Introduction

EUS-guided choledochoduodenostomy using a lumen-apposing metal stent (EUS-CDSL) has been shown in randomized controlled trials (RCT) to be effective compared to endoscopic retrograde cholangiopancreatography (ERCP) in patients with advanced malignant distal biliary obstruction (MDBO). We aimed to further ascertain the safety of EUS-CDSL, which has been limited by inadequate trial sample sizes.

Aims & Methods

We undertook aggregate and individual patient data (IPD) meta-analyses following the PRISMA-IPD statement. A literature search was performed from January 2013 to November 2024 using OVID MEDLINE, EMBASE, Cochrane Library, and ISI Web of Science. Additional searches were performed for abstracts and the grey literature. RCTs comparing EUS-CDSL to ERCP were included. The primary outcome was the rate of procedure-related 14-day severe or fatal adverse events (AE). Secondary outcomes included technical success, 30-day AE, clinical success, stent dysfunction, and procedure time.

Results

A total of 2679 citations were screened with three RCTs included (519 patients). There was no difference in severe or fatal AEs between EUS-CDSL and ERCP (OR 0.64, 95% CI 0.22- 1.83 for IPD data and RR 0.76, 95% CI 0.22, 1.77 for aggregate data). Technical success was greater for EUS-CDSL (OR 4.22, 95% CI 2.35,7.61 and RR 1.14, 95% CI 1.04, 1.25) with shorter procedural time (mean difference -10.50 minutes (95% CI -15.28, -5.73). No significant differences were noted in 30-day AEs, clinical success, and stent dysfunction.

Conclusion

Our aggregate and IPD meta-analyses demonstrate the safety of EUS-CDSL as a first-line alternative to ERCP in advanced MDBO. In addition, EUS-CDSL is technically superior in terms of success rate and procedure time.

Introduction

Eosinophilic Esophagitis (EoE) is a clinicopathological disease that requires an integrated assessment combining clinical, endoscopic, and histological findings. Despite this, treatment decisions often remain symptom based. A treat-to-target strategy has recently been proposed to guide EoE management.

Aims & Methods

Retrospective single-center study of EoE patients followed between March 2012 and January 2024, with ≥12 months of follow-up. Clinical, endoscopic, histological data, and complications were assessed using the I-SEE score.

Results

A total of 82 patients with EoE were evaluated [75.6% (n=62) male, mean age 29 ± 13 years], with 37.8% (n=31) diagnosed during childhood. The most frequent symptom was food impaction (74.4%), and atypical symptoms were more common in pediatric patients (p=0.014). At baseline, 55.1% (n=43) presented with a fibrostenotic phenotype, more frequently in adults (p=0.012), and 32.9% (n=27) had moderate-to-severe disease based on the I-SEE score.
During follow-up, 56.1% (n=46) developed complications, most commonly food impaction requiring endoscopy. The presence of a fibrostenotic phenotype on initial endoscopy was a predictor of complications (OR 3.122; 95% CI 1.210–8.055; p=0.019). Both fibrostenotic phenotype (p=0.018) and moderate-to-severe I-SEE scores (p=0.004) were associated with increased need for therapeutic switching.
At 12 months, 50.0% (n=41) were asymptomatic; however, only 12.2% (n=10) had endoscopic healing and 9.8% (n=8) histologic remission. Throughout the study period, the rates of endoscopic and histologic healing remained below 25%.

Conclusion

The authors highlight the clinical dissociation of inflammatory activity and emphasize the importance of endoscopic and histologic healing to prevent disease progression.

References

Dellon, Evan S., et al. "A clinical severity index for eosinophilic esophagitis: development, consensus, and future directions." Journal of Allergy and Clinical Immunology 150.1 (2022): 33-47.

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.
   

Introduction

Emerging epidemiologic evidence suggested that moderate-to-vigorous physical activity (MVPA) was associated with a lower risk of steatotic liver disease (SLD).¹ However, several issues remain unanswered. First, prospective association between PA and hepatic steatosis was less investigated, with few studies mainly in Western populations,^{2, 3} but not in Chinese populations. Second, since sedentary behavior and PA are interrelated and may jointly affect the health outcomes,⁴ a key concern is whether moderate-to-vigorous physical activity (MVPA) can mitigate the detrimental link between sedentary time and SLD. Moreover, PA was shown to affect the gut microbiome by altering the bile acid profile and promoting the production of metabolites such as short-chain fatty acids^5,6 with benefit to SLD in animal models.⁷ However, PA-related gut microbes and metabolites, as well as their associations with SLD risk were rarely investigated at the population level.

Aims & Methods

We investigated the association between PA and the SLD risk in a cohort of 2,942 adults from the Anhui Liver Disease Study (ALDS), in which PA and SLD were measured using a validated self-reported questionnaire and transient elastography, respectively. In a subset of ALDS (n=330), we further identified gut microbial changes and serum metabolites related to MVPA assessed by accelerometer, and examined their associations with SLD risk. Fecal samples for 16S ribosomal RNA sequencing were collected twice (1-year apart) to evaluate 1-year microbial changes, targeted metabolomics analysis of baseline serum samples was performed using liquid chromatography tandem mass spectrometry, while PA was measured using a wrist-worn accelerometer for 3 consecutive days at baseline. Cox and Logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs) with 95%CIs, respectively.

Results

From 2020 to 2025, 565 SLD cases were newly diagnosed. MVPA levels were inversely (per 1-SD increase HR=0.91, 95%CI: 0.83–0.99) and sedentary hours were positively associated with the risk of SLD (HR=1.13, 95%CI: 1.03–1.24). Relative to long-low group (i.e., participants with long sedentary time and low MVPA level), HRs (95%CIs) for SLD risk were 1.00 (0.78–1.28), 0.93 (0.73–1.19), and 0.75 (0.58–0.97) for long-high, short-low, and short-high group, respectively. The α-diversity decreased in the low MVPA group (p=0.024) and the β-diversity changed in both low and high MVPA groups (all p=0.001). We identified 14 microbial genera whose relative abundance significantly changed in low or high MVPA group (all p_FDR<0.05). Among these genera, Proteus and Synergistes were associated with both low and high MVPA but in opposite directions, and were associated with SLD with ORs (95%CIs) of 1.15 (1.01–1.32) and 0.91 (0.78–1.06), respectively. Targeted metabolomics showed an inverse association between MVPA and serum L-Valine (β=-0.068, p_FDR=0.031), which was positively related to SLD risk (OR=16.40, 95%CI: 2.67–111.94). Significant correlations were also found between PA-associated microbial genera and L-Valine.

Conclusion

MVPA may modify gut microbial diversity and composition, as well as serum metabolite levels, and is associated with lower SLD risk, whereas sedentary behavior is associated with higher SLD risk.

References

[1] European Association for the Study of the Liver . Electronic address eee, European Association for the Study of D, European Association for the Study of O, et al. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492-542.
[2] McDonough DJ, Mathew M, Pope ZC, et al. Aerobic and Muscle-Strengthening Physical Activity, Television Viewing, and Nonalcoholic Fatty Liver Disease: The CARDIA Study. Journal of Clinical Medicine 2023;12.
[3] Liu M, Ye Z, Zhang Y, et al. Accelerometer-derived moderate-to-vigorous physical activity and incident nonalcoholic fatty liver disease. BMC Medicine 2024;22.
[4] Ekelund U, Tarp J, Steene-Johannessen J, et al. Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis. Bmj 2019;366:l4570.
[5] Penney N, Barton W, Posma JM, et al. Investigating the Role of Diet and Exercise in Gut Microbe-Host Cometabolism. mSystems 2020;5.
[6] Campaniello D, Corbo MR, Sinigaglia M, et al. How Diet and Physical Activity Modulate Gut Microbiota: Evidence, and Perspectives. Nutrients 2022;14.
[7] Chen J, Vitetta L. Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications. Int J Mol Sci 2020;21.

Introduction

The lactulose breath test (L-BT) is a non-invasive method to assess small intestinal bacterial overgrowth (SIBO). However, diagnostic criteria for intestinal methanogenic overgrowth (IMO) differ among experts, and international guidelines lack a definition. Methanogenic flora is linked to slower gut transit in irritable bowel syndrome (IBS), but the effects of methane-targeting treatments on methanogens, colonic transit, and stool form remain unclear.

Aims & Methods

To examine relationships between methanogenesis, constipation, pain and bloating in healthy volunteers and patients with and without IBS. METHODS: Cross-sectional study on adults with L-BT between 2016–2024 at a single center. Each patient completed a Rome IV questionnaire, sociodemographic and medical data and Bristol stool scale. IMO was diagnosed if there were more than 3 measurements of CH₄ over 10 ppm over 180 minutes. We examineded 3 alternate diagnostic thresholds: (A) 10 ppm at any time (American criteria or C1); (B) 10 ppm over baseline before 90 minutes (C2); and (C) 10 ppm over baseline before 60 minutes (C3), We considered “high producers” of CH₄ those that had 2 measurements over 60 ppm. Statistical analysis with Mann-Whitney and Kruskal Wallis test.

Results

We included 5,053 subjects who underwent L-BT (mean age 49 years, 81% women). Of these, 10% were exclusive H2 producers, 2% CH4 producers, and 2.7% were non H2/CH4 producers. CH4 producers had a higher frequency of constipation (p<0.001) and greater total CH4 production in the Bristol 1-2 group. CH4 production over 180 minutes was lower in IBS-D patients, though the overall methane production rate was similar to healthy volunteers. Based on diagnostic thresholds, 92.6% of constipated patients met C1, 52.3% C2, and 18.1% C3, with significant differences (p=0.001). Stricter IMO criteria were associated with greater bloating and pain intensity.

Conclusion

The high proportion of methane production in our asymptomatic controls, compared to previous series, may reflect demographic differences. Methane producers had a higher frequency of constipation. The IMO diagnosis rate varied depending on the criteria used, with stricter criteria identifying patients with more frequent constipation, bloating, and abdominal pain.

Disclosure

None