Laureate Professor Nick Talley

Background and aims: A low fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (FODMAP) diet alleviates symptoms of irritable bowel syndrome (IBS). We aimed to investigate the relationship between habitual FODMAP intake and post-prandial bowel symptoms in adults with IBS, functional diarrhoea (FD), or constipation (FD) (functional bowel disorders), and in healthy adults (controls). Methods: 292 participants (173 with functional bowel disorders and 119 controls) completed a food and symptom times diary. Estimated meal portion sizes were entered into the Monash FODMAP Calculator to analyse FODMAP content. Wilcoxon and ANOVA tests were used to investigate the relationship between FODMAP intake and post-prandial bowel symptoms. Results: IBS participants experienced more post-prandial bowel symptoms compared to participants with other functional bowel disorders or controls. Meals associated with abdominal pain contained on average increased excess fructose (0.31 g vs. 0.18 g, p < 0.05), sorbitol (0.27 g vs. 0.10 g, p < 0.01), and total FODMAP (3.46 g vs. 2.96 g, p < 0.05) compared to meals not associated with pain. Abdominal swelling was associated with increased sorbitol (0.33 g vs. 0.11 g, p < 0.01), and total FODMAP (3.26 g vs. 3.02 g, p < 0.05) consumption. Abdominal bloating was associated with increased galacto oligosaccharide consumption (0.18 g vs. 0.14 g, p < 0.05). Conclusion: These findings support the role of FODMAP in post-prandial bowel symptom onset, however, the amount and type of FODMAP triggering symptoms vary between individuals. Future research should investigate the relationship between the effect of individual FODMAP consumption on post-prandial bowel symptoms for each subtype, the interaction of FODMAP with differing functional bowel disorders and whether longitudinally symptoms and dietary intake are stable.

Amino acids are important in several biochemical pathways as precursors to neurotransmitters which impact biological processes previously linked to functional gastrointestinal disorders (FGIDs). Dietary protein consumption, metabolic host processes, and the gut microbiome can influence the plasma concentration of amino acids and neurotransmitters, and their uptake by tissues. The aim of this analysis was to quantify 19 proteogenic and 4 non-proteogenic amino acids and 19 neurotransmitters (including precursors and catabolites, herein referred to as neurotransmitters) to ascertain if their circulating concentrations differed between healthy participants and those with FGIDs. Plasma proteogenic and non-proteogenic amino acids and neurotransmitters were measured using ultra-performance liquid chromatography and liquid chromatography¿mass spectrometry, respectively, from 165 participants (Rome IV: irritable bowel syndrome (IBS-constipation, IBS-diarrhea), functional constipation, functional diarrhea, and healthy controls). There were significant differences (p < 0.05) in pairwise comparisons between healthy controls and specific FGID groups for branched-chain amino acids (BCAAs), ornithine, and alpha-aminobutyric acid. No other significant differences were observed for the neurotransmitters or any other amino acids analyzed. Multivariate and bivariate correlation analyses between proteogenic and non-proteogenic amino acids and neurotransmitters for constipation (constipation (IBS-C and functional constipation) and phenotypes diarrhea (IBS-D and functional diarrhea)) and healthy controls suggested that associations between BCAAs, 5-hydroxytryptophan, and kynurenine in combination with tyrosine, 3,4-dihydroxyphenylalanine, and 3,4-dihydroxyphenylacetic acid and associations with gamma-aminobutyric acid, glutamate, asparagine, and serine are likely disrupted in FGID phenotypes. In conclusion, although correlations were evident between some proteogenic and non-proteogenic amino acids and neurotransmitters, the results showed minor concentration differences in plasma proteogenic and non-proteogenic amino acids, amino acid-derived metabolites, and neurotransmitters between FGID phenotypes and healthy controls.

Introduction: Controlling for potential placebo effects is an important aspect of gaining an accurate estimate of how much the therapy alone changes patient symptoms or other end points. When the placebo effect is large, this can lead to only a small fraction of changes seen in the active therapy group being attributed to the therapy itself. This problem has been well studied in some disorders of brain-gut interaction but not in functional dyspepsia where placebo response rates of 40% and higher have been reported. Understanding risk factors for placebo response might lead to changes in trial design that could reduce the magnitude of the problem. This study sought to identify risk factors for the placebo effect in a functional dyspepsia clinical trial with a longer-term aim of suggesting trial design changes that might minimize the problem. Methods: A secondary analysis of the clinical trial data was undertaken using 2 arms deemed to involve placebo therapy. Potential predictors were drawn from a wide range of patient characteristics including psychological, clinical, and physiological features. Results: Predictors of a stronger placebo effect on the gastrointestinal symptom rating scale included higher functional dyspepsia symptom burden at baseline (b = -0.101), coexisting irritable bowel syndrome (b = -0.436), and higher scores on the Nepean Dyspepsia Index eat/drink domain (-0.005). Baseline symptom burden and coexisting irritable bowel syndrome were found to be independent placebo predictors, explaining 13% of the variance in change in gastrointestinal symptom rating scale. Anxiety, childhood sexual abuse, sleep amount, and frequent abdominal pain were also found to be predictors of change in individual symptom scores. Discussion: The findings of this study yield actionable insights into trial methodology that may help to reduce the magnitude of the placebo effect in future functional dyspepsia treatment trials.

Goals: We aimed to develop and validate a patient-reported experience measure for gastrointestinal (GI) endoscopy, the Comprehensive Endoscopy Satisfaction Tool that captures relevant domains that influence the patient's experience and identify factors that shape satisfaction. Background: Patient-reported experience measures are used to capture specific quality aspects of health care services. GI endoscopic services are high-volume services, and there is a lack of specific, validated instruments to capture various domains that shape the patients' experience with routine clinical endoscopic services. Study: After an environmental scan and structured literature review, focus groups with patients were conducted to identify relevant factors influencing the patient experience with GI endoscopic services. After an initial validation in 101 patients undergoing routine GI endoscopies, the instrument was tested in 7800 patients. In addition, the influence of sociodemographic factors on global satisfaction was explored. Results: The final version included 26 specific items plus 4 global ratings for preprocedure, experience on day of procedure, postprocedure care, and infrastructure. In addition, a global rating of the overall experience was included. Patient satisfaction was significantly higher in older patients (P<0.001) but not influenced by gender, nationality, marital status, education, or employment status. Interestingly, during periods of coronavirus disease-19-related service interruptions, the Net Promoter Score was significantly reduced (P<0.0001) providing evidence for the responsiveness of the instrument. Conclusions: The Comprehensive Endoscopy Satisfaction Tool is a valid measure for the patient experience with the various components of endoscopic services, allows for the identification of domains that impact on the patient experience and is a practical tool to compare patient satisfaction over time and across facilities.

Background: Crohn's disease (CD), ulcerative colitis (UC), and indeterminate colitis are inflammatory bowel diseases (IBDs) that adversely affect the healthcare needs and quality of life (QoL) of people with IBD. The aim of this study was to explore the needs and perceptions of people with IBD in a primary care setting. Methods: This sequential explanatory mixed-methods study consisted of a cross-sectional survey (included validated tools), followed by semistructured interviews on participants' perceptions: IBD management, healthcare professionals, IBD care, flare management, and pharmacist's IBD roles. Results: Sixty-seven participants completed the survey, and 8 completed interviews. Quantitative findings: Age at diagnosis had significant association with medication nonadherence (P =. 04), QoL (P =. 04), and disease control (P =. 01) among the respondents. The odds of medication nonadherence were 8 times (adjusted odds ratio [AOR] = 8.04, 95% confidence interval [CI] = 1.08, 60.10) higher among younger participants aged <30 years. Those diagnosed with CD (P =. 02) reported more likely to have unfavorable perceptions of pharmacists' role in managing their IBD (AOR = 9.45, 95% CI = 1.57, 56.62) than those with UC and indeterminate colitis. Qualitative findings: General practitioners were considered the most important care provider and the first point of contact for patients in managing all aspects of IBD. Participants identified their key need to be timely access to specialized IBD care and found that other primary healthcare professionals lacked disease-specific knowledge for managing IBD. Conclusions: Primary healthcare professionals are well positioned but need targeted training to influence the needs of IBD patients. The specialty role of an IBD educator could complement existing services to deliver and address patient-specific care.

Introduction: Gastro-oesophageal reflux disease (GERD) is the most common non-allergic comorbidity in adults with asthma; however, comorbidity with other atopic diseases such as eczema and hay fever is unclear. The objective was to assess the comorbidity of GERD with asthma and atopic diseases and to investigate possible mechanisms, including genetic and/or affective factors. Methods: A co-twin control study harnessing 46 583 adult twins. Questionnaires on health status were linked to national patient and prescribed drug register data. Analyses tested associations of comorbidity between multiple definitions of atopic diseases (self-report and register-based) with GERD. Comparisons were made between unpaired, monozygotic (MZ) and dizygotic (DZ) twins to assess genetic liability. Affective traits (depression, anxiety and neuroticism) were added to models as possible explanatory factors. Results: The risk of GERD in those with asthma was OR (odds ratio) 1.52 (95% CI 1.38, 1.68), hay fever OR 1.22 (95%CI 1.12, 1.34) and eczema OR 1.23 (95%CI 1.10, 1.38). Adjusting for affective traits completely attenuated the comorbidity associations for hay fever and eczema with GERD, and partly for asthma with GERD. Co-twin control associations attenuated suggesting a shared cause for both GERD and atopic diseases. For example, all twins adjOR 1.32 (95%CI 1.00, 1.74), 0.97 (95% CI 0.76¿1.23) and 1.11 (95%CI 0.85¿1.45) for self-report asthma, hay fever and eczema with GERD respectively. Conclusions: GERD is a common comorbidity in adults with asthma, hay fever and/or eczema. We found evidence for shared mechanisms suggesting common underlying causes that may involve affective traits requiring further investigation.

Background: Co-occurring (overlapping) irritable bowel syndrome (IBS), functional dyspepsia (FD), and heartburn has been observed. However, whether it is a distinct entity has not been established, nor what clinical, demographic, lifestyle, and psychological traits are associated with it. This study sought to estimate the prevalence and temporal stability of this overlap and to identify features specific to it in order to gain some insights into the potential etiopathogenesis. Methods: Two waves of a survey to a population-representative sample were conducted 3¿years apart, recruiting 1312 individuals for this study. The chance-expected probability of complete overlap (CO) was calculated and compared with the observed CO. A range of demographic, lifestyle factors, medical diagnoses, sleep quality, and psychological distress were tested to identify predictors of overlap using logistic regression. Key Results: CO was observed in 2.1% (95% confidence interval 1.9, 3.7) of the sample and was closely replicated in wave 2 at 2.0%. The observed CO was greater than expected by chance (0.2%) to a statistically significant extent (p¿<¿0.001). Overlap between IBS subtypes, FD subtypes, and heartburn was also elevated above chance expectation. Individuals with CO were separately differentiated from others with respect to elevated rates of self-reported medically diagnosed asthma, elevated psychological distress score, and elevated impact on sleep quality. The discrimination provided by these factors was further independent of age and sex. Conclusions and Inferences: Overlap between IBS, FD, and heartburn (GERD) appears to be a distinct entity that has a profile including psychological morbidity, sleep disturbance, and elevated rates of atopy.

Functional dyspepsia (FD) affects up to 15% of the population and is characterised by recurring upper gastrointestinal (GI) symptoms occurring in the absence of clinically identifiable pathology. Psychological stress is a key factor associated with the onset of FD and locally acting hypothalamic¿pituitary¿adrenal (HPA) axis hormones have been implicated in GI motility and barrier dysfunction. Recent pre-clinical work has identified mechanistic pathways linking corticotropin-releasing hormone (CRH) with the innate epithelial immune protein NLRP6, an inflammasome that has been shown to regulate GI mucus secretion. We recruited twelve FD patients and twelve healthy individuals to examine whether dysregulation of hypothalamic-pituitary adrenal (HPA) axis hormones and altered NLRP6 pathways were evident in the duodenal mucosa. Protein expression was assessed by immunoblot and immunohistochemistry in D2 duodenal biopsies. Plasma HPA axis hormones were assayed by ELISA and enteroid and colorectal cancer cell line cultures were used to verify function. FD patients exhibited reduced duodenal CRH-receptor 2, compared to non-GI disease controls, indicating a dysregulation of duodenal HPA signalling. The loss of CRH-receptor 2 correlated with reduced NLRP6 expression and autophagy function, processes critical for maintaining goblet cell homeostasis. In accordance, duodenal goblet cell numbers and mucin exocytosis was reduced in FD patients compared to controls. In vitro studies demonstrated that CRH could reduce NLRP6 in duodenal spheroids and promote mucus secretion in the HT29-MTX-E12 cell line. In conclusion, FD patients exhibit defects in the NLRP6-autophagy axis with decreased goblet cell function that may drive symptoms of disease. These features correlated with loss of CRH receptor 2 and may be driven by dysregulation of HPA signalling in the duodenum of FD patients.

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.

Introduction: The concept of gut-to-brain communication via microbial or inflammatory pathways is gaining increased attention but genuine pathology directly linking gut perturbation to anxiety is lacking. We hypothesized that duodenal eosinophilia, as known to occur in functional dyspepsia (FD), may be an underlying cause of anxiety and may help explain the striking association between FD and anxiety. Methods: Randomly selected subjects from the national population register of Sweden completed the validated Abdominal Symptom Questionnaire; 1000 completed esophagogastroduodenoscopy and the Hospital Anxiety and Depression Scale questionnaire. Duodenal biopsies were obtained from 1st (D1) and 2nd portion (D2). Eligible subjects who underwent endoscopy (n¿=¿887) were invited to participate in a 10-year follow-up study with the same questionnaires. Among endoscopy normal subjects, FD was identified by Rome criteria, and controls were symptom free. Duodenal eosinophilia was based on pre-defined cut-offs. Finding are reported as odds ratios (ORs) with 95% confidence interval and p-value. Results: The study population comprised 89 cases with FD and 124 healthy controls (mean age 62¿years, SD 12, 34% male). Clinical anxiety at follow-up was elevated in those with D1 eosinophilia at baseline considering either new-onset anxiety (OR¿=¿4.5, 95% CI 0.8, 23.8; p¿=¿0.08) or follow-up anxiety adjusting for baseline anxiety (OR¿=¿4.51 (95% CI 1.03, 19.81; p¿=¿0.046). Conclusion: Duodenal eosinophilia may potentially be a mechanism linked to anxiety independent of FD.

Background Functional gastrointestinal disorders (FGIDs) are diagnosed according to expert consensus criteria based on recall of symptoms over periods of 3 months or longer. Whether the expert opinion concords with underlying disease process and whether individual recall is accurate are both in doubt. This study aimed to identify naturally occurring clusters of individuals with respect to symptom pattern, evaluate their significance, compare cluster profiles with expert opinion and evaluate their temporal stability. Methods As part of a random population study of FGID-related symptoms, we first explored the use of prospective stool and symptom diaries combined with empirical grouping of individuals into clusters using nonhierarchical cluster analysis. Results The analysis identified two clusters of individuals, one of which was characterized by elevated scores on all domains of symptoms (26% of the sample) and one that was low to average on all domains (74% of the sample). Cluster membership was found to be stable over a long interval. Clusters were found to differ on most domains of quality-of-life (d = 0.46-0.74), self-rated health (d =-0.42) and depression (d =-0.42) but not anxiety. Prevalence of clinically diagnosed irritable bowel syndrome (IBS) was higher in the more impacted cluster (33%) compared with the healthy cluster (13%; P < 0.0001). Conclusion A naturalistic classification of individuals challenges consensus criteria in showing that some IBS individuals have a symptom experience not unlike health. The proposed approach has demonstrated temporal stability over time, unlike consensus criteria. A naturalistic disease classification system may have practical advantages over consensus criteria when supported by a decision-Analytic system.

Metabolic uptake of lead (Pb) is controlled by its bioaccessibility. Most studies have examined bioaccessibility of Pb in the absence of gut microbes, which play an important role in the metabolic uptake of nutrients and metal(loid)s in intestine. In this study, we examined the effect of three gut microbes, from various locations in the gut, on the bioaccessibility of soil ingested Pb. The gut microbes include Lactobacillus acidophilus, Lactobacillus rhamnosus and Escherichia coli. Lead toxicity to these three microbes was also examined at various pH values. Bioaccessibility of Pb was measured using gastric and intestinal extractions. Both Pb spiked and Pb-contaminated shooting range field soils were used to measure Pb bioaccessibility in the presence and absence of gut microbes. The results indicated that Pb toxicity to gut microbes, as measured by LD50 value, decreased with increasing pH, and was higher for Lactobacillus species. Gut microbes decreased the bioaccessible Pb; the effect was more pronounced at low pH, mimicking gastric conditions than in conditions closer to the intestine. Lead adsorption by these microbes increased at the higher pH tested, and E. coli adsorbed higher amounts of Pb than did the Lactobacillus species. The effect of gut microbes on reducing Pb bioaccessibility may be attributed to microbially-induced immobilization of Pb through adsorption, precipitation, and complexation reactions. The study demonstrates that bioaccessibility and subsequently bioavailability of metal(loid)s can be modulated by gut microbes, and it is important to undertake bioaccessibility measurements in the presence of gut microbes.

Gastroesophageal reflux disease (GERD) is a common disorder, and empirical proton pump inhibitor (PPI) treatment is often the first step of management; however, up to 40% of patients remain symptomatic despite PPI treatment. Refractory reflux refers to continued symptoms despite an adequate trial of PPI, and management remains challenging. The differential diagnosis is important; other oesophageal (e.g. eosinophilic oesophagitis) and gastroduodenal disorders (e.g. functional dyspepsia) should be ruled out, as this changes management. A combination of clinical assessment, endoscopic evaluation and in selected cases oesophageal function testing can help characterize patients with refractory reflux symptoms into oesophageal phenotypes so appropriate therapy can be more optimally targeted. Medical options then may include adding a H2 receptor antagonist, alginates, baclofen or antidepressant therapy, and there is emerging evidence for bile acid sequestrants and diaphragmatic breathing. The demonstration of a temporal association of symptoms with reflux events on pH-impedance testing (reflux hypersensitivity) serves to focus the management on modulating oesophageal perception and reducing the reflux burden, or identifies those with no obvious pathophysiologic abnormalities (functional heartburn). Anti-reflux surgery based on randomized controlled trial evidence has a role in reflux hypersensitivity or continued pathological acid reflux despite PPI in carefully considered, fully worked up cases that have failed medical therapy; approximately two of three cases will respond but there is a small risk of complications. In patients with persistent volume reflux despite medical therapy, given the lack of alternatives, anti-reflux surgery is a consideration. Promising newer approaches include endoscopic techniques. This review aims to summarize current diagnostic approaches and critically evaluates the evidence for the efficacy of available treatments.

In this study, the intestinal permeability of metal(loid)s (MLs) such as arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg) was examined, as influenced by gut microbes and chelating agents using an in vitro gastrointestinal/Caco-2 cell intestinal epithelium model. The results showed that in the presence of gut microbes or chelating agents, there was a significant decrease in the permeability of MLs (As-7.5%, Cd-6.3%, Pb-7.9% and Hg-8.2%) as measured by apparent permeability coefficient value (Papp), with differences in ML retention and complexation amongst the chelants and the gut microbes. The decrease in ML permeability varied amongst the MLs. Chelating agents reduce intestinal absorption of MLs by forming complexes thereby making them less permeable. In the case of gut bacteria, the decrease in the intestinal permeability of MLs may be associated to a direct protection of the intestinal barrier against the MLs or indirect intestinal ML sequestration by the gut bacteria through adsorption on bacterial surface. Thus, both gut microbes and chelating agents can be used to decrease the intestinal permeability of MLs, thereby mitigating their toxicity.

Background: Small intestinal bacterial overgrowth may play a role in gastrointestinal and non-gastrointestinal diseases. Aims: To use quantitative polymerase chain reaction (qPCR) to determine and compare bacterial loads of duodenal biopsies in asymptomatic controls, and patients with functional gastrointestinal disorders (FGIDs) and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn¿s disease (CD). To define effects of gastric acid inhibition on bacterial load, explore links of bacterial load and gastrointestinal symptoms in response to a standardised nutrient challenge and compare bacterial load with glucose breath test results. Methods: In 237 patients (63 controls, 84 FGID and 90 IBD), we collected mucosal samples under aseptic conditions during endoscopy extracted and total DNA. Bacterial load metric was calculated utilising qPCR measurements of the bacterial 16S rRNA gene, normalised to human beta-actin expression. Standard glucose breath test and nutrient challenge test were performed. Results: The duodenal microbial load was higher in patients with FGID (0.22¿±¿0.03) than controls (0.07¿±¿0.05; P¿=¿0.007) and patients with UC (0.01¿±¿0.05) or CD (0.02¿±¿0.09), (P¿=¿0.0001). While patients treated with proton pump inhibitors (PPI) had significantly higher bacterial loads than non-users (P¿<¿0.05), this did not explain differences between patient groups and controls. Bacterial load was significantly (r¿=¿0.21, P¿<¿0.016) associated with the symptom response to standardised nutrient challenge test. Methane, but not hydrogen values on glucose breath test were associated with bacterial load measured utilising qPCR. Conclusions: Utilising qPCR, a diagnosis of FGID and treatment with PPI were independently associated with increased bacterial loads. Increased bacterial loads are associated with an augmented symptom response to a standardised nutrient challenge.

Background & Aims: There is controversy about whether psychological factors (anxiety and depression) increase health care seeking by patients with irritable bowel syndrome (IBS). We investigated whether psychological factors increase health care seeking by patients with IBS and the effects of extragastrointestinal (extra-GI) symptoms. Methods: We performed a population-based prospective study of health care use over a 12-year period in Sweden. From 2002 through 2006, 1244 subjects were selected randomly for an examination by a gastroenterologist and to complete questionnaires, including the Rome II modular questionnaire. Psychological factors were measured with the valid Hospital Anxiety and Depression scale and extra-GI symptoms were measured with a symptom checklist. Responses from 1159 subjects (57% female; mean age, 48.65 y) were matched with health records in 2016 (164 were classified as having IBS based on Rome II criteria). Results: The overall association between depression or anxiety and health care use varied in subjects with and without IBS at baseline. The presence of extra-GI symptoms strengthened the relationship between anxiety and depression and prospective psychiatric visits for subjects with IBS and without IBS (incidence rate ratio, 1.14¿1.26). Extra-GI symptoms did not alter the association of anxiety or depression with use of GI or extra-GI health care. Conclusions: In a population-based study in Sweden, we found that individuals with high baseline anxiety or depression were more likely to seek psychiatric health care, but not GI or extra-GI health care, in the presence of extra-GI symptoms at baseline. Patients with IBS might benefit from more thorough assessments that examine extra-GI and psychological symptoms, to reduce health care utilization.

INTRODUCTION:We conducted a systematic review and meta-analysis to compare the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) and controls.METHODS:Electronic databases were searched up to December 2018 for studies reporting SIBO prevalence in patients with IBS. Prevalence rates, odds ratios (ORs), and 95% confidence intervals (CIs) of SIBO in patients with IBS and controls were calculated.RESULTS:We included 25 studies with 3,192 patients with IBS and 3,320 controls. SIBO prevalence in patients with IBS was significantly increased compared with controls (OR = 3.7, 95% CI 2.3-6.0). In studies using only healthy controls, the OR for SIBO in patients with IBS was 4.9 (95% CI 2.8-8.6). With breath testing, SIBO prevalence in patients with IBS was 35.5% (95% CI 33.6-37.4) vs 29.7% (95% CI 27.6-31.8) in controls. Culture-based studies yielded a SIBO prevalence of 13.9% (95% CI 11.5-16.4) in patients with IBS and 5.0% (95% CI 3.9-6.2) in controls with a cutoff value of 105 colony-forming units per milliliter vs 33.5% (95% CI 30.1-36.9) in patients with IBS and 8.2% (95% CI 6.8-9.6) in controls with a cutoff value of 103 colony-forming unit per milliliter, respectively. SIBO prevalence diagnosed by lactulose breath test is much greater in both patients with IBS (3.6-fold) and controls (7.6-fold) compared with glucose breath test. Similar difference is seen when lactulose breath test is compared with culture methods. OR for SIBO in patients with IBS-diarrhea compared with IBS-constipation was 1.86 (95% CI 1.83-2.8). Methane-positive breath tests were significantly more prevalent in IBS-constipation compared with IBS-diarrhea (OR = 2.3, 95% CI 1.2-4.2). In patients with IBS, proton pump inhibitor was not associated with SIBO (OR = 0.8, 95% CI 0.5-1.5, P = 0.55).DISCUSSION:This systematic review and meta-analysis suggests a link between IBS and SIBO. However, the overall quality of the evidence is low. This is mainly due to substantial "clinical heterogeneity"due to lack of uniform selection criteria for cases and controls and limited sensitivity and specificity of the available diagnostic tests.

Objective The ethiopathogenesis of irritable bowel syndrome (IBS) is unknown. While a link to the gut microbiome is postulated, the heterogeneity of the healthy gut makes it difficult to draw definitive conclusions. We aimed to describe the faecal and mucosa-associated microbiome (MAM) and health correlates on a community cohort of healthy and IBS individuals with no colonoscopic findings. Design The PopCol study recruited a random sample of 3556 adults; 745 underwent colonoscopy. IBS was defined by Rome IV criteria and organic disease excluded. 16S rRNA gene sequencing was conducted on sigmoid biopsy samples from 376 representative individuals (63 IBS cases) and faecal samples from 185 individuals (32 IBS cases). Results While sigmoid MAM was dominated by Lachnospiraceae, faeces presented a higher relative abundance of Ruminococcaceae. Microbial richness in MAM was linearly correlated to that in faeces from the same individual (R2=0.255, p<3E-11) as was diversity (R2=0.06, p=0.0022). MAM diversity decreased with increasing body mass index (BMI; Pearson's r=-0.1, p=0.08) and poorer self-rated health (r=-0.15, p=0.007), but no other health correlates. Faecal microbiome diversity was correlated to stool consistency (r=-0.16, p=0.043). Several taxonomic groups were correlated to age, BMI, depression and self-reported health, including Coprococcus catus associated with lower levels of depression (r=-0.003, p=0.00017). The degree of heterogeneity observed between IBS patients is higher than that observed between healthy individuals. Conclusions No distinct microbial signature was observed in IBS. Individuals presenting with low self-rated health or high BMI have lower gut microbiome richness.

Background: In recent decades, the prevalence of gastroesophageal reflux disease (GERD) and obesity has been increasing while Helicobacter pylori infection has been decreasing. Objective: To evaluate if H. pylori treatment, excess body weight and other anthropometric measurements are associated with incident erosive esophagitis, as a secondary objective of a trial which tested the efficacy of treatment of H. pylori on the symptoms of functional dyspepsia. Subjects/methods: Upper gastrointestinal endoscopy and anthropometric assessments were performed, at baseline and after 12 months, in H. pylori positive patients with functional dyspepsia who had no baseline reflux symptoms or esophagitis. Patients were randomly assigned to receive omeprazole, amoxicillin, and clarithromycin (antibiotic group; n = 201) or omeprazole plus placebo (control group; n = 203). The primary outcome was the incidence of esophagitis 12 months after randomization, according to treatment groups, and the association of BMI and other anthropometric measurements. Results: Four hundred and four patients were included (mean age, 46.1 years; 78.7% women). The 12-month follow-up endoscopic esophagitis rates for the antibiotic and control groups were 10.9% (22/201) and 9.4% (19/203), respectively (p = 0.60). The number needed to harm was 67. Baseline anthropometric measurements were performed in 94% (380/404) of patients. The 12-month follow-up esophagitis rates for overweight and normal body weight patients were 13.6% (29/213) and 6.0% (10/167), respectively (p = 0.015); rates for patients with and without increased baseline waist circumference were 15.4% (24/156) and 6.7% (15/224), respectively (p = 0.006). Following logistic regression, only the combination of increased baseline body mass index and waist, but not H. pylori treatment, was independently associated with new-onset esophagitis (OR 2.88; 95% CI: 1.28¿6.45). Conclusions: Excess body weight and concomitant increased waist circumference, but not H. pylori treatment, predicts new-onset esophagitis.

Gastrointestinal symptoms are highly prevalent, but many people who have them will have no organic explanation for their symptoms. Most of these people will be labelled as having a functional gastrointestinal disorder, such as irritable bowel syndrome, functional dyspepsia, or functional constipation. These conditions affect up to 40% of people at any one point in time, and two-thirds of these people will have chronic, fluctuating symptoms. The pathophysiology of functional gastrointestinal disorders is complex, but involves bidirectional dysregulation of gut¿brain interaction (via the gut¿brain axis), as well as microbial dysbiosis within the gut, altered mucosal immune function, visceral hypersensitivity, and abnormal gastrointestinal motility. Hence, nomenclature refers to the conditions as disorders of gut¿brain interaction. Psychological comorbidity is common; however, whether or not this predates, or is driven by, symptoms is not clear. Patients with functional gastrointestinal disorders can feel stigmatised, and often this diagnosis is not communicated effectively by physicians, nor is education provided. Prompt identification and treatment of these conditions is crucial as they have a considerable impact on health-care systems and society as a whole because of repeated consultations, unnecessary investigations and surgeries, prescriptions and over-the-counter medicine use, and impaired health-related quality of life and ability to work. Symptom-based criteria are used to make a diagnosis, with judicious use of limited investigations in some patients. The general principles of treatment are based on a biopsychosocial understanding and involve management of physical symptoms and, if present, psychological comorbidity. In the future, treatment approaches to functional gastrointestinal disorders are likely to become more personalised, based not only on symptoms but also underlying pathophysiology and psychology.

Dyspepsia is a complex of symptoms referable to the gastroduodenal region of the gastrointestinal tract and includes epigastric pain or burning, postprandial fullness, or early satiety. Approximately 80% of individuals with dyspepsia have no structural explanation for their symptoms and have functional dyspepsia. Functional dyspepsia affects up to 16% of otherwise healthy individuals in the general population. Risk factors include psychological comorbidity, acute gastroenteritis, female sex, smoking, use of non-steroidal anti-inflammatory drugs, and Helicobacter pylori infection. The pathophysiology remains incompletely understood, but it is probably related to disordered communication between the gut and the brain, leading to motility disturbances, visceral hypersensitivity, and alterations in gastrointestinal microbiota, mucosal and immune function, and CNS processing. Although technically a normal endoscopy is required to diagnose functional dyspepsia, the utility of endoscopy in all patients with typical symptoms is minimal; its use should be restricted to people aged 55 years and older, or to those with concerning features, such as weight loss or vomiting. As a result of our incomplete understanding of its pathophysiology, functional dyspepsia is difficult to treat and, in most patients, the condition is chronic and the natural history is one of fluctuating symptoms. Eradication therapy should be offered to patients with functional dyspepsia who test positive for Helicobacter pylori. Other therapies with evidence of effectiveness include proton pump inhibitors, histamine-2 receptor antagonists, prokinetics, and central neuromodulators. The role of psychological therapies is uncertain. As our understanding of the pathophysiology of functional dyspepsia increases, it is probable that the next decade will see the emergence of truly disease-modifying therapies for the first time.

Background and aims: This cross-sectional observational case-control study was initiated in July 2016 with the aim of increasing an understanding of the underlying disease mechanisms in functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS), functional diarrhoea (FD), and functional constipation (FC). Specific areas of interest include the effect of food, microbiome, host and microbial genetics, metabolome, and psychological variables on unexplained chronic gastrointestinal (GI) symptoms. Methods: This study recruited consecutive patients who were attending one of two endoscopy centres in Christchurch, New Zealand, for colonoscopy and a subgroup of participants from the general public who did not undergo colonoscopy. Participants with known GI disease other than an FGID were excluded. Those with symptoms were recruited as cases, whilst those without symptoms were recruited as controls. In the days prior to preparation for colonoscopy, or an agreeable time for those not undergoing colonoscopy, demographic, symptom, psychological, dietary, and health data were collected in addition to biological samples (breath, faeces, blood, and urine). Colonic biopsies were taken at the time of colonoscopy from participants in the colonoscopy subgroup. Results: Between July 2016 and December 2018, 349 participants were recruited, 315 of whom completed the study, 220 participants were from the colonoscopy subgroup, and 95 from the non-colonoscopy subgroup. This included 129 controls and 186 cases (57 IBS-diarrhoea predominant, 30 IBS-constipation predominant, 41 IBS-mixed, 42 FC, and 16 FD). The mean age of FGID cases was 53.4 years and controls 54.4 years. Cases (149/186, 80.1%) and controls (57/72, 55.8%) were predominantly female. Education levels were similar across the cohort. Smoking and alcohol rates were also similar. Biological samples were collected as planned from participants. Conclusions: The COMFORT cohort is a unique clinical cohort of FGID cases and controls with a wide range of demographic, dietary, clinical, psychological, and health data in addition to biological samples. Future research will aim to use a systems biology approach to establish the potential role of diet, host-microbiome interactions, and other factors in the pathogenesis of FGIDs.

Chronic unexplained gastrointestinal symptoms impact more than 1 in 5 Americans and their families; these disorders include the irritable bowel syndrome (IBS) and functional dyspepsia (FD), currently classified by Rome IV as functional gastrointestinal disorders. By definition, IBS and FD have no established pathology, but emerging evidence suggests this paradigm may need revision. Immune activation and, in subsets, subtle intestinal pathology have been identified in FD (most notably, postprandial distress syndrome) and IBS-diarrhea. A disease model is proposed that accounts for all of the intestinal and extraintestinal symptoms, relationship to food and infection, and the overlap with gastroesophageal reflux disease. It is speculated that antigen presentation to the mucosa (e.g., microbial antigens or food proteins after acute gastroenteritis) induces, in a genetically primed host, immune activation of the intestine with low-grade intestinal inflammation and subsequently neuronal structural and functional alterations, producing regional intestinal hypersensitivity and motor dysfunction. Immune activation may explain the female predominance and fluctuations in immune activity for symptom variability over time. In the future, as further evidence accumulates, the management paradigm may potentially shift to objective pathology-based subtyping based on serological, microbiological, and clinical assessments to identify when targeted therapies should be deployed in subsets. Potential targeted interventions may include therapies to dampen down immune activation or block release of key mediators such as histamine, specific microbial targeted treatments that may reverse disease, and dietary advice to eliminate relevant food antigens after objective in vivo testing. Only by identifying causation can we eventually anticipate cure, and as the true pathology unravels in subsets, this may become a reality.

Background: Functional gastrointestinal disorders are common and costly to the health-care system. Most specialist care is provided by a gastroenterologist, but only a minority of patients have improvement in symptoms. Although they have proven to be effective, psychological, behavioural, and dietary therapies are not provided routinely. We aimed to compare the outcome of gastroenterologist-only standard care with multidisciplinary care. Methods: In an open-label, single-centre, pragmatic trial, consecutive new referrals of eligible patients aged 18¿80 years with Rome IV criteria-defined functional gastrointestinal disorders were randomly assigned (1:2) to receive gastroenterologist-only standard care or multidisciplinary clinic care. The multidisciplinary clinic included gastroenterologists, dietitians, gut-focused hypnotherapists, psychiatrists, and behavioural (biofeedback) physiotherapists. Randomisation was stratified by Rome IV disorder and whether referred from gastroenterology or colorectal clinic. Outcomes were assessed at clinic discharge or 9 months after the initial visit. The primary outcome was a score of 4 (slightly better) or 5 (much better) on a 5-point Likert scale assessing global symptom improvement. Modified intention-to-treat analysis included all patients who attended at least one clinic visit and who had answered the primary outcome question. This study is registered with ClinicalTrials.gov, NCT03078634. Findings: Between March 16, 2017, and May 10, 2018, 1632 patients referred to the hospital gastrointestinal clinics were screened, of whom 442 were eligible for a screening telephone call and 188 were randomly assigned to receive either standard care (n=65) or multidisciplinary care (n=123). 144 patients formed the modified intention-to-treat analysis (n=46 in the standard-care group and n=98 in the multidisciplinary-care group), 90 (63%) of whom were women. 61 (62%) of 98 patients in the multidisciplinary-care group patients saw allied clinicians. 26 (57%) patients in the standard-care group and 82 (84%) patients in the multidisciplinary-care group had global symptom improvement (risk ratio 1·50 [95% CI 1·13¿1·93]; p=0·00045). 29 (63%) patients in the standard-care group and 81 (83%) patients in the multidisciplinary-care group had adequate relief of symptoms in the past 7 days (p=0·010). Patients in the multidisciplinary-care group were more likely to experience a 50% or higher reduction in all Gastrointestinal Symptom Severity Index symptom clusters than were patients in the standard-care group. Of the patients with irritable bowel syndrome, a 50-point or higher reduction in IBS-SSS occurred in 10 (38%) of 26 patients in the standard care group compared with 39 (66%) of 59 patients in the multidisciplinary-care group (p=0·017). Of the patients with functional dyspepsia, a 50% reduction in the Nepean Dyspepsia Index was noted in three (11%) of 11 patients in the standard-care group and in 13 (46%) of 28 in the multidisciplinary-care group (p=0·47). After treatment, the median HADS scores were higher in the standard-care group than in the multidisciplinary-care group (13 [8¿20] vs 10 [6¿16]; p=0·096) and the median EQ-5D-5L quality of life visual analogue scale was lower in the standard-care group compared with the multidisciplinary-care group (70 [IQR 50¿80] vs 75 [65¿85]; p=0·0087). The eight SF-36 scales did not differ between the groups at discharge. After treatment, median Somatic Symptom Scale-8 score was higher in the standard-care group than in the multidisciplinary-care group (10 [IQR 7¿7] vs 9 [5¿13]; p=0·082). Cost per successful outcome was higher in the standard-care group than the multidisciplinary-care group. Interpretation: Integrated multidisciplinary clinical care appears to be superior to gastroenterologist-only care in relation to symptoms, specific functional disorders, psychological state, quality of life, and cost of care for the treatment of functional gastrointestinal disord...

Introduction: Functional dyspepsia (FD), characterised by symptoms of epigastric pain or early satiety and post prandial distress, has been associated with duodenal eosinophilia, raising the possibility that it is driven by an environmental allergen. Non-coeliac gluten or wheat sensitivity (NCG/WS) has also been associated with both dyspeptic symptoms and duodenal eosinophilia, suggesting an overlap between these two conditions. The aim of this study was to evaluate the role of wheat (specifically gluten and fructans) in symptom reduction in participants with FD in a pilot randomized double-blind, placebo controlled, dietary crossover trial. Methods: Patients with Rome III criteria FD were recruited from a single tertiary centre in Newcastle, Australia. All were individually counselled on a diet low in both gluten and fermentable oligo-, di-, mono-saccharides, and polyols (FODMAPs) by a clinical dietitian, which was followed for four weeks (elimination diet phase). Those who had a >30% response to the run-in diet, as measured by the Nepean Dyspepsia Index, were then re-challenged with ¿muesli¿ bars containing either gluten, fructan, or placebo in randomised order. Those with symptoms which significantly reduced during the elimination diet, but reliably reappeared (a mean change in overall dyspeptic symptoms of >30%) with gluten or fructan re-challenge were deemed to have wheat induced FD. Results: Eleven participants were enrolled in the study (75% female, mean age 43 years). Of the initial cohort, nine participants completed the elimination diet phase of whom four qualified for the rechallenge phase. The gluten-free, low FODMAP diet led to an overall (albeit non-significant) improvement in symptoms of functional dyspepsia in the diet elimination phase (mean NDI symptom score 71.2 vs. 47.1, p = 0.087). A specific food trigger could not be reliably demonstrated. Conclusions: Although a gluten-free, low-FODMAP diet led to a modest overall reduction in symptoms in this cohort of FD patients, a specific trigger could not be identified. The modified Salerno criteria for NCG/WS identification trialled in this dietary rechallenge protocol was fit-for-purpose. However, larger trials are required to determine whether particular components of wheat induce symptoms in functional dyspepsia.

Background:Treatment with a duodenal-jejunal bypass sleeve (DJBS) induces clinically significant weight loss, but little is known about the mechanisms of action of this device.Aim:The aim of this study was to characterize the mechanisms of action of the DJBS and determine the durability of weight loss and metabolic improvements.Materials and Methods:We studied a cohort of 19 subjects with severe obesity and type 2 diabetes (baseline body mass index: 43.7±5.3 kg/m2). Anthropometry, body composition, blood pressure, biochemical measures, and dietary intake were monitored for 48 weeks after DJBS implantation, and then for 1 year after device removal. Gastric emptying and triglyceride absorption were measured at baseline, 8 weeks after implant, and within 3 weeks of device explant. Visceral sensory function was assessed at baseline, 4 weeks after implant, and within 3 weeks after explant.Results:Significant weight loss (P<0.01) occurred following DJBS placement, with a mean weight reduction of 17.0±6.5% at 48 weeks. The symptom burden following a standardized nutrient challenge was increased after DJBS implantation (P<0.05), returning to baseline after DJBS removal. Neither gastric emptying nor triglyceride absorption changed with the device in situ. A significant reduction in energy intake was observed [baseline: 7703±2978 kJ (1841±712 kcal), 24 weeks: 4824±2259 kJ (1153±540 kcal), and 48 weeks: 4474±1468 kJ (1069±351 kcal)]. After 1 year, anthropometry remained significantly improved, but there was no durable impact on metabolic outcomes.Conclusions:DJBS treatment resulted in substantial weight loss. Weight loss is related to reduced caloric intake, which seems linked to an augmented upper gastrointestinal symptom response, but not altered fat absorption.

Introduction: Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders and is classified into postprandial distress and epigastric pain syndrome. Despite the recognition of duodenal inflammation as a potential trigger of symptoms, only limited anti-inflammatory therapies exist. Areas covered: This narrative review summarizes the recent advances in the pathophysiology and treatment of FD; it identifies potential therapeutic targets and gaps in the field. An electronic literature search was conducted in Pubmed up to 31st of December 2019. Expert opinion: There is compelling evidence for the role of duodenal inflammation and the eosinophil-mast cell axis in the pathogenesis of dyspeptic symptoms. Traditional prokinetic drugs and neuromodulators target gastric dysmotility and visceral hypersensitivity but are hampered by limited efficacy and side effects. Independent of acid suppression, the anti-inflammatory action of proton pump inhibitors, which remain the first-line therapy in FD, may also explain their therapeutic effect. Other existing and newly established anti-inflammatory drugs should be investigated while trials including probiotics and selective antibiotics should examine the host microbiome and immune activation. Targeted treatments for potential causes of duodenal pathology, such as impaired permeability and dysbiosis, are likely to emerge in the future.

Introduction: Duodenal eosinophilia is a key feature of functional dyspepsia, particularly in those with early satiety. Duodenal eosinophilia is also recognised in coeliac disease, although its relevance to symptoms is not understood. We aimed to determine if duodenal eosinophilia is present in patients with coeliac disease presenting with dyspepsia, and whether other histological characteristics were associated with clinical features on presentation. Methods: The coeliac study population comprised 61 patients with a new presentation of coeliac disease to a single centre from 2003 to 2013. A standard symptom assessment was documented for all patients. The control population (55 adults) presenting for endoscopy without coeliac disease was drawn from the same centre with similar demographics for age and gender. Duodenal biopsies from both groups were assessed for eosinophil counts and histological features. Results: Dyspepsia was present in 18.0% of coeliac patients and early satiety in 24.6%. The eosinophil counts were significantly higher in the stomach (12.1/mm2 vs. 4.0/mm2, p <.001) and duodenum (60.4/mm2 vs. 18.0/mm2, p <.001) of coeliac patients compared with controls. There was no significant difference in the mean duodenal eosinophil count in coeliac disease with and without early satiety (55.4/mm2 vs. 66.9/mm2, p =.51). Duodenal eosinophilia was not associated with the severity of coeliac enteropathy. The degree of villous atrophy was associated with iron deficiency at presentation (p =.01), but not symptoms. Conclusions: Although duodenal eosinophil counts are higher in coeliac disease than controls, we were not able to demonstrate an association with presenting symptoms or markers of disease severity.

Background: The Gastrointestinal Symptom Rating Scale¿Irritable Bowel Syndrome (GSRS-IBS) is a 13-item measure of IBS symptom severity. The scale has been used in several studies, but its psychometric properties have been insufficiently investigated and population-based data are not available. Objective: The objective of this article is to establish the factor structure and discriminant and convergent validity of the GSRS-IBS. Methods: The study was based on a Swedish population sample (the Popcol study), of which 1158 randomly selected participants provided data on the GSRS-IBS. We used confirmatory factor analysis (CFA) and compared total and subscales scores in different groups, including IBS diagnostic status, treatment-seeking behavior, and predominant bowel habits. The GSRS-IBS scores were also correlated with quality of life indexes. Results: The sample included 164 participants with a confirmed Rome III IBS diagnosis and 994 participants without the disease. The CFA confirmed the subscales with one exception, in which the incomplete bowel-emptying item belonged to the constipation subscale rather than the diarrhea subscale. The GSRS-IBS total score and subscales were associated with diagnostic status, treatment-seeking behavior, and quality of life dimensions. The relevant subscales scores also differed between the diarrhea- and constipation-predominant subtypes of IBS. Conclusion: The GSRS-IBS total score and subscales have high discriminant and convergent validity. The CFA confirmed the overall validity of the subscales but suggest that a sense of incomplete emptying belongs to the constipation rather than the diarrhea symptom cluster. We conclude that the GSRS-IBS is an excellent measure of IBS symptom severity in the general population.

Goals and Background:Baseline impedance measured during high-resolution impedance manometry (HRIM) can distinguish patients with gastroesophageal reflux disease (GERD) from controls, presumably due to differences in esophageal acid exposure. The characteristics of regurgitation and reflux in rumination syndrome and GERD are very different, and thus we investigated whether baseline esophageal impedance would differ in these 2 patient groups compared with controls.Study:We compared 20 patients with rumination syndrome with 20 patients who had GERD and 40 controls. Baseline impedance was measured over 15 seconds during the landmark period of HRIM in all 18 impedance sensors on a HRIM catheter.Results:The mean distal baseline impedance measured in ohms during HRIM was 1336 O [95% confidence interval (CI)=799, 1873) in patients with GERD, 1536 O in rumination syndrome (95% CI=1012, 2061), and 3379 O in controls (95% CI=2999, 3759) (P<0.0001). Proximal impedance was significantly lower in the GERD and rumination groups compared with controls; rumination syndrome (2026; 95% CI=1493, 2559 O), GERD (2572; 95% CI=2027, 3118 O), and controls (3412; 95% CI=3026, 3798 O) (P<0.001).Conclusions:Baseline impedance measured during HRIM in patients with rumination syndrome is significantly lower than controls and appears similar to patients with GERD both in the proximal and distal esophagus. These findings suggest that the postprandial regurgitation in rumination syndrome alters both the distal and proximal esophageal mucosal barrier.

The pathophysiology of functional dyspepsia (FD) remains poorly understood, but alterations of the small intestinal microbiome have been observed. The place of probiotics in treatment is uncertain. We performed a systematic review and meta-analysis of the currently available randomized, controlled trials (RCTs) to evaluate the potential beneficial effects and risks of probiotics in FD. Pubmed, EMBASE, Scopus, Web of Science and the Cochrane Controlled Trials Register were searched (up to May 2019) for RCTs evaluating the effects of probiotic supplementation compared to placebo in adults with FD. Two reviewers independently assessed eligibility, trial quality and extracted information from identified articles. To compare the effects of probiotics with placebo, risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random effects models. Six trials, including 422 participants were included but only three RCTs could be included in the meta-analysis. Lactobacillus strains showed potential positive effects in terms of improving upper gastrointestinal (GI) symptoms in patients with FD. Probiotic supplementation tended to improve global dyspepsia score (n = 3 RCTs, risk ratio [RR]: 1.35, 95% CI 0.99 to 1.84; P = 0.061) and bacterial composition in the GI tract. Probiotics were well tolerated without any serious adverse events. While the available data suggest that supplementation with probiotics may improve GI symptoms in patients with FD, the evidence is insufficient to draw clear conclusions regarding efficacy. Thus, high-quality RCTs are needed to establish the beneficial effects of probiotic supplementation on FD outcomes.

Introduction: Psychological distress is associated with functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS) and functional dyspepsia (FD) but only evidence from prospective longitudinal and treatment studies can indicate whether the link between FGIDs and psychological distress is causal. Emerging evidence suggests underlying biological mechanisms may explain the association of psychological distress with FGIDs. Areas covered: This review critically evaluates whether anxiety and/or depression and FGIDs are causally related including evidence for a temporal sequence, strength and specificity of the association, biological gradient, and biological plausibility. Expert opinion: Accumulating evidence suggests that psychological factors are causal for symptoms in a subset of FGID patients and not explained by health care seeking behavior (brain-gut disorder). In other cases, psychological factors may arise secondary to intestinal disease (gut-brain disorder). Prospective population-based studies are needed in FGIDs other than IBS and FD to determine if a similar brain-gut and gut-brain syndrome exists. Treatment studies have not phenotyped FGIDs according to brain-gut versus gut-brain origins which may be important in understanding true treatment efficacy. Future research needs to unravel biological mechanisms that may explain the link between psychological factors and FGIDs but promising data in the area of the brain-gut¿immune-microbe axis is emerging.

Purpose of reviewEosinophilic colitis is a rare condition, with a prevalence rate in the USA of 2-3/100 000 persons (0.003%), but diagnosed in 0.1% of biopsies in those colonoscoped for diarrhoea. Secondary colonic eosinophilia is more common and associated with systemic, colonic and infectious diseases. In this review, the latest advances in diagnosis, treatment and prognosis are summarized and discussed.Recent findingsWhat constitutes a 'normal' count of eosinophils is poorly documented but there are recent studies that establish normal colonic eosinophil ranges as well as distinguishing histological and clinical findings in primary eosinophilic colitis and secondary colonic eosinophilia in children and adults. Primary eosinophilic colitis is rare, relatively straightforward to diagnose, but may be difficult to treat. Colonic eosinophilia may be overt in parasite infection and connective tissue disease. More subtle, secondary colonic eosinophilia is a useful biomarker for gastrointestinal diseases, such as inflammatory bowel disease, colonic spirochaetosis and collagenous colitis, but the eosinophilia may more often be overlooked. A limited number of drugs are also known to cause left sided colonic eosinophilia such as clopidogrel, ibuprofen and oestroprogestinic agents.SummaryAdvances in our understanding of primary eosinophilic colitis and secondary colonic eosinophilia is progressing and if present, colonic eosinophilia should point the clinician and pathologist to a list of differential diagnoses worth considering to direct optimal management.

Goal: The aim of this analysis was to assess in patients with inflammatory bowel disease (IBD) the risk of celiac disease and in celiac disease patients the risk of IBD.Background: Previous studies report a possible association between IBD and celiac disease; however, this link is controversial.Study: Using the search terms "inflammatory bowel disease" and "celiac disease," we identified initially 1525 publications. In total 27 studies met inclusion criteria. Proportions and 95% confidence intervals (CIs) for the prevalence of IBD in celiac disease and vice versa were compared with published prevalence rates for the respective geographic regions.Results: We included 41,482 adult IBD patients (20,357 with Crohn's disease; 19,791 with ulcerative colitis; and 459 patients with celiac disease). Overall, in IBD patients the prevalence of celiac disease was 1110/100,000 (95% CI, 1010-1210/100,000) as compared with a prevalence of 620/100,000 (95% CI, 610-630/100,000) in the respective populations (odds ratio, 2.23; 95% CI, 1.99-2.50). In contrast, in patients with celiac disease, 2130/100,000 had IBD (95% CI, 1590-2670/100,000) as compared with 260/100,000 (95% CI, 250/100,000-270/100,000) in the respective populations (odds ratio, 11.10; 95% CI, 8.55-14.40). This effect was not different for ulcerative colitis and Crohn's disease. Although there was no evidence for publication bias for celiac disease in IBD, the funnel plot suggested that the association between IBD in celiac disease might be influenced by publication bias.Conclusions: The data are consistent with the notion that celiac disease is a risk factor for IBD and to lesser degree patients with IBD have an increased risk of celiac disease.

The authors conducted a systematic review and meta-analysis to assess the effect of antibiotic therapy in primary sclerosing cholangitis (PSC). Effect of antibiotic therapy on Mayo PSC Risk Score (MRS), serum alkaline phosphatase (ALP), total serum bilirubin (TSB), and adverse events (AEs) rates were calculated and expressed as standardized difference of means or proportions. Five studies including 124 PSC patients who received antibiotics were included. Overall, antibiotic treatment was associated with a statistically significant reduction in ALP, MRS, and TSB by 33.2, 36.1, and 28.8%, respectively. ALP reduction was greatest for vancomycin (65.6%, p < 0.002) and smallest with metronidazole (22.7%, p = 0.18). Overall, 8.9% (95% confidence interval: 3.9-13.9) of patients had AEs severe enough to discontinue antibiotic therapy. In PSC patients, antibiotic treatment results in a significant improvement in markers of cholestasis and MRS. Antibiotics, particularly vancomycin, may have a positive effect on PSC either via direct effects on the microbiome or via host-mediated mechanisms.

Background: According to Rome IV criteria, functional dyspepsia (FD) and irritable bowel syndrome (IBS) are distinct functional gastrointestinal disorders (FGID); however, overlap of these conditions is common in population-based studies, but clinical data are lacking. Aims: To determine the overlap of FD and IBS in the clinical setting and define risk factors for the overlap of FD/IBS. Methods: A total of 1127 consecutive gastroenterology outpatients of a tertiary center were recruited and symptoms assessed with a standardized validated questionnaire. Patients without evidence for structural or biochemical abnormalities as a cause of symptoms were then categorized based upon the symptom pattern as having FD, IBS or FD/IBS overlap. Additionally, this categorization was compared with the clinical diagnosis documented in the integrated electronic medical records system. Results: A total of 120 patients had a clinical diagnosis of a FGID. Based upon standardized assessment with a questionnaire, 64% of patients had FD/IBS overlap as compared to 23% based upon the routine clinical documentation. In patients with severe IBS or FD symptoms (defined as symptoms affecting quality of life), the likelihood of FD/IBS overlap was substantially increased (OR = 3.1; 95%CI 1.9¿5.0) and (OR = 9.0; 95%CI 3.5¿22.7), respectively. Thus, symptom severity for IBS- or FD symptoms were significantly higher for patients with FD/IBS overlap as compared to patients with FD or IBS alone (p all < 0.01). Age, gender and IBS-subtype were not associated with overlap. Conclusion: In the clinical setting, overlap of FD and IBS is the norm rather than the exception. FD/IBS overlap is associated with a more severe manifestation of a FGID.

Background: It is unexplained why functional dyspepsia and gastro-oesophageal reflux disease (GERD) overlap more often than expected by chance. Post-prandial distress syndrome has been linked to impaired gastric fundic accommodation which may induce increased transient lower oesophageal sphincter relaxations and consequent GERD. Duodenal eosinophilia has been linked to functional dyspepsia and post-prandial distress syndrome. Aim: To identify if there is an association between duodenal eosinophilia in functional dyspepsia and symptoms of GERD and whether post-prandial distress syndrome or epigastric pain syndrome are associated with new onset GERD. Methods: Participants (n¿=¿1000) were randomly selected from the national Swedish population register and surveyed by questionnaires and oesophagogastroduodenoscopy in 1999-2001. All eligible subjects (n¿=¿887) were invited to a follow-up study in 2010 (response rate 79%). In a case-control study of 213 subjects (functional dyspepsia vs healthy controls), histology from the duodenum was evaluated at baseline and the possible association of eosinophilia to new onset GERD symptoms was analysed. Results: Functional dyspepsia (OR 7.6; 95% CI 2.93-19.4, P¿<¿0.001) and post-prandial distress syndrome at baseline (OR 9.0, 95% CI 3.36-24.0, P¿<¿0.001) were associated with an increased risk of GERD at follow-up. Eosinophilia in the second part of duodenum only was independently associated with an increased risk of GERD amongst those with functional dyspepsia (OR 4.2; 95% CI 1.2-4.77, P¿=¿0.024) and post-prandial distress syndrome at baseline (OR 6.0; 95% CI 1.50-23.6, P¿=¿0.011), respectively. Conclusions: Duodenal eosinophilia is associated with increased risk of GERD at 10-year follow-up in those with functional dyspepsia and post-prandial distress syndrome at baseline. Duodenal eosinophilia may explain the link between GERD and functional dyspepsia, suggesting subsets of functional dyspepsia and GERD may be part of the same disease spectrum.

Background: The pathogenesis of functional GI disorders (FGIDs) is uncertain. However, underlying immune activation and psychological distress has been documented in irritable bowel syndrome (IBS) and functional dyspepsia (FD). Epidemiological data from the UK suggest that FGIDs are linked to atopy and certain autoimmune diseases but this has not been confirmed. Aim: To test if allergic or autoimmune diseases are independently associated with FGIDs, irrespective of psychological distress in a large population based study. Methods: A total of 3542 people (mean age 57.9¿years and 52.7% females) randomly selected from the Australian population, returned a mail survey (response rate¿=¿43%). The survey asked about a physician diagnosis of autoimmune disease (scleroderma, psoriasis, rheumatoid arthritis and diabetes mellitus) or allergic conditions (asthma, food, pollen and/or animal allergy). The questionnaire assessed psychological distress and Rome III criteria for FD and IBS. Results: Asthma, food, pollen and animal allergies, psoriasis and rheumatoid arthritis were univariately significantly associated with IBS and FD. Food allergy (OR¿=¿1.66; 95% CI¿=¿1.15-2.40, P¿=¿0.007), psoriasis (OR¿=¿1.81; 95% CI¿=¿1.19-2.74, P¿=¿0.006) and rheumatoid arthritis (OR¿=¿1.68; 95% CI¿=¿1.15-2.4, P¿=¿0.007) were independent risk factors for IBS, controlling for age, gender and psychological distress. In FD, asthma (OR¿=¿1.32; 95% CI¿=¿1.04-1.68, P¿=¿0.025) and food allergy (OR¿=¿1.78; 95% CI¿=¿1.28-2.49, P¿=¿0.001) were independent predictors, controlling for age, sex and psychological distress. Conclusions: There is evidence that both atopic and autoimmune diseases are risk factors for FGIDs, independent of psychological distress, differing in IBS and FD. This provides evidence that different peripheral pathways may be involved in the pathogenesis of certain FGIDs.

Background and study aims: Barrett's esophagus is a premalignant condition in the distal esophagus associated with esophageal adenocarcinoma. Since gastroesophageal reflux is known to be of etiological importance in both Barrett's esophagus and esophageal adenocarcinoma, we aimed to study which endoscopic alterations at the Z-line can be attributed to a previous history of reflux symptoms. Patients and methods: From 1988, a population cohort in Sweden has been prospectively studied regarding gastrointestinal symptoms, using a validated questionnaire. In 2012, the population was invited to undergo a gastroscopy and participate in the present study. In order to determine which endoscopic alterations that can be attributed to a previous history of gastroesophageal reflux, three different endoscopic definitions of columnar-lined esophagus (CLE) were used: (1) ZAP I, An irregular Z-line with a suspicion of tongue-like protrusions; (2) ZAP II/III, Distinct, obvious tongues of metaplastic columnar epithelium; (3) CLE =1 cm, The Prague C/M-classification with a minimum length of 1 cm. Results: A total of 165 community subjects were included in the study. Of these, 40 had CLE = 1 cm, 99 had ZAP I, and 26 had ZAP II/III. ZAP II/III was associated with an over threefold risk of previous GER symptoms (OR: 3.60, CI: 1.49¿8.70). No association was found between gastroesophageal reflux and ZAP I (OR: 2.06, CI: 0.85¿5.00), or CLE =1 cm (OR: 1.64, CI: 0.77¿3.49). Conclusions: In a general community, the only endoscopic alteration to the Z-line definitely linked to longstanding GER symptoms was the presence of obvious tongues of metaplastic columnar epithelium (ZAP II/III).

Food ingestion is heavily implicated in inducing symptoms of irritable bowel syndrome (IBS) and functional dyspepsia (FD), which affect over one-third of adults in developed countries. The primary aim of this paper was to assess the alignment of dietary assessment and symptom-reporting capture periods in diet-related studies on IBS or FD in adults. Secondary aims were to compare the degree of alignment, validity of symptom-reporting tools and reported significant associations between food ingestion and symptoms. A five-database systematic literature search resulted in 40 included studies, from which data were extracted and collated. The food/diet and symptom capture periods matched exactly in 60% (n = 24/40) of studies, overlapped in 30% (n = 12/40) of studies and were not aligned in 10% (n = 4/40) of studies. Only 30% (n = 12/40) of studies that reported a significant association between food and global gastrointestinal symptoms used a validated symptom-reporting tool. Of the thirty (75%) studies that reported at least one significant association between individual gastrointestinal symptoms and dietary intake, only four (13%) used a validated symptom tool. Guidelines to ensure that validated symptom-reporting tools are matched with fit-for-purpose dietary assessment methods are needed to minimise discrepancies in the alignment of food and symptom tools, in order to progress functional gastrointestinal disorder research.

INTRODUCTION:Low-grade chronic inflammation has been suggested to play a role in uncomplicated asymptomatic and symptomatic diverticular disease. However, population-based studies are lacking. We investigated whether community participants with diverticulosis, with or without symptoms, would have colonic inflammation on histology and serology.METHODS:In a nested case-control study of 254 participants from the population-based colonoscopy (PopCol) study, colonic histological inflammatory markers and serological C-reactive protein levels were analyzed in cases with diverticulosis and controls without diverticulosis. Statistical methods included logistic and linear regression models.RESULTS:Background variables including age (P = 0.92), sex (P = 1.00), body mass index (P = 0.71), smoking (P = 0.34), and recent antibiotic exposure (P = 0.68) were similar between cases and controls. Cases reported more abdominal pain (P = 0.04) and diarrhea symptoms (mushy and high-frequency stools) than controls (P = 0.01 and P = 0.03, respectively) but were otherwise similar. The median C-reactive protein levels were similar among cases and controls [1.05 mg/L (0.3, 2.7) vs 0.8 (0.4, 2.2), P = 0.53]. There was a trend of increased numbers of cecal lymphoid aggregates in cases vs controls (P = 0.07), but no other associations between diverticulosis and inflammatory markers on histology were found. Similarly, no serological or mucosal inflammation was associated with symptomatic cases of diarrhea or abdominal pain vs asymptomatic controls.CONCLUSIONS:In a general community sample, both asymptomatic and symptomatic diverticulosis are not associated with colonic mucosal inflammation. Other explanations for symptomatic colonic diverticulosis need to be identified.

Gastroparesis is a complex syndrome with symptoms that include nausea, vomiting, and postprandial abdominal pain, and is frequently accompanied by significant delays in gastric emptying. The pathophysiology of diabetic gastroparesis is fairly well understood; however, idiopathic gastroparesis, which accounts for one-third of all cases, may stem from infections, or autoimmune or neurologic disorders, among other causes. To date, few population-based studies have estimated the true prevalence and incidence of gastroparesis. Nonetheless, its prevalence appears to be rising, as does its incidence among minority populations, documented via hospitalizations, which can impose significant economic burdens on patients.

Background Clinical understanding of gastrointestinal symptoms is commonly based on patient reports of symptom experience. For diagnosis and treatment choices to be appropriate, symptom reports need to be accurate. We examined the agreement between questionnaire recall and prospective diary enumeration of symptoms relevant to the irritable bowel syndrome. Patients and methods Data are reported from a randomly selected general population sample (n= 238) and also a primary healthcare centre (PHC) sample (n =503, 10 PHCs). All the patients completed the questionnaires, which included Rome IIIqualifying irritable bowel syndrome items and a stool and symptom diary over either 7 or 14 days. Agreement between retrospective questionnaire reports and prospective diaries was evaluated. Results Concordance between questionnaires and diaries was highest for the simple construct of the occurrence of abdominal pain, although after adjusting for possible chance, agreement was only moderate in the general population sample. More complex constructs, such as pain relieved by defecation, yielded poorer concordance. In general, concordance was stronger among PHC respondents than in the general population sample. Conclusion Concordance between questionnaires and diaries was generally poor and related to the complexity of the symptom construct and the type of respondent. The information used to classify individuals based on patient self-report may be unreliable, and therefore, more effort is needed to develop data collection instruments.

Background The Nepean Dyspepsia Index (NDI) has been in widespread use since its publication in 1999 and the addition of a short form in 2001. The NDI was one of the first disease-specific quality-of-life instruments created for functional dyspepsia (FD). However, its psychometric properties have never been validated in an independent sample. Aim This study aimed to evaluate the validity and reliability of the NDI in an a-priori driven approach in an independent population. Patients and methods In 289 individuals who fulfilled the Rome criteria for FD enrolled in a randomized placebo-controlled trial (FD treatment trial), we examined construct validity, convergent validity, and internal consistency. Results Construct validity was supported in its 25-item unweighted and weighted forms as well as the 10-item short form. All items in the 25-item form yielded considerable (>0.5) standardized loadings on their respective latent variables and all reached statistical significance (P<0.0001), supporting their relationships with the hypothesized domains. Convergent validity was strongly supported, with every domain being correlated with multiple external instruments; the majority of correlations were in the range 0.3-0.5 (in absolute values). The items comprising each domain showed good internal consistency, with the lowest value of Chronbach a at 0.80. Scores based on the short form (10-item) version of the NDI correlated strongly with the full 25-item form (tension ¿=0.88, interference ¿=0.94, eat/drink ¿=0.95, knowledge ¿=0.84 and work/study ¿=0.97; all P<0.0001). Conclusion The NDI is a valid instrument that can be used to measure the disease-specific impact of FD on quality of life.

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 ¿-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.

Background: Pregabalin is a calcium channel a2d 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.