A Minority of Childhood Disorders of Gut-Brain Interaction Persist Into Adulthood: A Risk-Factor Analysis.

INTRODUCTION: Disorders of gut-brain interaction (DGBIs) may originate in childhood. There are currently limited data on persistence of DGBI into adulthood and risk factors for persistence. Furthermore, there are no data on this question from general practice, where the majority of DGBIs are diagnosed and managed. This study documents the proportion of childhood-diagnosed DGBIs that persisted into adulthood and what factors were associated with persistence. METHODS: General practice records were obtained for more than 60,000 patients whose medical record spanned both childhood and adulthood years. Patients with diagnosed organic gastrointestinal disorder were excluded. Medical records were also interrogated for potential risk factors. RESULTS: Eleven percent of patients with irritable bowel syndrome (IBS) and 20% of patients with functional dyspepsia (FD) diagnosed in childhood had repeat diagnoses of the same condition in adulthood. Female sex (odds ratio [OR] 2.02) was associated with persistence for IBS, while a childhood diagnosis of gastritis (OR 0.46) was risk-protective. Childhood non-steroidal anti-inflammatory drug use (OR 1.31, 95% confidence interval [CI] 1.09-1.56) was a risk factor for persistence in IBS. For FD, a childhood diagnosis of asthma (OR 1.30, 95% CI 1.00-1.70) was a risk factor, as was anxiety for both IBS (OR 1.24, 95% CI 1.00-1.54) and FD (OR 1.48 95% CI 1.11-1.97) with a similar finding for depression for IBS (OR 1.34, 95% CI 1.11-1.62) and FD (OR 1.88 95% CI 1.47-2.42). DISCUSSION: Childhood DGBIs persist into adulthood in 10%-20% of patients, suggesting that management monitoring should continue into adulthood. Those diagnosed with anxiety or mood disorders in childhood should receive particular attention, and prescription of non-steroidal anti-inflammatory drugs in children should be made judiciously.

Preinjection With Ligation-Assisted Endoscopic Mucosal Resection for Barrett's Dysplasia and Early Esophageal Adenocarcinoma: Characteristic Histological Features of the Depth of Resection.

BACKGROUND AND AIM: Endoscopic mucosal resection (EMR) is an established technique for the diagnosis and treatment of high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) in Barrett's esophagus. Submucosal preinjection is not universally used or generally recommended when performing routine ligation-assisted EMR. Prior studies, however, have demonstrated evidence of at least superficial muscle injury on ligation-assisted EMR without submucosal injection. There are limited published data supporting any potential benefit of submucosal preinjection. Our aim was to review this technique and determine the rate of any degree of muscle injury in patients with Barrett's HGD and EAC treated with submucosal preinjection before ligation-assisted EMR. METHODS: Patients undergoing submucosal preinjection before ligation-assisted EMR for Barrett's esophagus at a single institution between 2012 and 2016 were identified. Data were collected regarding patient demographics and medical history, endoscopy and histopathology findings, adverse events, and subsequent outcomes. All EMR specimens were reviewed by an expert gastrointestinal pathologist. RESULTS: One hundred fifty consecutive EMR procedures were performed on 70 patients. Of 70 patients, 85.7% of patients were men, with a median age of 68 years. EAC was identified in 75 specimens (50%) and HGD in 44 specimens (29.3%). Deep resection margins were clear of adenocarcinoma in all specimens. Muscularis propria was not identified in any of the 150 specimens. There were no cases of post-EMR perforation. CONCLUSIONS: Preinjection before ligation-assisted EMR achieved complete excision with histologically clear margins, without histological evidence of any inadvertent muscularis propria.

Prevalence of small intestinal bacterial overgrowth in intestinal failure syndrome: A systematic review and meta-analysis.

BACKGROUND AND AIM: Patients with intestinal failure (IF) have abnormal intestinal anatomy, secretion, and dysmotility, which impairs intestinal homeostatic mechanisms and may lead to small intestinal bacterial overgrowth (SIBO). We conducted a systematic review and meta-analysis to determine the prevalence of SIBO in patients with IF and to identify risk factors for SIBO. METHODS: MEDLINE (PubMed) and Embase electronic databases were searched from inception to December 2023 for studies that reported the prevalence of SIBO in IF. The prevalence rates, odds ratio (OR), and 95% confidence intervals of SIBO in IF and the risk factors for SIBO in IF were calculated using random effects model. RESULTS: Final dataset included nine studies reporting on 407 patients with IF. The prevalence of SIBO in IF was 57.5% (95% CI 44.6-69.4), with substantial heterogeneity in this analysis (I2 = 80.9, P = 0.0001). SIBO prevalence was sixfold higher in patients with IF who received parenteral nutrition (PN) compared with IF patients not on PN (OR = 6.0, 95% CI 3.0-11.9, P = 0.0001). Overall, the prevalence of SIBO in patients with IF using PPI/acid-suppressing agents (72.0%, 95% CI 57.5-83.8) was numerically higher compared with IF patients not using these agents (47.6%, 95% CI 25.7-70.2). CONCLUSIONS: This systematic review and meta-analysis suggests that there is an increased risk of SIBO in patients with IF and that PN, and potentially, the use of PPI/acid-suppressing agents is risk factors for SIBO development in patients with IF. However, the quality of evidence is low and can be attributed to lack of case-control studies and clinical heterogeneity seen in the studies.

Efficacy and Safety of STW 5-II for Functional Dyspepsia Treatment: A Patient Data-Based Meta-Analysis.

INTRODUCTION: Functional dyspepsia (FD) is a chronic relapsing gastroduodenal disorder with limited treatment options. Herbal products, like the six-herb combination STW 5-II, can target multiple FD gastrointestinal symptoms. In this meta-analysis, we evaluated the efficacy and safety of STW 5-II for overall FD, and key symptoms, based on Rome IV criteria. METHODS: We systematically screened the literature for randomized controlled clinical studies testing STW 5-II in FD. Meta-analysis was performed using data from individual patients with at least one key FD symptom (fullness, early satiety, or epigastric pain) of at least moderate severity at baseline. ANCOVA-based meta-analyses were performed on improvements in the total symptom sum score, and single symptoms, after 4 and 8 weeks. Safety data were analyzed by calculating odds ratios for all adverse events. RESULTS: Four randomized controlled trials, including 613 patients, were identified, and two were eligible for efficacy analysis. STW 5-II significantly improved the FD symptom sum score (mean difference of 1.74 after 4 weeks and 2.07 after 8 weeks) and key FD symptoms of fullness (0.28 and 0.29), early satiety (0.25 and 0.26), and epigastric/upper abdominal pain (0.26 and 0.3). Treatment-related or severe adverse events did not differ between STW 5-II and placebo. CONCLUSION: The results support that STW 5-II significantly improves FD symptoms after 4 and 8 weeks of treatment with no difference in relation to safety signals compared to placebo. Thus, STW 5-II can be considered an effective and safe treatment option for FD.

An 'Adaptive Treatment Strategy' for Oral Vancomycin in Patients with the Orphan Disease Primary Sclerosing Cholangitis.

Decision-making in clinical medicine ideally is based upon evidence from randomized, placebo-controlled trials (RCTs) and subsequent systematic reviews and meta-analyses. However, for orphan diseases, the expectation of having one or multiple RCTs that inform clinical guidelines or justify specific treatments can be unrealistic and subsequent therapeutic nihilism can be detrimental to patients. This article discusses the benefits of therapeutic decision-making in the context of orphan diseases, focusing on primary sclerosing cholangitis (PSC) as an example of an orphan disease with poor clinical outcomes. PSC is a rare disorder characterized by inflammation and progressive fibrosis of the bile ducts. It carries a high risk of liver failure, malignancies, and debilitating symptoms that impair quality of life. Liver transplantation is currently the only life-prolonging intervention for PSC, but it is not a curative option. The article highlights the potential benefits of treating PSC patients with oral vancomycin (OV), which has shown significant clinical responses and improved quality of life in some cases. However, access to OV therapy is limited due to the lack of RCTs supporting its use. The standard requirement of having evidence from RCTs may result in withholding potentially life-altering and/or life-saving treatments for patients with orphan diseases. Conducting RCTs is challenging in these patient populations due to difficulties in recruiting the required patient cohorts and limited commercial returns. A standardized 'adaptive treatment strategy' is proposed to address this. This approach leverages the best available evidence for specific treatments, considers individual clinical responses, and adjusts treatment over time.

Healthcare Utilization Patterns: Irritable Bowel Syndrome, Inflammatory Bowel Disease, and Gastroesophageal Reflux Disease.

BACKGROUND: Limited information is available about patterns of healthcare utilization for prevalent gastrointestinal conditions and their link to symptom burden. AIM: To identify patterns of healthcare utilization among outpatients with highly prevalent gastrointestinal conditions and define the link between healthcare utilization, symptom burden, and disease group. METHODS: We randomly selected patients from the gastroenterology outpatient clinic at Princess Alexandra Hospital who had chronic gastrointestinal conditions such as constipation-predominant irritable bowel syndrome (IBS-C, n = 101), diarrhea-predominant IBS (IBS-D, n = 101), mixed IBS (n = 103), inflammatory bowel disease with acute flare (n = 113), IBD in remission (n = 103), and gastroesophageal reflux disease (n = 102). All had presented at least 12 months before and had a 12-month follow-up after the index consultation. Healthcare utilization data were obtained from state-wide electronic medical records over a 24-month period. Intensity of gastrointestinal symptoms was measured using the validated Structured Assessment of Gastrointestinal Symptoms (SAGIS) Scale. Latent class analyses (LCA) based on healthcare utilization were used to identify distinct patterns of healthcare utilization among these patients. RESULTS: LCA revealed four distinct healthcare utilization patterns across all diagnostic groups: Group A: Emergency department utilizers, Group B: Outpatient focused care utilizers, Group C: Inpatient care utilizers and Group D: Inpatient care and emergency department utilizers. LCA groups with high emergency utilization were characterized by high gastrointestinal symptom burden at index consultation regardless of condition (Mean (standard deviation)) SAGIS score Group A: 24.63 (± 14.11), Group B: 19.18 (± 15.77), Group C: 22.48 (± 17.42), and Group D: 17.59 (± 13.74, p < 0.05). CONCLUSION: Distinct healthcare utilization patterns across highly prevalent gastrointestinal conditions exist. Symptom severity rather than diagnosis, likely reflecting unmet clinical need, defines healthcare utilization.

Double-blind, randomized, 8-week multicenter study of the efficacy and safety of STW 5-IIversus placebo in functional dyspepsia.

Background and Aim: Herbal products are widely used to treat patients with disorders of gut brain interaction but clinical efficacy and safety data for treatments lasting >4 weeks are widely lacking. We evaluated the efficacy and safety of 8 weeks of treatment with the herbal combination product STW 5-II for patients with functional dyspepsia (FD) meeting Rome II criteria. We also conducted a post hoc analysis including patients meeting Rome IV criteria for FD and evaluated the effect of the G-protein beta 3 (GNB3) subunit polymorphism (C825T) on therapeutic response. Methods: This multicenter, placebo-controlled, double-blind study included 272 FD patients meeting Rome II criteria in the intention-to-treat cohort and 266 meeting Rome IV criteria. We used the validated Gastrointestinal Symptom Score (GIS) to assess GI symptoms, defining response rate as the proportion of patients with ≥50% GIS improvement in at least three of four assessments. Results: After 8 weeks, the response rate was significantly higher in the STW 5-II group versus placebo (61.2% vs 45.1%, P = 0.008). Mean GIS non-significantly improved with STW 5-II treatment (7.9 ± 4.41 vs 6.7 ± 4.91 with placebo; P = 0.07). In the Rome IV subgroup analysis, STW 5-II yielded a better response rate (P = 0.01) versus placebo and greater postprandial distress symptom improvement (P = 0.04) versus placebo. Safety parameters did not differ between groups, and GNB3 status was not linked with therapeutic response. Conclusion: STW 5-II is efficacious, with no observed safety signals at up to 8 weeks of treatment in patients with FD meeting Rome II or IV criteria.

What impact has the Centre of Research Excellence in Digestive Health made in the field of gastrointestinal health in Australia and internationally? Study protocol for impact evaluation using the FAIT framework.

INTRODUCTION: The need for public research funding to be more accountable and demonstrate impact beyond typical academic outputs is increasing. This is particularly challenging and the science behind this form of research is in its infancy when applied to collaborative research funding such as that provided by the Australian National Health and Medical Research Council to the Centre for Research Excellence in Digestive Health (CRE-DH). METHODS AND ANALYSIS: In this paper, we describe the protocol for applying the Framework to Assess the Impact from Translational health research to the CRE-DH. The study design involves a five-stage sequential mixed-method approach. In phase I, we developed an impact programme logic model to map the pathway to impact and establish key domains of benefit such as knowledge advancement, capacity building, clinical implementation, policy and legislation, community and economic impacts. In phase 2, we have identified and selected appropriate, measurable and timely impact indicators for each of these domains and established a data plan to capture the necessary data. Phase 3 will develop a model for cost-consequence analysis and identification of relevant data for microcosting and valuation of consequences. In phase 4, we will determine selected case studies to include in the narrative whereas phase 5 involves collation, data analysis and completion of the reporting of impact.We expect this impact evaluation to comprehensively describe the contribution of the CRE-DH for intentional activity over the CRE-DH lifespan and beyond to improve outcomes for people suffering with chronic and debilitating digestive disorders. ETHICS AND DISSEMINATION: This impact evaluation study has been registered with the Hunter New England Human Research Ethics Committee as project 2024/PID00336 and ethics application 2024/ETH00290. Results of this study will be disseminated via medical conferences, peer-reviewed publications, policy submissions, direct communication with relevant stakeholders, media and social media channels such as X (formely Twitter).

Efficacy and safety of biologics in primary sclerosing cholangitis with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an immune-mediated, chronic cholestatic liver disease. Currently, liver transplantation is the only established life-saving treatment. Several studies have evaluated the effect of different biologic therapies on PSC with inconclusive findings. We conducted a systematic review and meta-analysis to assess the effects of biologics in PSC and associated inflammatory bowel disease (IBD). METHODS: MEDLINE, Scopus, and Embase were searched up to July 31, 2023, for studies reporting the effects of biologics in patients with PSC-IBD. Effects of biologic therapy on alkaline phosphatase, total bilirubin, ulcerative colitis response score, and adverse events were calculated and expressed as standardized difference of means (SMD), proportions, and 95% CI using a random-effects model. RESULTS: Six studies, including 411 PSC-IBD patients who received biologics, were included. Biologic treatment was associated with no change in alkaline phosphatase (SMD: 0.1, 95% CI: -0.07 -0.17, p=0.43), but a small and statistically significant increase in total bilirubin (SMD: 0.2, 95% CI: 0.05-0.35, p<0.01). 31.2% (95% CI: 23.8-39.7) of patients with IBD achieved endoscopic response, and there was a significant improvement in ulcerative colitis response score (SMD: -0.6,95% CI: -0.88 to 0.36, p<0.01). Furthermore, 17.6% (95% CI: 13.0-23.5) of patients experienced adverse events severe enough to discontinue therapy, and 29.9% (95% CI: 25.2-34.8) had a loss of response to biologics. CONCLUSIONS: Treatment of patients with PSC-IBD with biologics (vedolizumab, infliximab, and adalimumab) was not associated with improvement of biochemical markers of cholestasis. Biologics are effective in treating the colitis associated with PSC. Vedolizumab was associated with worsening liver enzymes in contrast to other biologics, a finding that warrants further study.

A multifaceted ecological approach to explore links between environmental factors and the epidemiology of disorders of gut-brain interaction.

BACKGROUND: Disorders of gut-brain interaction (DGBI) are characterized by debilitating symptoms not explained by structural or biochemical abnormalities. While functional conditions present with complex, likely heterogeneous pathophysiology, we aimed to investigate if proxy measures of sociocultural and environmental factors are associated with the prevalence of various DGBI in populations across the world. METHODS: We performed an ecological study utilizing peer-reviewed published datasets reporting for 26 countries prevalence rates of DGBI (Rome Foundation Global Epidemiology Study, RFGES), with six independent variables: Helicobacter pylori prevalence and household size as proxy measures for orofecal infections, gross domestic product per capita (GDP), and median age as a proxy measures for socioeconomic development, density of fast food outlets (FFO) per 100,000 population as proxy measure for processed food exposure, and suicide mortality rate per 100,000 people, and world happiness scores were used as a proxy for psychological stress. The data were retrieved from publicly accessible datasets (United Nations, CIA World Factbook, World Bank, World Happiness Report, commercial/financial reports of a global FFO chain). We used linear regression to assess variables in univariate and multivariate analysis and report standardized ß coefficients with 95% confidence intervals (CI). KEY RESULTS: The regression model revealed that the overall prevalence of DGBI was inversely associated with both GDP per capita (ß = -0.57, 95% CI: -0.92, -0.22, p = 0.002) and happiness scores (ß = -0.433 95% CI: 0.821, -0.065, p = 0.023), while being positively associated with H. pylori prevalence (ß = 0.40, 95% CI: 0.008, 0.81, p = 0.046). The prevalence of functional constipation (FC) was also inversely associated with GDP per capita (ß = -0.50, 95% CI: -0.86, -0.13, p = 0.01) and happiness scores (ß = -0.497, 95% CI: -0.863, -0.132, p = 0.01), while being positively associated with H. pylori prevalence (ß = 0.53, 95% CI: 0.16, 0.91, p = 0.007). The Multivariate model analysis revealed that combining the factors of H. pylori prevalence, suicide rate, household size and happiness scores showed statistically significant association with FC (p = 0.039). Household size (ß = -0.43, 95% CI: -0.82, 0.038, p = 0.033) and suicide rates (ß = 0.55, 95% CI: 0.19, 0.90, p = 0.004) were statistically significantly associated with functional diarrhea. Irritable bowel syndrome (IBS) was associated with GDP per capita (ß = -0.40, 95% CI: -0.79, -0.014, p = 0.043) and happiness scores (ß = -0.390, 95% CI: -0.778, -0.003, p = 0.049). CONCLUSIONS & INFERENCES: Utilizing publicly available data, the prevalence of DGBI across diverse countries is linked to various socio-cultural and environmental factors. Collectively, the data suggests that the prevalence of DGBI is increased in less prosperous regions of the world.

The COVID-19 pandemic as a modifier of DGBI symptom severity: A systematic review and meta-analysis.

BACKGROUND: This SRMA reviewed and assessed the changes in the severity of disorders of gut-brain interaction (DGBI) symptoms during the COVID-19 pandemic, and evaluated factors associated with symptom severity changes. METHODS: Electronic databases were searched until February 2024, for articles reporting on changes in symptom severity in DGBI patients during the COVID-19 pandemic. The proportion of DGBI patients who reported a change in their symptom severity were pooled using a random-effects model, and subgroup analyses were conducted to assess the effect of socio-cultural modifiers on symptom severity in DGBI. KEY RESULTS: Twelve studies including 3610 DGBI patients found that 31.4% (95% CI, 15.9-52.5) of DGBI patients experienced symptom deterioration, while 24.3% (95% CI, 10.2-47.5) experienced improvement. Countries with high gross domestic product (GDP) had a 43.5% (95% CI, 16.3-75.2) likelihood of symptom deterioration, compared to 9.2% (95% CI, 1.4-42.2) in lower GDP countries. Similarly, countries with low COVID fatality rates had a 60.1% (95% CI, 19.7-90.3) likelihood of symptom deterioration, compared to 18.3% (95% CI, 7.8-36.9) in higher fatality rate countries. Countries with lenient COVID policies had a 58.4% (95% CI, 14.1-92.3) likelihood of symptom deterioration, compared to 19% (95% CI, 8.2-38.1) in countries with stricter policies. Patients in high vaccine hesitancy countries had a 51.4% (95% CI, 19.5-82.2) likelihood of symptom deterioration, compared to 10.6% (95% CI, 2.7-33.4) in low vaccine hesitancy countries. CONCLUSIONS & INFERENCES: This meta-analysis reveals that a significantly higher proportion of DGBI patients experienced deterioration of symptoms during the COVID-19 pandemic. Various sociocultural, economic and environmental factors potentially modify the effects of the COVID-19 pandemic on DGBI.