The Natural History of Chronic Unexplained Gastrointestinal Disorders and Gastroesophageal Reflux During 20 Years: A US Population-Based Study.

OBJECTIVE: To explore the natural history of chronic unexplained gastrointestinal (GI) symptoms and to determine the longitudinal trends of prevalence during a 20-year period in a single US community. METHODS: Between January 1, 1990, and December 31, 2009, valid self-report questionnaires of GI symptoms were mailed to randomly selected cohorts of a community. The study used respondents who answered questions on 1 or more of 3 surveys (initial, 1990-1992; second, 2003-2004; and third, 2008-2009). The trends of prevalence of GI symptoms over time were analyzed in responders who completed 3 surveys, and the natural history or transition was evaluated. RESULTS: The overall prevalence of major symptom groupings including gastroesophageal reflux disease was consistent among residents in a community on 3 survey time points (1990-1992, 2003-2004, and 2008-2009). The transitions of GI symptoms were common in 228 patients who responded to all 3 surveys; only 29% had the same symptom category in 3 surveys; otherwise, symptoms changed over time, resolving, recurring, or transitioning to another disorder. Observed proportions of symptom transitions were significantly different from expected during 20 years (P<.001). Higher non-GI somatic symptom scores were significantly associated with both symptom transitions (odds ratio, 3.9; 95% CI, 1.38 to 10.77) and having sustained symptoms (odds ratio, 12.7; 95% CI, 4.62 to 34.90). CONCLUSION: The overall population prevalence of chronic unexplained GI symptoms is stable, but in individuals, transitions seem to be the rule. As these various GI syndromes appear to be so intimately interconnected, the common underlying pathogenesis may account for a major subgroup of chronic unexplained GI disorders.

Survival Times of Patients With Menetrier's Disease and Risk of Gastric Cancer.

BACKGROUND & AIMS: Menetrier's disease is a rare acquired disorder associated with giant gastric folds along with protein-losing enteropathy, low stomach acid, or achlorhydria, and histologic features of massive foveolar hyperplasia. Little is known about the etiology, clinical features, or epidemiology of this disorder, including risk of gastric cancer. We investigated the outcomes and characteristics of patients with Menetrier's disease, including development of gastric cancer and survival times. METHODS: We performed a case-control study of all Menetrier's disease cases (n = 76; mean age, 56 ± 45 y; 59% male; mean body mass index, 24) diagnosed at Mayo Clinic, Rochester, MN, from January 1975 through 2005. Diagnosis of Menetrier's disease was based on a combination of clinical, endoscopic, radiologic, and histologic features. Patients with dyspepsia who underwent gastric biopsy analysis were included as controls. We obtained demographic, clinical history, laboratory, imaging, histopathology, and follow-up data from medical records. Clinical characteristics of Menetrier's disease were analyzed using descriptive statistics. The Kaplan-Meier method was used to estimate overall survival in cases. RESULTS: Clinical features found in a significantly higher proportion of patients with Menetrier's disease than controls included vomiting, abdominal pain, postprandial fullness, and weight loss of 10 lb or more. Smoking was associated with Menetrier's disease (P = .002 vs controls), but not alcohol use. Infection with Helicobacter pylori was not associated with Menetrier's disease (2.6% of patients vs 4.0% of controls; P = 1.00). There was no significant difference between patients with Menetrier's disease vs controls in proportions with inflammatory bowel disease. Gastric cancer developed in 8.9% of patients with Menetrier's disease by 10 years after the Menetrier's disease diagnosis vs 3.7% of controls over the same time period (P = .09). Of patients with Menetrier's disease, 72.7% and 65.0% survived for 5 and 10 years, respectively, compared with 100% of controls (P < .0001 for both time periods). CONCLUSIONS: In a case-control study of 76 patients with Menetrier's disease, we found this rare disorder to be associated with increased mortality. Patients with Menetrier's disease therefore should be followed up with surveillance endoscopy.

SCN5A mutation G615E results in NaV1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity.

SCN5A is expressed in cardiomyocytes and gastrointestinal (GI) smooth muscle cells (SMCs) as the voltage-gated mechanosensitive sodium channel NaV1.5. The influx of Na+ through NaV1.5 produces a fast depolarization in membrane potential, indispensable for electrical excitability in cardiomyocytes and important for electrical slow waves in GI smooth muscle. As such, abnormal NaV1.5 voltage gating or mechanosensitivity may result in channelopathies. SCN5A mutation G615E - found separately in cases of acquired long-QT syndrome, sudden cardiac death, and irritable bowel syndrome - has a relatively minor effect on NaV1.5 voltage gating. The aim of this study was to test whether G615E impacts mechanosensitivity. Mechanosensitivity of wild-type (WT) or G615E-NaV1.5 in HEK-293 cells was examined by shear stress on voltage- or current-clamped whole cells or pressure on macroscopic patches. Unlike WT, voltage-clamped G615E-NaV1.5 showed a loss in shear- and pressure-sensitivity of peak current yet a normal leftward shift in the voltage-dependence of activation. In current-clamp, shear stress led to a significant increase in firing spike frequency with a decrease in firing threshold for WT but not G615E-NaV1.5. Our results show that the G615E mutation leads to functionally abnormal NaV1.5 channels, which cause disruptions in mechanosensitivity and mechano-electrical feedback and suggest a potential contribution to smooth muscle pathophysiology.

Randomised clinical trial: pregabalin vs placebo for irritable bowel syndrome.

BACKGROUND: Pregabalin is a calcium channel α2δ ligand that modifies visceral hypersensitivity in IBS patients. Clinical data for pregabalin in IBS are lacking. AIM: To test the efficacy of pregabalin on gastrointestinal symptoms in IBS patients. METHODS: A double-blind, placebo-controlled trial was performed. Adults meeting IBS Rome III criteria with ≥3 pain attacks per month were randomised to pregabalin 225 mg vs placebo twice daily for 12 weeks. Questionnaires were completed weekly. The primary endpoint was average pain Bowel Symptom Scale (BSS) scores weeks 9-12. An intention-to-treat analysis of covariance evaluated treatment effects on quantitative endpoints, adjusting for age and gender. Adequate relief and change in pain score were assessed using a chi-squared test. RESULTS: Eighty-five patients were recruited and randomised. Sample characteristics include: mean age 39.4 (SD = 14.6); 73 (86%) female; 37 (44%) IBS-D, 29 (35%) IBS-M, 18 (21%) IBS-C. The pregabalin arm had lower average pain-BSS scores weeks 9-12 (25 vs 42, P = 0.008). Compared with placebo, the overall IBS BSS severity score was lower in the pregabalin arm (26 vs 42, P = 0.009). Differences were observed for the diarrhoea-BSS and bloating-BSS scores (P = 0.049 and 0.016, respectively). No differences between groups were seen for constipation-BSS scores. Adequate relief was not different between the two arms (46% vs 36%, P = 0.35). 63% pregabalin vs 45% placebo had a change in pain score ≥30 at week 12 from baseline (P = 0.10). Post-treatment IBS-QoL scores did not differ between groups. CONCLUSION: This trial suggests that pregabalin may be beneficial for IBS abdominal pain, bloating and diarrhoea.

Comparison of Lactase Variant MCM6 -13910 C>T Testing and Self-report of Dairy Sensitivity in Patients With Irritable Bowel Syndrome.

GOALS: To evaluate agreement of MCM6-13910 with self-report of dairy sensitivity (DS) and lactose hydrogen methane breath test (LHMBT) results in subjects with irritable bowel syndrome (IBS). BACKGROUND: IBS is a functional gastrointestinal disorder with symptoms including abdominal pain, variable bowel habits, and bloating. Adult patients with lactose malabsorption may present with similar symptoms. Patients with lactose malabsorption have a lactase nonpersistent (LNP) phenotype. Recent studies found 2 single nucleotide polymorphisms associated with LNP: G/A-22018 and C/T-13910. STUDY: Genotyping the MCM6-13910 variant of LNP in 538 IBS patients and 317 controls (without IBS). Subjects completed questionnaires pertaining to gastrointestinal problems and dietary consumption, with charts abstracted. RESULTS: Self-reported DS was higher in IBS (45%) than controls (9.8%, odds ratio=6.46, P<0.001). The C/C-13910 genotype was similar in IBS cases and controls, 81 (15.1%) and 47 (14.8%). Among subjects reporting DS, 49 (18.0%) had the C/C genotype. Overall agreement between genotype and self-reported DS was 0.06 in IBS and 0.07 in controls. There were 20 subjects with LHMBT results; 3 had positive results, 17 were negative. LNP genotypes were found in all 3 of positive LHMBT results; 16 had negative LHMBT among the 17 who were lactase persistent. Agreement between C/C-13910 genotype and LHMBT was excellent with κ-statistic of 0.83 (0.50-1.00). CONCLUSIONS: In IBS patients, self-report of lactose intolerance are highly prevalent but are a poor indicator of underlying C/C-13910 genotype. LHMBT had excellent agreement with C/C-13910 genotype.

A Systematic Review and Meta-Analysis Evaluating the Efficacy of a Gluten-Free Diet and a Low FODMAPs Diet in Treating Symptoms of Irritable Bowel Syndrome.

OBJECTIVE: Dietary triggers such as gluten and highly fermentable oligo-, di- and monosaccharides and polyols (FODMAP)-containing foods have been associated with worsening irritable bowel syndrome (IBS) symptoms. However, the true impact of dietary restriction on IBS symptoms has remained unclear. The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) examining the efficacy of exclusion diets (we focused on low FODMAP and gluten-free diets (GFD)) in IBS. METHODS: We conducted a search of the literature using the electronic databases MEDLINE (1946 to November 2017), EMBASE (1974 to November 2017), Cochrane Central Register of Controlled Trials (November 2017), and Cochrane Database of Systematic Reviews (2005 to November, 2017) for RCTs of exclusion diets in IBS. Two independent reviewers screened citations and a third reviewer resolved disagreement. Two independent reviewers performed eligibility assessment and data abstraction. For inclusion, RCTs that evaluated an exclusion diet versus an alternative or usual diet and assessed improvement in either global IBS symptoms or abdominal pain were required. Data were synthesized as relative risk of symptoms remaining using a random effects model. Quality of evidence was assessed using GRADE methodology. RESULTS: A total of 1726 citations were identified. After full-text screening a total of nine studies were eligible for the systematic review. There were two RCTs of a GFD, involving 111 participants. Both selected patients who responded to a GFD and then randomized them to continue the diet or have the diet "spiked" with gluten. A GFD was associated with reduced global symptoms compared with a control diet (RR = 0.42; 95% CI 0.11 to 1.55; I2 = 88%), although this was not statistically significant. There were seven RCTs comparing a low FODMAP diet with various control interventions in 397 participants. A low FODMAP diet was associated with reduced global symptoms compared with control interventions (RR = 0.69; 95% CI 0.54 to 0.88; I2 = 25%). The three RCTS that compared low FODMAP diet with rigorous control diets had the least heterogeneity between studies, but also the least magnitude of effect. The overall quality of the data was "very low" according to GRADE criteria. CONCLUSIONS: There is insufficient evidence to recommend a GFD to reduce IBS symptoms. There is very low quality evidence that a low FODMAP diet is effective in reducing symptoms in IBS patients.

Effects of Amitriptyline and Escitalopram on Sleep and Mood in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Tricyclic antidepressants are effective in reducing symptoms of functional dyspepsia (FD). We performed a post hoc analysis of data from a previous randomized clinical trial to determine whether the benefits of an antidepressant on gastrointestinal symptoms in patients with FD were mediated by improving sleep or reducing anxiety. We explored the relationships between psychological measures, quality of sleep, and relief of symptoms. METHODS: We analyzed data from a multicenter, double-blind trial that evaluated the efficacy of antidepressants on symptoms of FD, from October 2006 through October 2012. Patients (n = 292) were randomly assigned to groups given 50 mg amitriptyline, 10 mg escitalopram, or placebo for 12 weeks. During the study, participants completed the following validated psychological questionnaires: Symptom Check List 90, Symptom Somatic Checklist, Hospital Anxiety Depression Scale, Profile of Mood States, State Trait Anxiety Inventory, and Pittsburgh Sleep Quality Index at baseline and 12 weeks following treatment. RESULTS: Baseline scores for the psychological and sleep measures were similar among groups; after 12 weeks there were no significant differences in scores among groups. Baseline mean global Pittsburgh Sleep Quality Index scores indicated poor sleep quality in all groups at baseline and after 12 weeks. Overall, antidepressants affected sleep duration scores: patients given amitriptyline had lower (better) scores than patients given placebo or escitalopram (P = .019). In all groups, responders had decreased anxiety and improvements in some sleep components. CONCLUSIONS: In a post hoc analysis of data from a clinical trial that evaluated the effects of antidepressants in patients with FD, amitriptyline was found to reduce symptoms of FD, but its mechanism is unlikely to involve reductions in psychological distress. The drug may modestly improve sleep. Clinicaltrials.gov no: NCT00248651.

Irritable bowel syndrome patients have SCN5A channelopathies that lead to decreased NaV1.5 current and mechanosensitivity.

The SCN5A-encoded voltage-gated mechanosensitive Na+ channel NaV1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2-3% of patients have SCN5A missense mutations that alter NaV1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered NaV1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function. NEW & NOTEWORTHY The voltage-gated Na+ channel NaV1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the NaV1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant NaV1.5 channels were loss of function in voltage dependence or mechanosensitivity.

Celiac disease is uncommon in irritable bowel syndrome in the USA.

BACKGROUND AND AIMS: Routine serologic testing for celiac disease (CD) may be useful in irritable bowel syndrome (IBS) patients, but this is controversial. We aimed to compare the prevalence of unrecognized CD in a large cohort of patients with and without IBS. PARTICIPANTS AND METHODS: This is a family case-control IBS study conducted at a single US academic medical center. Stored serum and DNA were available. Tissue transglutaminase (TTg) immunoglobulin A was performed, followed by indirect immunofluorescence testing for endomysial antibodies with positive or weakly positive TTg results. Individuals were considered to have CD if both results were positive. χ and Fisher's exact tests were used to compare prevalence between the two groups. RESULTS: Serum samples were studied from 533 cases and 531 controls. In all, 80% of participants were female, with a median age of 50 years; 65% of cases and 0% controls met the Rome criteria for IBS. Previous serological testing for CD had occurred in 142 (27%) cases and 13 (2%) controls, but none had CD on subsequent testing. Six (1.1%) cases versus five (0.9%) controls had positive or weakly positive TTg test. Six cases (1.1%) versus three (0.6%) controls were confirmed to have CD by endomysial antibody (P=0.51). CONCLUSION: No difference in the prevalence of CD between patients with IBS and patients without IBS at a tertiary medical center was observed. Our findings do not support routine celiac serologic or genetic testing in patients with IBS in all US populations.

Early Infections and the Risk of Irritable Bowel Syndrome: A Case-Control Study.

GOALS: The goal of this study is to evaluate the association between early life infections and subsequent adult onset irritable bowel syndrome (IBS). BACKGROUND: Infections during adulthood are a known risk factor for adult-onset IBS. This investigation examined the role of childhood infections and infection risk factors in the development of IBS symptoms. STUDY: In total, 1010 subjects (509 outpatients with IBS, 501 matched controls) were mailed questionnaires regarding early-life infections during infancy (0 to 12 mo), toddler years (1 to 3 y), and child years (4 to 18 y). Comparisons between cases and controls were performed using logistic regression adjusting for age, gender, and somatization score. RESULTS: Around 648 (64.2%) subjects responded. The median age was 51.3 years (range, 18.0 to 70.7 y) and 535 (83%) were female. Childhood (below 18 y) infections were common in cases and controls (98% vs. 98%; P=0.465), with no differences between cases and controls during infant, toddler, and child-age periods. For gastrointestinal infections experienced below 18 years, no differences were observed by infection type (bacterial, viral, or parasitic) or age group. Cases were more likely to report bronchitis by age 18 [43% vs. 25%; P=0.003; odds ratio, 1.73 (1.20-2.51)], but not other common infections. Regular antibiotic exposure was greater amongst cases (43%) than controls (30%) [P=0.09; odds ratio, 1.37 (0.96-1.96)]. The association between bronchitis and IBS case status remained significant after adjusting for antibiotic use (P=0.01). CONCLUSIONS: Greater early childhood gastrointestinal infections rates were not observed in adult individuals with IBS compared with adult controls. The study does not support a statistically significant link between early life infections and IBS aside from bronchitis.

Polymorphisms of 5-HTT LPR and GNß3 825C>T and Response to Antidepressant Treatment in Functional Dyspepsia: A Study from The Functional Dyspepsia Treatment Trial.

OBJECTIVES: The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNß3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNß3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy. METHODS: Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNß3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods. RESULTS: GNß3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy-Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNß3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43). CONCLUSIONS: GNß3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.

A case-control comparison of direct healthcare-provider medical costs of chronic idiopathic constipation and irritable bowel syndrome with constipation in a community-based cohort.

OBJECTIVE: Patients with constipation account for 3.1 million US physician visits a year, but care costs for patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) compared to the general public have received little study. The study aim was to describe healthcare utilization and compare medical costs for patients with IBS-C or CIC vs matched controls from a community-based sample. METHODS: A nested case-control sample (IBS-C and CIC cases) and matched controls (1:2) for each case group were selected from Olmsted County, MN, individuals responding to a community-based survey of gastrointestinal symptoms (2008) who received healthcare from a participating Rochester Epidemiology Project (REP) provider. Using REP healthcare utilization data, unadjusted and adjusted standardized costs were compared for the 2- and 10-year periods prior to the survey for 115 IBS-C patients and 230 controls and 365 CIC patients and 730 controls. Two time periods were chosen as these conditions are episodic, but long-term. RESULTS: Outpatient costs for IBS-C ($6,800) and CIC ($6,284) patients over a 2-year period prior to the survey were significantly higher than controls ($4,242 and $5,254, respectively) after adjusting for co-morbidities, age, and sex. IBS-C outpatient costs ($25,448) and emergency room costs ($6,892) were significantly higher than controls ($21,024 and $3,962, respectively) for the 10-year period prior. Unadjusted data analyses of cases compared to controls demonstrated significantly higher imaging costs for IBS-C cases and procedure costs for CIC cases over the 10-year period. LIMITATIONS: Data were collected from a random community sample primarily receiving care from a limited number of providers in that area. CONCLUSIONS: Patients with IBS-C and CIC had significantly higher outpatient costs for the 2-year period compared with controls. IBS-C patients also had higher ER costs than the general population.

The Effect of Dietary Intervention on Irritable Bowel Syndrome: A Systematic Review.

OBJECTIVES: Elimination diets have been used for many years to treat irritable bowel syndrome (IBS). These approaches had fallen out of favor until a recent resurgence, which was based on new randomized controlled trial (RCT) data that suggested it might be effective. The evidence for the efficacy of dietary therapies has not been evaluated systematically. We have therefore conducted a systematic review to examine this issue. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched up to December 2013. Trials recruiting adults with IBS, which compared any form of dietary restriction or addition of an offending food group in patients already on a restricted diet vs. placebo, control therapy, or "usual management", were eligible. Dichotomous symptom data were pooled to obtain a relative risk of remaining symptomatic after therapy as well as the number needed to treat with a 95% confidence interval. RESULTS: We identified 17 RCTs involving 1,568 IBS patients that assessed elimination diets. Only three RCTs involving 230 patients met our eligibility criteria, all of which evaluated different approaches, and thus a meta-analysis could not be conducted. CONCLUSIONS: More evidence is needed before generally recommending elimination diets for IBS patients.

Irritable bowel syndrome: new and emerging treatments.

Irritable bowel syndrome is one of the most common gastrointestinal disorders in developed nations. It is characterized by abdominal pain, altered bowel habits, and bloating. Several non-pharmacological and pharmacological agents, which target the peripheral gastrointestinal system and central nervous system, are used to treat the syndrome. The individual and societal impact of investigating and managing the syndrome is substantial, and despite newer treatments, many patients have unmet needs. Intense research at many international sites has improved the understanding of pathophysiology of the syndrome, but developing treatments that are effective, safe, and that have tolerable side effects remains a challenge. This review briefly summarizes the currently available treatments for irritable bowel syndrome then focuses on newer non-pharmacological and pharmacological therapies and recent evidence for older treatments. Recent guidelines on the treatment of irritable bowel syndrome are also discussed.

Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study.

BACKGROUND & AIMS: Antidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. METHODS: We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use antidepressants. Patients (n = 292; 44 ± 15 years old, 75% were female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary end point was adequate relief of FD symptoms for ≥5 weeks of the last 10 weeks (of 12). Secondary end points included GE time, maximum tolerated volume in Nutrient Drink Test, and FD-related quality of life. RESULTS: An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P = .05, after treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life. CONCLUSIONS: Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. ClinicalTrials.gov ID: NCT00248651.

Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis.

OBJECTIVES: Irritable bowel syndrome (IBS) and chronic idiopathic constipation (CIC) are functional bowel disorders. Evidence suggests that disturbance in the gastrointestinal microbiota may be implicated in both conditions. We performed a systematic review and meta-analysis to examine the efficacy of prebiotics, probiotics, and synbiotics in IBS and CIC. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Randomized controlled trials (RCTs) recruiting adults with IBS or CIC, which compared prebiotics, probiotics, or synbiotics with placebo or no therapy, were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). Continuous data were pooled using a standardized or weighted mean difference with a 95% CI. RESULTS: The search strategy identified 3,216 citations. Forty-three RCTs were eligible for inclusion. The RR of IBS symptoms persisting with probiotics vs. placebo was 0.79 (95% CI 0.70-0.89). Probiotics had beneficial effects on global IBS, abdominal pain, bloating, and flatulence scores. Data for prebiotics and synbiotics in IBS were sparse. Probiotics appeared to have beneficial effects in CIC (mean increase in number of stools per week=1.49; 95% CI=1.02-1.96), but there were only two RCTs. Synbiotics also appeared beneficial (RR of failure to respond to therapy=0.78; 95% CI 0.67-0.92). Again, trials for prebiotics were few in number, and no definite conclusions could be drawn. CONCLUSIONS: Probiotics are effective treatments for IBS, although which individual species and strains are the most beneficial remains unclear. Further evidence is required before the role of prebiotics or synbiotics in IBS is known. The efficacy of all three therapies in CIC is also uncertain.

The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis.

OBJECTIVES: Fiber has been used for many years to treat irritable bowel syndrome (IBS). This approach had fallen out of favor until a recent resurgence, which was based on new randomized controlled trial (RCT) data that suggested it might be effective. We have previously conducted a systematic review of fiber in IBS, but new RCT data for fiber therapy necessitate a new analysis; thus, we have conducted a systematic review of this intervention. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched up to December 2013. Trials recruiting adults with IBS, which compared fiber supplements with placebo, control therapy, or "usual management", were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy as well as number needed to treat (NNT) with a 95% confidence interval (CI). RESULTS: We identified 14 RCTs involving 906 patients that had evaluated fiber in IBS. There was a significant benefit of fiber in IBS (RR=0.86; 95% CI 0.80-0.94 with an NNT=10; 95% CI=6-33). There was no significant heterogeneity between results (I(2)=0%, Cochran Q=13.85 (d.f.=14), P=0.46). The benefit was only seen in RCTs on soluble fiber (RR=0.83; 95% CI 0.73-0.94 with an NNT=7; 95% CI 4-25) with no effect seen with bran (RR=0.90; 95% CI 0.79-1.03). CONCLUSIONS: Soluble fiber is effective in treating IBS. Bran did not appear to be of benefit, although we did not uncover any evidence of harm from this intervention, as others have speculated from uncontrolled data.

Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis.

OBJECTIVES: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence relating to the treatment of this condition with antidepressants and psychological therapies continues to accumulate. METHODS: We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Trials recruiting adults with IBS, which compared antidepressants with placebo, or psychological therapies with control therapy or "usual management," were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). RESULTS: The search strategy identified 3,788 citations. Forty-eight RCTs were eligible for inclusion: thirty-one compared psychological therapies with control therapy or "usual management," sixteen compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Ten of the trials of psychological therapies, and four of the RCTs of antidepressants, had been published since our previous meta-analysis. The RR of IBS symptom not improving with antidepressants vs. placebo was 0.67 (95% CI=0.58-0.77), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms not improving with psychological therapies was 0.68 (95% CI=0.61-0.76). Cognitive behavioral therapy, hypnotherapy, multicomponent psychological therapy, and dynamic psychotherapy were all beneficial. CONCLUSIONS: Antidepressants and some psychological therapies are effective treatments for IBS. Despite the considerable number of studies published in the intervening 5 years since we last examined this issue, the overall summary estimates of treatment effect have remained remarkably stable.