Introduction

Approximately 50% of patients with disorders of gut-brain interaction (DGBI) report intolerance of wheat products [2]. While dietary gluten restrictions would be a feasible approach to managing gastrointestinal symptoms, in DGBI patients with gluten-related symptoms, there are challenges in relation to compliance and even adverse long-term effects of a gluten and wheat-free diet.

Aims & Methods

This study aims to test the feasibility of a double-blind gluten exposure test and determine the rate of patients with DGBI who respond with a change of symptom severity after exposure to gluten.
From a cohort of 70 consecutive patients referred to our Integrated Care Clinic for patients with complex DGBI, 35 agreed to participate in a double-blind gluten exposure test. This test was aligned with the gluten exposure test outlined in the Salerno criteria [1]. After exclusion of coeliac disease (endoscopy and serology), a seven-week gluten-free run-in, patients received one week of encapsulated gluten (8 g per day) or identical placebo. Each week with daily gluten exposure or placebo exposure was separated by one week of washout. Gluten and placebo were administered in a double-blind randomised fashion. The Structured Assessment of Gastrointestinal Symptoms (SAGIS) score was used at baseline before commencing the gluten exposure test and at the end of every week to assess changes of gastrointestinal symptoms.

Results

34 patients completed the challenge test, of whom seven initially had self-reported symptoms associated with gluten or wheat consumption. Only one of these seven patients responded to gluten exposure with a >25% increase of the SAGIS score. 16 out of 34 patients (47 %, 95% CI 30-65) reported improved gastrointestinal symptoms while on a gluten-free diet. Overall, 2 of the 34 patients (5.9%, 95% CI 0.7-20.0) showed a deterioration of symptoms during the gluten challenge week, while 8 patients (23.5%, 95% CI 10.8-41.2) reported a reduction of the symptoms while exposed to placebo. No effects of gluten exposure on extraintestinal symptoms were observed.

Conclusion

A standardised, double-blind gluten exposure test is suitable in the routine clinical setting to rule out gluten intolerance in patients with self-reported gluten sensitivity. Overall, gluten exposure is rarely associated with an increase of gastrointestinal symptoms in patients with DGBI. Self-reported non-celiac wheat sensitivity is a poor predictor for developing symptoms during double-blind gluten exposure.

References

[1] Catassi C, Elli L, Bonaz B, et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria. Nutrients 2015;7:4966-77.
[2] Shah A, Talley NJ, Kang S, et al. Self-reported non-celiac wheat sensitivity in patients with chronic unexpalined (functional) gastrointestinal symptoms: gut function, immune activation and duodenal mucosa associated microbiome. Gastroenterology 2020;158:S-488

Introduction

Disorders of brain gut interaction (DBGI) including irritable bowel syndrome (IBS) and functional dyspepsia (FD), and gastro-oesophageal reflux disease (GERD) including reflux oesophagitis (RE) and non-erosive reflux disease (NERD) are all prevalent in the general population. It is well established that many patients with GERD also report a DGBI, an overlap not due to chance [1]. Psychological comorbidity is known to be strongly associated with DGBI [2]. Individuals with GERD also report elevated rates of anxiety and depression. Those with overlapping DGBI and GERD have poorer physical and mental health outcomes [3-4]. Whether the psychological comorbidity seen in GERD is due to the overlap with DGBI or is a direct result of the condition itself remains unclear.

Aims & Methods

To investigate in a large sample of primary care patients whether the overlap of IBS and/or FD with RE and NERD explains the apparent link between GERD and anxiety/depression or whether the link is independent of DGBI presence. Data were collected from a retrospective study of 1,256,331 patients at general practices in the United Kingdom. A diagnosis of RE was defined as reflux with the presence of documented oesophagitis and NERD as reflux in the absence of oesophagitis. Psychological comorbidity was a diagnosis of anxiety or depression. Multiple logistic regression was used to assess the association of psychological comorbidity and a diagnosis of IBS and/or FD and RE and NERD, adjusting for the other disorder along with age at first contact and sex.

Results

Approximately 13.4% (95%CI 13.36,13.49) of patients reported a diagnosis of IBS, 20.7% (95%CI 20.67,20.81) FD, 4.2% (95%CI 4.19,4.27) RE and 5.1% (95%CI 5.09,5.17) NERD. Psychological comorbidity was significantly higher in patients with RE versus no RE (40.0% vs 24.4%, P<0.001), NERD versus no NERD (39.7% vs 24.2%, P<0.001) and IBS and/or FD (38.9% vs 18.6%, P<0.001). Psychological comorbidity was significantly associated with RE (OR=2.07; 95%CI 2.03,2.11, P<0.0001) and NERD (OR=2.06;95%CI 2.02,2.09, P<0.0001). However, this effect was reduced once IBS and/or FD was adjusted for in the models for both RE (OR=1.52; 95%CI 1.49,1.55, P<0.0001) and NERD (OR=1.53; 95%CI 1.50,1.55, P<0.0001) and persisted when age and sex were controlled for in the analysis for RE (OR=1.55, 95%CI 1.52,1.57, P<0.001) and NERD (OR=1.52; 95%CI 1.50,1.55, P<0.0001). With respect to IBS and/FD, psychological comorbidity was a significant independent predictor of an IBS and/or FD diagnosis (OR=2.79, 95%CI 2.77, 2.82, P<0.001). The likelihood of psychological comorbidity predicting an IBS and/or FD diagnosis remained more than twice as high even after controlling for RE (OR=2.72, 95%CI 2.70, 2.74, P<0.0001) and NERD (OR=2.71;95%CI2.68,2.73, P<0.0001) and age and sex along with RE (OR=2.49; 95%CI 2.47,2.51, P<0.000) and NERD (OR=2.48; 95%CI 2.46,2.50, P<0.0001).

Conclusion

In a large sample of primary care patients, the association of IBS/FD and psychological comorbidity is independent of reflux oesophagitis (RE) and NERD, but the link between RE and NERD with anxiety/depression is partly explained by IBS/FD presence.

References

1. Jones MP, et al. Neurogastroenterol Motil. 2022 Sep;34(9):e14349.
2. Zamani M, et al. Aliment Pharmacol Ther. 2019 Jul;50(2):132-143.
3. Li P, Tang Y, Liu L, Yang L, et al. BMC Gastroenterol. 2025 Mar 5;25(1):136.\
4. Lee SW, Chang CS. J Neurogastroenterol Motil. 2021 Apr 30;27(2):176-184.

Introduction

Functional dyspepsia (FD) is a disorder of gut-brain interaction (DGBI) characterised by relapsing and remitting gastro-duodenal symptoms, in the absence of identifiable pathology via routine clinical screening. An association between FD and wheat-containing foods has been reported in observational studies, and recent work demonstrates increased gut-homing T cells in peripheral blood of FD patients reporting sensitivity to wheat, compared to those without wheat sensitivity and controls. We have also recently shown increased populations of mucosal lymphocytes with a T helper (Th)2- and Th17-like phenotype in FD patients compared to controls, however, a mucosal adaptive lymphocyte response specific to wheat has not been demonstrated.

Aims & Methods

We aimed to examine whether proteins present in wheat could provoke a response from FD duodenal lymphocytes isolated from mucosal biopsies. Lamina propria mononuclear cells (LPMCs) were isolated from duodenal biopsies from 50 FD patients (38 female, 46.8±16.8 years) and 23 controls (11 female, 52.1±13.1 years). LPMCs were exposed to gluten (0.2mg/mL) or gliadin (0.2mg/mL) for 24 hours. Flow cytometry was performed to phenotype lymphocytes using a surface marker panel. Quantitative polymerase chain reaction (qPCR) was used to measure expression of the gliadin-associated T-cell receptor alpha variant (TRAV)26-2.

Results

In response to gliadin (but not gluten) stimulation, the effector Th2-like population was increased in FD LPMCs compared to controls (16.34 ± 13.17 vs 25.83 ± 14.87, p = 0.01) and unstimulated FD LPMCs (19.40 ± 14.35 vs 25.83 ± 14.87, p = 0.04). Duodenal gene expression of TRAV26-2 was decreased in FD compared to controls (0.013 ± 0.015 vs 0.003 ± 0.005, p = 0.04). We identified a positive association between gene expression of this T cell receptor variant and LPMC effector Th17-like cell populations in FD patients (rs = 0.3733, p = 0.04), but not controls (rs = 0.2238, p = 0.485) following exposure to gluten, but not gliadin.

Conclusion

Our findings in this observational study suggest differential T cell responses to gluten and gliadin in a subset of FD patients, and suggest Th2 responses previously reported in FD may occur in response to food components such gliadin. We also show that FD patients have reduced expression of TRAV26-2, previously associated with T cell responses against gliadin in celiac disease. TRAV26-2 expression correlated with Th17-like populations in FD patients, suggesting that specific TCR variants in may be associated with an immune response to the consumption of wheat-containing foods in FD.

Introduction

Little is known about the variation in the mucosa-associated microbiota (MAM) along the human gastrointestinal (GI) tract. We set out to characterize biogeography of the MAM in subjects with and without gastrointestinal disease, and to explore and compare the intrinsic links between the MAM, proton pump inhibitor (PPI) therapy, symptom response to a standardized nutrient challenge as a surrogate marker for visceral sensory function, and the severity of gastrointestinal symptoms across various segments of GI tract in asymptomatic controls and patients with inflammatory bowel disease (IBD).

Aims & Methods

After informed consent, the type and severity of GI symptoms were recorded using a standardized valid questionnaire (Structured assessment of gastrointestinal symptoms, SAGIS). Patients underwent a nutrient challenge test and the cumulative symptom response to a standardized test meal (Ensure, 600 cc) were recorded. Clinical data and demographic information were obtained from the integrated Electronic Medical Record (iEMR). During endoscopy, mucosal samples were collected utilising the Brisbane Aseptic Biopsy Forceps (MTW, Germany) from the duodenum to avoid working channel contamination of tissue and utilizing routine biopsy forceps from the terminal ileum (TI), right colon (RC), rectum (R), from 59 asymptomatic/healthy control subjects, and 75 IBD patients in clinical remission (44 ulcerative colitis (UC) and 31 Crohn’s disease (CD)). Microbial composition was assessed via 16S rRNA amplicon analysis and the bacterial load of DU, TI, R and RC biopsies were assessed via qPCR, allowing for calculation of absolute and relative abundance profiles of the MAM. MAM composition was examined in the context of PPI usage, the severity of gastrointestinal and extraintestinal symptoms, and the sensitivity to nutrient challenge tests.

Results

The biogeography of MAM exhibited substantial heterogeneity between UC and CD patients and across the GI tract, with differences in the relative abundance of MAM, as examined in other studies, not always corresponding with differences in absolute abundance. Compared to controls, UC and CD patients were characterised by relative and absolute depletion of butyrate-producing genera, with the largest differentiation being depletion of Faecalibacterium in the lower GI tract of CD patients. Interestingly, PPI therapy was associated with a significant shift in MAM composition, particularly for Faecalibacterium whose depleted levels were restored to healthy-control levels in CD patients. The severity of gastrointestinal and extraintestinal symptoms, was significantly associated with MAM composition, with Faecalibacterium enrichment in UC and CD patients paradoxically associated with elevated symptom severity. The response to standardised nutrient challenge tests, was significantly associated with a shift in MAM composition and Faecalibacterium depletion.

Conclusion

The absolute and relative composition of the MAM is variable across different levels of the human GI tract and linked to the presence/absence of specific inflammatory bowel disorders (CD/UC), medication with a PPI, the severity of gastrointestinal symptoms, and the intensity of GI symptoms during a standardized nutrient challenge. The consistently strong association of clinically relevant bacterial genera such as Faecalibacterium in these analyses, as well as several other genera, provides focal points for future investigations and strategies to develop microbiome-mediated therapies for IBD and for modulation of the gut-brain axes.

Introduction

In functional dyspepsia (FD) and irritable bowel syndrome (IBS), both prevalent DGBIs that overlap more than expected by chance, increased tissue eosinophils and mast cells have been observed in the duodenum, and both disorders have been linked to immune activation to food antigens (1). Eosinophilic oesophagitis (EoE) is characterised by oesophageal eosinophil infiltration secondary to food antigen exposures. However, whether there is an increased risk of DGBI in EoE is unknown.

Aims & Methods

The aim of this study was to determine the relationship between adult EoE and DGBIs and other risk factors. General practice electronic medical records were sourced from the United Kingdom (UK) via The Health Improvement Network (THIN). Adult EoE and DGBIs were identified through Read codes.

Results

There were 1,061,813 unique adults available for analysis. There were 209 adult EoE cases (0.02%) with a mean age at first diagnosis of 35.7 years (SD=10.4), and 68% male.
Statistically significant univariate risk factors, symptoms, and medications for adult EoE are shown in Table 1.
For adult EoE, the multiple logistic regression model (adjusted for age and sex) identified male sex (OR: 2.93, 95%CI: 2.18-3.95, p<0.001), IBS (OR: 0.34, 95%CI: 0.20-0.57, p<0.001) and DGBIs (i.e., IBS, FD, and chronic constipation), (OR: 0.35, 95%CI: 0.24-0.50, p<0.001), allergy (OR: 1.78, 95%CI: 1.05-3.01, p=0.032), Helicobacter pylori infection (OR: 2.12, 95%CI: 1.07-4.19, p=0.031), and duodenitis (OR: 2.39, 95%CI: 1.40-4.09, p=0.001), as statistically significant independent risk factors. Additional modelling identified that adult EoE patients were more likely to take proton pump inhibitors (PPIs) (OR: 11.60, 95%CI: 6.55-20.56, p<0.001), anti-inflammatory agents (OR: 5.58, 95%CI: 3.71-8.39, p<0.001), and have a lower mortality (OR: 0.12, 95%CI: 0.03-0.48, p=0.030).

Conclusion

Adult EoE cases are less likely to have IBS and DGBIs are less likely to occur, while other factors increase the risk (e.g., allergy). The main medications utilized were PPIs and anti-inflammatory agents. Adult EoE patients had a lower mortality compared to the background primary care population.

References

Ford AC, Staudacher HM, Talley NJ. Postprandial symptoms in disorders of gut-brain interaction and their potential as a treatment target. Gut. 2024;73(7):1199-1211.

Disclosure

Guy D. Eslick and Michael P. Jones have nothing to disclose. Nicholas J. Talley Disclosures: GutSee Ltd (consulting microbiome, 2025), Brown University, Agency for Health Care Research and Quality (fiber and laxation) (2024), Rome Foundation (member gastroduodenal committee) (present) Biocodex (FD diagnostic tool) (present) Microba (consulting microbiome - commencing 2025) Comvita Manuka Honey (FD trial consulting) (2025), BluMaiden outside the submitted work. In addition, Dr. Talley has a patent Nepean Dyspepsia Index (NDI) 1998, a patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to Mayo/Talley, “Diagnostic marker for functional gastrointestinal disorders” Australian Provisional Patent Application 2021901692, ”Methods and compositions for treating age-related neurodegenerative disease associated with dysbiosis” US Patent Application No. 63/537,725.
Boards: The Gut Foundation Board (2025-present), Asia Pacific Association of Medical Editors (APAME) Board (President 2023-2025), Doctors for the Environment (Chair 2024-present), Luminal Faculty GESA (Chair) (2023-2025).
Editorial: UptoDate (Section Editor), Mayo Clinic Proceeding Associate Editor (2023-present).
Financial support: Dr. Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre for Research Excellence in Digestive Health and he holds an NHMRC Investigator grant.

Introduction

Diabetes is one of the most common metabolic diseases worldwide with rapidly growing of incidence. While the recent Rome Global Epidemiology Study revealed significant insight into the epidemiology of disorders of gut-brain interaction (DGBI) in the general population at a large-scale multi-national level, the prevalence of DGBI in diabetic population remains to be characterized in detail. Gastrointestinal symptoms are commonly presented in patients with diabetes because of diabetic neuropathy, chronic inflammation, and disrupted gut microbiota.

Aims & Methods

Aim: To assess the prevalence of the DGBI among subjects with type 1 and type 2 diabetes in the community setting.
Methods: We conducted a prospective survey of diabetic subjects by distributing online questionnaires via the Diabetes League (independent diabetic patient support and information organization in Belgium) and via general practitioners. Participants filled out an online survey. The survey contained the Adult Rome IV Diagnostic Questionnaire, PHQ-15, PROMIS Global-10, Visceral Sensitivity Index, GAD-7, PAGI-SYM, PAGI-QOL, Waiting Room Questionnaire and SF-NDI. Using the Rome Diagnostic Questionnaire, we selected patients who fulfilled the diagnosis criteria of DGBI, including chronic nausea vomiting syndrome (CNVS), cyclic vomiting syndrome (CVS), rumination syndrome, functional dysphagia, functional dyspepsia (FD) and irritable bowel syndrome (IBS). Patients who self-reported a relevant organic gastrointestinal disease, were taking Glucagon-like peptide-1 agonists or had a history of extensive abdominal surgery were excluded. Prevalences are reported as percentages with 95% Confidence Intervals. To compare two groups, Pearson’s chi-squared tests (Fishers exact test if any one cell of 2x2 table <5) and 2 sample T-tests were used.

Results

210 diabetic patients (72.4% type 1 diabetes, 62.4% female, mean age 44.6±15.6 years, BMI 26.0±4.5 kg/m², 126 recruited through the diabetes association) were included. 41.0% of diabetic subjects had self-reported gastrointestinal symptoms. The prevalence of CNVS, CVS, rumination syndrome, functional dysphagia, FD and IBS was 1.4% (95% CI: 0.3-4.1), 0.5% (95% CI:0.0-2.6), 4.3% (95% CI:2.0-8.0), 2.4% (95% CI: 0.8-5.5), 7.6% (including 5.7% postprandial distress syndrome (PDS), 1.4% epigastric pain syndrome (EPS) and 0.5% overlap; 95% CI: 4.4-12.1) and 6.7% (95% CI: 3.7-10.9), respectively. Comparing type 1 and type 2 diabetes, the patients with type 2 diabetes had significantly older age and higher BMI (both p<0.001). There was no significant difference in the prevalence of DGBI between the two groups (Table 1). In type 1 diabetes, IBS (7.2%) was the most frequently observed among DGBI, while those with type 2 diabetes were more commonly affected by FD (12.2%), but no statistical significance was obtained at the current sample size.

Table 1 Participants’ characteristics and prevalence of DGBI in Type 1 and Type 2 diabetes (% and 95% CI)

Conclusion

DGBI are prevalent among people with type 1 or type 2 diabetes in the community setting. Increasing awareness of DGBI and providing specific treatment options in this population might improve patient outcomes.

References

Sperber, Ami D. et al. "Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation Global Study." Gastroenterology 160.1 (2021): 99-114.

Disclosure

I have no conflict of interests