Clinical Case Summary

Non celiac gluten wheat sensitivity (NCGWS) is a syndrome whose symptoms are strictly related to gluten ingestion and presents with both intestinal and extraintestinal manifestations. However a liver involvement has never been shown. We report one case of NCGWS presenting with altered bowel habits, a persistent raise of alanine aminotransferase (ALT), aspartate aminotransferase (AST) since childhood and migraines. Gamma GT, alcaline phosphatase, bilirubin, were all within the range of normality over multiple testing. Viral serology (HAV, HBV, HCV), markers for autoimmune hepatitis (ANA, anti-smooth muscle and liver kidney microsome), protein electrophoresis, iron metabolism markers, urinary and blood copper were normal. Abdominal ultrasound reported liver size within the range of normality, regular structure and without focal lesions. No gallstones nor biliary tract dilation. Hepatic elastography was normal. Patient denied alcohol consumption at the time. Coeliac screening was negative (total IgA, IgA tTg-2 and IgA anti-endomysium). She performed a gastroscopy which showed regular macroscopic features of both stomach and duodenum. The histology showed non-specific signs of inflammation (Marsh 0). We found a rise of native IgG anti gliadin (AGA) >100 U/ml and serum zonulin (47,4 ng/ml, ULN <38). Therefore, we proposed a possible diagnosis of NCGWS following Salerno criteria and a gluten free diet (GFD) was recommended to the patient. The adherence to a GFD normalised bowel habits, migraines and the levels of liver enzymes. The pathogenesis of the liver damage in NCGWS is unclear. We hypothesized that the gut barrier dysfunction led to a translocation of toxins and antigens to the liver, therefore creating damage and a mild raise of hepatic transaminase. To date, this case is the first reporting a relation between altered liver enzymes and NCGWS. Further evidence is needed to better establish the link between these two conditions.

References

Hollon J, Puppa EL, Greenwald B, Goldberg E, Guerrerio A, Fasano A. Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity. Nutrients. 2015 Mar;7(3):1565–76.
Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018 Jul;15(7):397–411.
​Garcia-Mazcorro JF, Rivera-Gutierrez X, Cobos-Quevedo ODJ, Grube-Pagola P, Meixueiro-Daza A, Hernandez-Flores K, et al. First Insights into the Gut Microbiota of Mexican Patients with Celiac Disease and Non-Celiac Gluten Sensitivity. Nutrients. 2018 Nov;10(11):1641.

Introduction

Behaviours such as supra-gastric belching, gastric belching, and aerophagia, often identified during oesophageal physiology studies (e.g., 24-hour pH and impedance study), are known to exacerbate symptoms like reflux, bloating, and regurgitation. These behaviours are frequently misunderstood and may lead to unnecessary referrals to specialists or invasive interventions. Upper GI biofeedback (UGI BFB) therapy offers a tailored, non-invasive approach to help patients manage these behaviours. By teaching specific techniques such as diaphragmatic breathing, open-mouth posture, and the multiple rapid swallow technique, patients are empowered to take control of their symptoms, improve their quality of life, and reduce reliance on surgical or gastroenterology pathways.

Aims & Methods

• Participants: Between December 2022 and December 2024, 35 patients were referred for UGI BFB therapy. Most referrals (n=31) came after oesophageal physiology studies, with additional referrals from gastroenterologists for belching and bloating (n=2) and from clinical endoscopists for persistent hiccups and audible wheezing (n=2).
• Intervention: Patients attended a one-hour education session in the Gastrointestinal (GI) Physiology unit. This included a review of diagnostic findings and practical training in diaphragmatic breathing, open-mouth posture, and the multiple rapid swallow technique. A follow-up telephone consultation at 6–8 weeks allowed for monitoring progress. For cases of poor oesophageal clearance, referring clinicians were advised to consider prokinetics. For frequent gastric belching, small intestinal bacterial overgrowth (SIBO) breath testing was recommended to assess any additional contributing factors.

Results

• Supra-gastric belching episodes were reduced by 50% (mean: 24 episodes pre-therapy to 12 post-therapy; p<0.001).
• GERD-HRQL scores improved by 45%, indicating significant quality-of-life improvements (mean: 22 pre-therapy to 12 post-therapy; p<0.001).
• 75% of patients reported substantial reductions in belching, bloating, and reflux-like symptoms.
• Half of the patients (50%) no longer required specialist referrals, as symptoms were successfully managed with therapy or GP-led interventions, including prokinetics or medications for hypersensitivity.
• Stress emerged as a critical factor for most patients. Relaxation techniques, mindfulness, and stress management strategies played an important role in symptom control. One patient, who became a mental health first aider at work, reported long-term symptom relief due to stress reduction efforts.

Conclusion

Upper GI biofeedback therapy is a valuable approach for addressing behavioural contributors to symptoms like air swallowing, belching, and bloating. A multidisciplinary approach, involving cognitive behavioural therapy or hypnotherapy alongside UGI BFB, can be highly beneficial. The GI Physiology team also recognises its limitations and has found that referrals to Speech and Language Therapy can be instrumental when patients are unable to engage fully with the therapy. This collaborative, patient-centred approach ensures that UGI BFB therapy not only reduces the need for invasive procedures and specialist consultations but also empowers patients to adopt long-lasting lifestyle and behavioural changes.

Introduction

Avoidant Restrictive Food Intake Disorder (ARFID) is increasingly recognized within the paediatric population and specialist clinics. However, there is sparse data on the prevalence and burden of ARFID within the adult general population. We addressed this issue.

Aims & Methods

A population-based Internet survey with pre-defined demographic quotas was conducted across the UK and USA in 2023. The survey collected data on demographics, body mass index (BMI), ARFID (using the nine-item ARFID screening tool, NIAS), disorders of gut-brain interaction (using the Rome IV diagnostic questionnaire), PHQ-15 somatic symptoms, PHQ-4 anxiety and depression, PROMIS-10 quality of life, and healthcare utilisation.

Results

In total, 4002 adults (mean age 47 [range 18-91] years and 50% females) completed the survey. Overall, 26.0% (n=1035) screened positive for ARFID, with similar results between the UK (23.0%) and USA (29.0%). The prevalence of positive ARFID screens by NIAS subscale were 15.3% for poor appetite, 13.9% for picky eating, and 6.2% for fear of aversive consequences. In all, 18.2% had a single ARFID domain, 5.7% had two domains and 1.9% had all three domains.
ARFID was more common in females than males (29.6% vs. 22.1%, OR 1.5), and highest amongst people aged 18-39 years (31.6%), followed by those aged 40-64 years (25.0%), and lowest in those 65 years and over (16.1%); p<0.001.
Individuals with ARFID - compared to those without ARFID - had a significantly higher prevalence of disorders of gut-brain interaction (51% vs. 37.5%, OR 2.2), including irritable bowel syndrome (11.8% vs. 4.0%, OR 3.2) and functional dyspepsia (25.8% vs. 7.0%, OR 4.6). They were significantly more likely to be underweight (BMI<18.5; 7.0% vs. 1.5%), experience greater somatic symptoms and mood disturbances, reduced mental and physical quality of life, and increased healthcare utilization (i.e. medication use and doctor visits). An increase in the number of ARFID domains was associated with greater general health impairment; p<0.001.

Conclusion

Elevated ARFID symptoms are common within the adult general population, affecting 1-in-4 people, and associated with substantial health burden. Increased awareness of ARFID will aid clinical service provision and future research on how to best manage this patient group.

Disclosure

Nil

Introduction

Gut transit time is a key modulator of host-microbiome interactions, influencing gut microbiota composition and fecal metabolites concentrations. Prolonged colonic transit time is associated with greater microbial diversity, increased proteolytic fermentation activity and reduced concentrations of short-chain fatty acids (SCFAs). Metabolites derived from protein fermentation (such as ammonia, indole, p-cresol, and hydrogen sulfide) can impair epithelial integrity, while SCFAs, produced from nondigestible carbohydrates, support mucosal health through anti-inflammatory and antineoplastic effects. An imbalance between these metabolites may compromise colonic homeostasis, predisposing colonocytes to aberrant proliferation and increasing the risk of neoplastic transformation. These early alterations can be clinically detected through the presence of adenomatous polyps during colonoscopy, marking a critical window for preventive strategies.

Aims & Methods

The aim was to evaluate the role of gut transit time in shaping gut microbiota composition and fecal levels of bacterial-derived metabolites in individuals with a history of colorectal polyps. Thirty-three individuals who had undergone a colonoscopy were recruited and categorized based on gut transit time, assessed using the blue dye method. Fecal samples were collected and cocentrations of SCFAs, ammonium and indole were quantified using gas chromatography, a fluorometric assay and a colorimetric assay, respectively. The V3–V4 region of the 16S rRNA gene was sequenced using the Illumina NovaSeq platform. Sequence variant inference, quality filtering, chimera removal, and paired-end read merging were performed using the DADA2 pipeline in R, followed by taxonomic assignment with the Silva reference database. Alpha diversity was assessed by measuring richness (number of operational taxonomic units) and diversity (Shannon index). Beta diversity was analyzed using Canonical Correspondence Analysis (CCA) based on Bray–Curtis distances, with group differences tested via PERMANOVA. Linear discriminant analysis with an LDA score threshold >2 was applied to identify differentially abundant taxa.

Results

Alpha-diversity did not differ between groups with different gut transit times. Regarding Beta diversity, CCA based on Bray–Curtis distance showed a non-significant trend (p=0.095), whereas PERMANOVA analysis revealed a statistically significant effect (p=0.038), indicating that gut transit time explains a significant portion of the variance in microbial composition. Individuals with slow transit time exhibited an enrichment of several bacterial families from the phyla Actinobacteria (Micrococcaceae, Actinomycetaceae, Eggerthellaceae) and Firmicutes (Christensenellaceae, Ruminococcaceae, Lachnospiraceae, Peptostreptococcaceae and Veillonellaceae). A trend toward lower fecal SCFAs concentrations was observed in slow transit group compared to individuals with normal transit (69.2 ± 43.2 vs. 98.6 ± 34 umol/gr, p=0.087). No significant differences in fecal ammonium or indole concentrations were detected between groups. Multinomial logistic regression analysis indicated that higher levels of SCFA were linked to a lower likelihood of being in the slow transit group (p = 0.055). No differences were found in the frequency of polyp diagnosis according to transit time classification (p=0.495).

Conclusion

This study confirms that gut transit time influences both microbiota composition and SCFA levels. These findings highlight the relevance of gut transit modulation as a preventive target in individuals at risk of colorectal neoplasia.

Introduction

Small intestinal bacterial overgrowth (SIBO) is characterized by the presence of excessive gram-negative aerobic and anaerobic colonic bacteria in the small intestine^1,2, leading to increased carbohydrate fermentation and gas production. Symptomatology frequently overlaps with other gastrointestinal disorders³. This study aimed to identify factors associated with test positivity and improve patient selection for diagnostic evaluation.

Aims & Methods

Retrospective, unicentric study. A cohort of 34 patients underwent glucose hydrogen and methane breath testing for SIBO. Demographic, clinical, laboratory data and test results were analyzed.

Results

The cohort included 21 females (61.8%) and 13 males (38.2%), with a mean age of 46.5 ± 15.9 years. Chronic diarrhea was the leading indication for testing (82.4%), followed by abdominal pain (8.8%). Tests results were positive in 4 cases (11.8%). Positive patients had a higher mean age (56.0 ± 10.8 vs. 46.1 ± 15.8 years, p = 0.236) and a comparable gender distribution. Among positive patients, diarrhea was reported in 100% of cases, followed by abdominal distension (75%) and abdominal pain (50%). Folic acid levels were higher in the positive group (11.65 vs. 6.54 ng/mL, p = 0.074), while fecal calprotectin levels were significantly elevated (480 vs. 44.26 µg/g, p = 0.027). Altered small intestine anatomy due to prior surgical interventions was strongly associated with test positivity (p = 0.012), while systemic disorders affecting gastrointestinal motility showed a non-significant trend (p=0.136). Proton pump inhibitor use was not associated with test positivity (p = 1.0). Rifaximin treatment led to symptom improvement in all positive cases, but with no significant difference compared to negative patients (p = 0.444).

Conclusion

Elevated serum folate and fecal calprotectin levels may serve as indicators of underlying SIBO in the appropriate setting. Altered small intestine anatomy was strongly associated with test positivity, and could indicate SIBO under adequate intestinal transit time. These findings highlight the need for larger studies to refine patient selection and improve diagnostic strategies.

References

1. UpToDate. Small intestinal bacterial overgrowth: Etiology and pathogenesis. Available at: https://www.uptodate.com/contents/small-intestinal-bacterial-overgrowth-etiology-and-pathogenesis. Accessed January 19, 2025.
2. Pimentel M, Saad RJ, Long MD, Rao SSC. ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. Am J Gastroenterol. 2020;115(2):165-178. doi:10.14309/ajg.0000000000000501.
3. Sachdev AH, Pimentel M. Antibiotics for irritable bowel syndrome: Rationale and current evidence. Curr Gastroenterol Rep. 2012;14:439–45.

Introduction

Functional dyspepsia (FD) is a chronic gastrointestinal disorder characterised by meal-related symptoms, which a subset of patients attribute to the consumption of gluten-containing foods [1]. Recent evidence suggests that subtle duodenal immune activation is a feature of FD, as evidenced by elevated eosinophils [2] and impaired epithelial barrier function [3]. FD patients also exhibit an altered duodenal mucosa-associated microbiota (d-MAM) when compared to controls [4]. Given the microbiome’s involvement in the digestion of gluten, we hypothesised that the d-MAM determines the capacity for gluten to disrupt the epithelium and drive immune responses in FD patients.

Aims & Methods

Duodenal biopsies were collected from 10 FD patients and 7 asymptomatic controls. The d-MAM was cultured from biopsies in a habitat simulating media [5] containing 1% wheat-gluten, for up to 48hrs. Microbial cell pellets were frozen for future microbiome sequencing and the cell-free supernatants, containing d-MAM-digested gluten, were collected. Caco2 cells were challenged with the d-MAM-digested gluten, in a Transwell model of the intestinal epithelium (n=3, 2 technical replicates). Transepithelial electrical resistance (TEER) and protein expression of markers of epithelial integrity were measured in Caco2 cells and compared between treatments. Peripheral blood mononuclear cells (PBMCs) from FD patients (n=20) and controls (n=20) were stimulated with pooled samples of FD or control d-MAM-digested gluten, or left untreated, for 44 hours. For comparison to host enzymatic breakdown of gluten, matched PBMCs were also treated with α-chymotrypsin digested, deaminated gluten (CT gluten). The T cell phenotype and presence of activation-induced markers was assessed in PBMCs by flow cytometry.

Results

Challenge of Caco2 cells with gluten digested by the FD d-MAM resulted in a significant increase in Zonula occludens-1 (p=0.007), and reduction in Myd88 (p=0.03), compared to Caco2 cells challenged with control d-MAM-digested gluten. However, TEER readings were not altered between treatment groups in Caco2 experiments. In PBMC experiments, in response to stimulation with FD or control d-MAM-digested gluten, both FD and control PBMCs exhibited heightened expression of activation markers (CD4⁺OX40⁺CD25⁺), when compared to their respective unstimulated cells (p<0.05). When assessing the T-cell phenotype we observed that FD d-MAM-digested gluten promoted an increase in T-helper (Th) 2 cells in both FD (p=0.007) and control (p=0.0001) PBMCs. Meanwhile, control d-MAM-digested gluten stimulation resulted in elevated Th17.1 cells in FD (p<0.0001) and control (p=0.02) PBMCs, when compared to unstimulated cells. Alternatively, CT gluten stimulation did not alter any of the assessed lymphocyte populations in FD or control PBMCs when compared to unstimulated cells, suggesting host digestion of gluten isn’t sufficient to induce immune responses in FD.

Conclusion

Our findings suggest that the d-MAM of FD patients digest gluten in a way that promotes epithelial barrier remodelling and altered immune responses compared to the d-MAM from asymptomatic individuals. The promotion of a Th2 T-cell phenotype by the FD d-MAM is consistent with reports of increased Th2-associated cells, such as eosinophils, in FD patients [6]. These results highlight the likely role of microbiome-gluten interactions in FD, indicating the potential for novel dietary therapies and microbial approaches to management.

References

1. Potter, M., et al., Incidence and prevalence of self-reported non-coeliac wheat sensitivity and gluten avoidance in Australia. Med J Aust, 2020. 212(3): p. 126-131.
2. Shah, A., et al., Duodenal Eosinophils and Mast Cells in Functional Dyspepsia: A Systematic Review and Meta-Analysis of Case-Control Studies. Clinical Gastroenterology and Hepatology, 2022. 20(10): p. 2229-2242.e29.
3. Puthanmadhom Narayanan, S., et al., Duodenal Mucosal Barrier in Functional Dyspepsia. Clin Gastroenterol Hepatol, 2022. 20(5): p. 1019-1028.e3.
4. Shanahan, E.R., et al., Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia. Gut, 2023. 72(5): p. 929-938.
5. Schooth, L., Defining the Role of the Mucosa-Associated Microbiota in Digestive Health and Disease Using Novel ex-vivo Combinations of Microbe Culture with Metagenomics. 2024 [Doctoral thesis, The University of Queensland], UQ eSpace.
6. Burns, G.L., et al., Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia. Front Immunol, 2022. 13: p. 1051632.

Disclosure

JP, EH, CN, SS, SR, MS, KH, GB, and KD have no disclosures to report.
NT: Financial support from: BluMaiden (microbiome advisory board) (2021), Comvita Mānuka Honey (2021) (digestive health), Biocodex (functional dyspepsia tool), Microba (microbiome advisory board) outside the submitted work. In addition, Dr. Talley has a patent Nepean Dyspepsia Index (NDI) 1998, Biomarkers of IBS licensed, a patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to Mayo/Talley, a patent issued, “Diagnostic marker for functional gastrointestinal disorders” Australian Patent Application WO2022256861A1via the University of Newcastle and UniQuest (University of Queensland) and ”Methods and compositions for treating age-related neurodegenerative disease associated with dysbiosis” US Application No. 63/537,725. 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.
SK: Grants from National Health and Medical Research Council (Ideas Grant and Centre for Research Excellence), grants from Viscera Labs (Research contract), grants from Microba Life Science (Research contract), personal fees from Gossamer Bio, personal fees from Anatara Lifescience, personal fees from Immuron, personal fees from Microba Life Science.

Introduction

Eosynophilic oesophagitis (EoE) is a chronic disease which clinically presents with symptoms related to oesophageal dysfunction while pathologically it is characterized by eosinophilic infiltration of oesophageal epithelium. Most patients with EoE present food and/or inhalant allergies symptoms. The results of animal models studies and genetic studies, as well as efficacy of elimination diets in managing the symptoms, suggest an atopic background of the disease.

Aims & Methods

The aim of this study was to evaluate the prevalence of EoE in a group of patients with upper gastrointestinal symptoms and food and/or inhalant allergies and to assess the influence of drugs used in type I allergies on the results of endoscopic, histopathological and immunohistochemical tests.
Methods. This was a prospective observational study. Patients with inhalant/food allergies and upper esophageal symptoms formed study group while control group formed patients without allergy diagnosed with dyspepsia or irritbale bowel syndrome. All study participants were tested for allergies including prick testing, blood tests, all participants were evaluated with a gastroscopy with specimen collection. Oesophageal specimens were stained for eotaxin-1 and desmoglein-1.

Results

Based on histopathology results eosinophilic oesophagitis was found in 9 of the 73 patients from the study group. All patients with EoE presented with multimorbidity and were diagnosed with at least one allergic disease in addition to EoE. Positive staining for CCL-11 was found in 56 (78%) patients in the study group, including all patients with EoE while ony in 3 (17%) individuals from control group. The presence of DSG-1 in oesophageal specimens was detected in 6 (7%) subjects from the study group in contrary to 14 (78%) subjects from the control group. DSG-1 was not found in any of the specimens of patients diagnosed with EoE.

Conclusion

EoE is rare disease usually accompanied by allergic multimorbidity. Positive staining for eotaxin-1 and negative staining for desmoglein-1 in patients with esophageal symptoms and allergy but who did not met EoE diagnostic criteria, could be indicative of subclinical course of the disease or masking effect of corticosteroids. It is now critically important for both researchers and practicing clinicians to recognize that eosinophilic esophagitis (EoE) is not a homogeneous disease but rather consists of multiple subtypes (phenotypes). The so-called "classic" form of EoE—defined by current diagnostic criteria as having more than 15 eosinophils per high-power field on histopathological examination—appears to represent only the tip of the iceberg. There is an urgent need for further research to refine endoscopic techniques, expand the scope of histopathological assessments, and identify novel biomarkers to better define the distinct phenotypes of eosinophilic esophagitis.

References

1. Hirano, I.; Chan, E.; Rank, M.; Saraf, RN.; Stollman, NH.; Stukus, DR.; et al. AGA institute and the joint task force on allergy-immunology practice parameters clinical guidelines for the management of eosinophilic esophagitis. Ann Allergy Asthma Immunol 2020; 124: 416-23
   
2. Greuter, T.; Straumann, A.; Fernandez-Marrero, Y.; Germic, N.; Hosseini, A.; Yousefi, S.; et al. Characterization of
   eosinophilic esophagitis variants by clinical, histological, and molecular analyses: A cross-sectional multi-center study.
   Allergy. 2022;77(8):2520-2533. doi: 10.1111/all.15233.