CBT-based interventions and gut-directed hypnotherapy had the largest evidence base and were the most efficacious long term. TRIAL REGISTRATION NUMBER: The study protocol was published on the PROSPERO international prospective register of systematic reviews (registration number CRD 42020163246).

Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis.

OBJECTIVE: Over half of patients with IBS have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licenced pharmacological therapies is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. DESIGN: We searched MEDLINE, Embase, Embase Classic, the Cochrane central register of controlled trials, and Clinicaltrials.gov through January 2019 to identify randomised controlled trials (RCTs) assessing the efficacy of licenced pharmacological therapies (alosetron, eluxadoline, ramosetron and rifaximin) in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk with 95% CIs to summarise the effect of each comparison tested. Treatments were ranked according to their p score. RESULTS: We identified 18 eligible RCTs (seven alosetron, five ramosetron, two rifaximin and four eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS. Alosetron 1 mg twice daily was ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms of IBS and effect on stool consistency. Ramosetron 2.5µg once daily was ranked first for effect on abdominal pain. Total numbers of adverse events were significantly greater with alosetron 1 mg twice daily and ramosetron 2.5µg once daily, compared with placebo. Rifaximin 550 mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550 mg three times daily. CONCLUSION: In a network meta-analysis of RCTs of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective.

Epidemiological, Clinical, and Psychological Characteristics of Individuals with Self-reported Irritable Bowel Syndrome Based on the Rome IV vs Rome III Criteria.

OBJECTIVES: Few studies have examined the effects of applying the Rome IV criteria for irritable bowel syndrome (IBS) vs the previous standard, the Rome III criteria. We conducted a cross-sectional survey of individuals who self-identify as having IBS to examine this issue. METHODS: We collected complete demographic, symptom, mood, and psychological health data from 1375 adults who self-identified as having IBS, but were not recruited from a referral population. We applied the Rome III and the Rome IV criteria simultaneously to examine what proportion met each of these diagnostic criteria for IBS. We measured the level of agreement between the Rome III and Rome IV criteria, and assessed for presence of an alternative functional bowel disorder in individuals who no longer met diagnostic criteria for IBS with the more restrictive Rome IV criteria. Finally, we compared characteristics of individuals who met only Rome III criteria with those who met Rome IV criteria. RESULTS: In total, 1080 of 1368 individuals (78.9%) with IBS met the Rome III criteria. In contrast, 811 of 1373 individuals (59.1%) with IBS met the Rome IV criteria. Agreement between the criteria was only moderate (Kappa = 0.50). Among those who no longer had IBS according to the Rome IV criteria, 33 (11.5%) met Rome IV criteria for functional constipation, 118 (41.3%) for functional diarrhea, 68 (23.8%) for functional abdominal bloating or distension, and 67 (23.4%) for an unspecified functional bowel disorder. Individuals with Rome IV-defined IBS had more severe symptoms, and a higher proportion had a mood disorder and evidence of poor psychological health, compared with individuals who only met the Rome III criteria for IBS (P < .001). CONCLUSIONS: The characteristics of people who believe they have IBS differ between those who meet criteria as defined by Rome IV vs Rome III, including the spectrum of disease severity. Studies are needed to determine how these changes will affect outcomes of clinical trials.

Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. METHODS: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score. RESULTS: We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 µg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 µg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 µg twice daily). Nausea was significantly more common in patients who received lubiprostone. CONCLUSIONS: In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.

Unilateral Versus Bilateral Lung Transplantation: Do Different Esophageal Risk Factors Predict Chronic Allograft Failure?

GOALS: To assess the effect of unilateral versus bilateral lung transplantation (LTx) on esophageal motility and gastroesophageal reflux, and the association with the development of obstructive chronic lung allograft dysfunction (o-CLAD). BACKGROUND: We have shown that esophagogastric junction outflow obstruction, incomplete bolus transit, and proximal reflux are all independent risk factors for the development of chronic allograft failure. However, it remains unclear whether these factors are influenced by the type of surgery and how this relates to allograft failure. STUDY: Patients post-LTx (n=48, 24 female; aged 20 to 73 y) completed high-resolution impedance manometry and 24-hour pH/impedance. RESULTS: Patients who had undergone unilateral LTx were more likely to exhibit esophagogastric junction outflow obstruction (47% vs. 18%; P=0.046) and less likely to exhibit hypocontractility (0% vs. 21%; P=0.058) than those who had undergone bilateral LTx. Although the proportion of patients exhibiting gastroesophageal reflux was no different between groups (33% vs. 39%; P=0.505), those undergoing bilateral LTx were more likely to exhibit proximal reflux (8% vs. 37%; P=0.067). Univariate Cox proportion hazards regression analysis did not show a difference between unilateral versus bilateral LTx in the development of o-CLAD (hazard ratio=1.17; 95% confidence interval, 0.48-2.85; P=0.723). CONCLUSION: The type of LTx performed seems to lead to different risk factors for the development of o-CLAD. Physicians should be aware of these differences, as they may need to be taken into account when managing patient's post-LTx.

Fundamentals of Neurogastroenterology: Physiology/Motility - Sensation.

The fundamental gastrointestinal functions include motility, sensation, absorption, secretion, digestion and intestinal barrier function. Digestion of food and absorption of nutrients normally occurs without conscious perception. Symptoms of functional gastrointestinal disorders are often triggered by meal intake suggesting abnormalities in the physiological processes are involved in the generation of symptoms. In this manuscript, normal physiology and pathophysiology of gastrointestinal function, and the processes underlying symptom generation are critically reviewed. The functions of each anatomical region of the digestive tract are summarized. The pathophysiology of perception, motility, mucosal barrier, and secretion in functional gastrointestinal disorders as well as effects of food, meal intake and microbiota on gastrointestinal motility and sensation are discussed. Genetic mechanisms associated with visceral pain and motor functions in health and functional gastrointestinal disorders are reviewed. Understanding the basis for digestive tract functions is essential to understand dysfunctions in the functional gastrointestinal disorders.

Age, Gender and Women's Health and the Patient.

Patients with functional gastrointestinal disorders (FGIDs) often experience distress, reduced quality of life, a perceived lack of validation, and an unsatisfactory experience with health care providers. A health care provider can provide the patient with a framework in which to understand and legitimize their symptoms, remove self-doubt or blame, and identify factors that contribute to symptoms that the patient can influence or control. This framework is implemented with the consideration of important factors that impact FGIDs, such as gender, age, society, and the patient's perspective. Although the majority of FGIDs, including globus, rumination syndrome, IBS, bloating, constipation, functional abdominal pain, sphincter of Oddi dyskinesia, pelvic floor dysfunction, and extra-intestinal manifestations, are more prevalent in women than men, functional chest pain, dyspepsia, vomiting, and anorectal pain do not appear to vary by gender. Studies suggest sex differences in somatic but not visceral pain perception, motility, and central processing of visceral pain; although further research is required in autonomic nervous system dysfunction, genetics and immunologic/microbiome. Gender differences in response to psychological treatments, antidepressants, fiber, probiotics, and anticholinergics have not been adequately studied. However, a greater clinical response to 5-HT3 antagonists but not 5-HT4 agonists has been reported in women compared with men.

Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts.

OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11,326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.