Introduction

Bile acid malabsorption (BAM) arises from dysregulation of enterohepatic bile acid recycling and production, often manifesting as chronic, debilitating diarrhoea. Current first-line treatment involves bile acid sequestrants (eg.cholestyramine, colesevelam). However, response rates and tolerance to these treatments have been inconsistent.

Aims & Methods

This study aims to evaluate the management outcomes in our patients diagnosed with BAM over a five-year period. A retrospective analysis was conducted on 353 patients who underwent SeHCAT testing for suspected BAM from January 2019 for a five-year period. Clinical data, including treatment regimens, response and ancillary investigations, were extracted from medical records and analysed.

Results

Of the 353 patients reviewed, 175 (49.57%) were diagnosed with BAM, with over 90% presenting with chronic diarrhoea. Of these, using NICE guidelines, 47(26.86%) had mild, 63(36%) had moderate and 65(37.14%) had severe BAM. The main referrals for SeHCAT came from Gastroenterologists (76.44%); the remaining 41 patients were largely picked up by Colorectal surgeons with an interest in lower GI physiology, other referring specialties included other colorectal surgeons, general medicine, care of the elderly, respiratory medicine and even urology. Among these, 105 patients were prescribed cholestyramine; however, 47 of these were excluded from further analysis due to lack of follow-up data. Of the 58 evaluable patients, 55% demonstrated symptom improvement, while many experienced side effects such as headaches and abdominal discomfort, leading to poor adherence. For patient’s intolerant to cholestyramine, 34 were transitioned to colesevelam, with 50% reporting symptom relief. Among responders, 47% showed significant symptom control. Notably, 60% of all BAM-diagnosed patients were not followed up by specialty care and were discharged prematurely. Interestingly, co-prescribing antidiarrhoeals with bile acid sequestrants yielded a 100% response rate with no adverse effects reported.

Conclusion

Our findings highlight critical gaps in the management of BAM. Poor compliance with cholestyramine, primarily due to side effects, underscores the importance of individualized treatment plans and patient education. Furthermore, inadequate follow-up care likely contributed to suboptimal treatment outcomes. Severe BAM, as indicated by SeHCAT scores, correlated with poorer treatment responses, suggesting the need for alternative therapeutic strategies. Co-prescribing antidiarrhoeals alongside sequestrants showed promising efficacy and tolerability, potentially reducing the need for higher doses of sequestrants and their associated side effects. These findings call for improved follow-up protocols, patient-centered approaches to medication management, and further exploration of combination therapies to enhance outcomes in BAM management.

References

1. Orekoya O, McLaughlin J, Leitao E, Johns W, Lal S, Paine. Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy. P.Clin Med (Lond). 2015 Jun;15(3):252-7. doi: 10.7861/clinmedicine.15-3-252.
2. Kurien M, Thurgar E, Davies A, Akehurst R, Andreyev. Challenging current views on bile acid diarrhoea and malabsorption. J.Frontline Gastroenterol. 2018 Apr;9(2):92-97. doi: 10.1136/flgastro-2017-100808. Epub 2017 Jun 29.
3. NICE guidelines: SeHCAT (tauroselcholic [75 selenium] acid) for diagnosing bile acid diarrhoea: Diagnostics guidance; Reference number:DG44; Published: 17 November 2021

Introduction

Crohn’s Disease (CD), a subtype of Inflammatory Bowel Disease (IBD), is believed to arise from complex interactions between gut microbes, environment, and genetics. A significant proportion of patients develop fistulae, but unclear aetiopathogenesis impacts treatment outcomes, quality of life, and healthcare costs. Chronic granulomatous disease (CGD) is a monogenic condition caused by pathogenic variants in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes which can present as CD-like colitis, abscesses, and immunodeficiency. Given CD’s genetic and phenotypic similarities with CGD, we hypothesised that NADPH oxidases may contribute to CD phenotypes, specifically in relation to fistulating disease behaviour.

Aims & Methods

This study explores the role of genetic variation in NADPH oxidases in CD patients (Southampton IBD cohort) using a per-patient, per-gene deleteriousness score (GenePy) to determine whether CD fistulating disease behaviour can be predicted and establish any potential epistatic interactions between genetic variation of subunits of the NAPDH oxidase complexes relevant to CD. Key NADPH oxidase protein-coding genes involved in CD were identified via literature review. Protein-protein interaction databases were used to collate a comprehensive network of potentially implicated genes. To determine subgroups of patients with differing genetic variation in the NAPDH oxidase genes we employed a principal component analysis (PCA), followed by hierarchical clustering of patients using GenePy scores, with optimal cluster numbers determined by silhouette scores. Cluster enrichment for fistulating disease was explored using Fisher’s exact test. To identify genes driving separation between CD patients we assessed differences in GenePy scores for the top PCA gene drivers between fistulating and non-fistulating subgroups using a Mann-Whitney U-test. Mutational profile characterisation include potential gene-gene interactions were evaluated via Spearman correlations. Multiple test correction was applied.

Results

Twenty-nine protein-coding genes were analysed. Clustering patients by GenePy scores for these genes after PCA resulted in distinct clusters, but no significant association between fistulating phenotype and cluster assignments was observed. However, significant differences between the GenePy scores of the top 5% of fistulating and non-fistulating groups were found for NOX3 (p = 0.016) and DUOX2 (p = 0.001), with fistulating patients having lower GenePy score for these genes, indicating these genes may drive a proportion of inflammatory CD behaviour.
Four gene pairs were significantly correlated (Table 1), indicating potential epistasis within NADPH oxidase complexes for patients with CD. High deleteriousness scores in multiple genes within a complex may indicate oligogenic contribution to a disease phenotype within individuals.

Conclusion

NADPH oxidase genes, and epistatic interactions between them, may modify the risk of fistulating CD and drive disease phenotype in a proportion of patients.

Disclosure

JJA is a scientific advisory board member for Orchard Therapeutics

Introduction

Colorectal cancer, the third most prevalent malignancy globally[1], exhibits strong associations with aberrant DNA methylation patterning. While DNA methyltransferase inhibitors (DNMTis) demonstrate therapeutic efficacy in hematologic malignancies, their clinical application in solid tumors remains constrained by dose-limiting genomic instability secondary to genome-wide hypomethylation[2]. Recent mechanistic studies have established methyl-CpG-binding domain protein 2 (MBD2) as a pivotal mediator of methylation-dependent transcriptional repression; however, its potential involvement in context-dependent oncogene activation remains unresolved. This study elucidates that pharmacological MBD2 inhibition achieves dual epigenetic rectification – reactivating tumor suppressor genes through promoter demethylation while selectively attenuating WNT16 overexpression via methylation-sensitive suppression, thereby establishing a targeted therapeutic paradigm that circumvents the pleiotropic toxicity associated with conventional DNMTis.

Aims & Methods

A multi-dimensional platform encompassing clinical specimens, cell lines, patient-derived organoids, and PDX models was employed. Integrative whole-genome bisulfite sequencing and RNA-seq analyses delineated methylation-driven transcriptional networks. Chromatin immunoprecipitation sequencing characterized MBD2 binding at differentially methylated regions, with CRISPR interference validating functional regulatory elements.

Results

CRC cells exhibited pronounced hypomethylation at the WNT16 promoter accompanied by diminished MBD2 occupancy. MBD2 inhibitor treatment downregulated WNT16 expression at both RNA and protein levels, concomitant with suppression of Wnt/β-catenin signaling. In PDX models, MBD2 inhibition reduced tumor burden without inducing genomic instability—a hallmark toxicity of conventional DNMTis.

Conclusion

This study unveils a novel epigenetic mechanism wherein MBD2 facilitates oncogenic WNT16 activation via its "methylation reader" function. Compared to broad-spectrum DNMTis, MBD2-targeted therapy achieves precise correction of carcinogenic epigenetic lesions while avoiding genome-wide hypomethylation risks, advancing a paradigm for targeted CRC treatment.

References

[1] Jiexi Li, Xingdi Ma, Deepavali Chakravarti, Shabnam Shalapour, Ronald A DePinho. Genetic and biological hallmarks of colorectal cancer. Genes Dev.
2021;35(11-12):787-820
[2] Marie Lopez, Julie Gilbert, Jean Contreras, Ludovic Halby, Paola B Arimondo. Inhibitors of DNA Methylation. Adv Exp Med Biol. 2022;1389:471-513
[3] Yang Xie, Feng Wang, Jun Yu, Jing Zhang, Yuting Liu, Mengying Li, Jian Qi. Silencing of MBD2 and EZH2 inhibits the proliferation of colorectal carcinoma cells by rescuing the expression of SFRP. Oncol Rep. 2021;46(6):250.

Introduction

Self-expandable metallic stent (SEMS) placement is a palliative treatment for inoperable esophageal malignancies to improve the quality of life. Traditional methods rely on fluoroscopy and endoscopy, but anatomical landmarks can simplify the procedure.

Aims & Methods

To evaluate the technical success, safety and reproducibility of using vertebral column and diaphragm landmarks for SEMS placement.
This retrospective observational study included 801 patients with inoperable esophageal malignancies undergoing SEMS placement for dysphagia due to malignant esophageal strictures, by using vertebral column and diaphragm as landmarks, from 1^st January 2006 to 31^st December 2024. The primary endpoint was to assess the technical success, safety and reproducibility of this unique technique for SEMS placement.
Methodology for Stent Placement in Esophageal Tumors:
1. For Proximal or Mid-Esophageal Tumor, following algorithm was followed: Step 1: Identify key anatomical landmarks using fluoroscopy. Step 2: With the scope in place, under fluoroscopic guidance, identify the vertebra in line with the distal extent of the tumor using the diaphragm as a reference, followed by identification of vertebra at the proximal extent of the tumor. Count the vertebrae between the distal and proximal extent of the tumor. Assign a length of 2.5 cm per vertebral body. Ascertain the desired size of SEMS by calculating the total length of the stricture by counting the vertebrae, adding one vertebral body above and below the tumor for proper stent placement. Step 3: Using fluoroscopy, position the stent. Place the distal end of the stent at the distal vertebral marker. Position the proximal end of the stent at the proximal vertebral marker. Release the stent at the appropriate position to ensure full coverage of the stricture.
2. For Tumor Extending Beyond the Gastro-Esophageal Junction (GEJ), following algorithm was followed: Step 1: Identify the proximal extent of the tumor. Align the proximal extent of the tumor with the vertebra, using the diaphragm as a reference for precise alignment. Measure the distance from the proximal end of the tumor to the proximal stomach using the scope to decide the required size of the stent. Step 2: Place the stent under fluoroscopic guidance. Position the upper end of the stent at the identified vertebra. Extend the distal end of the stent into the stomach, past the GE junction to ensure proper coverage. Release the stent.

Results

408 (50.9%) patients were females. The age range was 18-95 years (mean50±Standard deviation15). Predominant presenting complaint was dysphagia (85.39%). Average duration of dysphagia was 3.84 months. 594 (74.16%) patients had squamous cell carcinoma, whereas 207 (25.84%) patients were diagnosed with adenocarcinoma on histopathology. 365 (45.57%) patients had tumor confined to the lower one-third of esophagus. Major cause of inoperability was distant metastasis (52.81%). 240 (30%) patients had involvement of GEJ. Average length of malignant stricture was 8.4 cm. 139 (17.40%) patients required dilatation by using savary gilliard dilators before SEMS placement. TEF was present in 48 (6%) patients. Range of length of SEMS was 8-18 cm (12.5±2.26). Technical success was achieved in 100% cases. No major immediate complications occurred. Minor complications were rare.

Conclusion

Using vertebral column and diaphragm landmarks is a reliable, safe, simplified and reproducible approach for SEMS placement in patients with inoperable esopahgeal malignancies.

References

1. Lander S, Lander E, Gibson MK. Esophageal Cancer: Overview, Risk Factors, and Reasons for the Rise. Curr Gastroenterol Rep. 2023 Nov;25(11):275-279. doi: 10.1007/s11894-023-00899-0. Epub 2023 Oct 9. PMID: 37812328.

2. Li J, Xu J, Zheng Y, Gao Y, He S, Li H, Zou K, Li N, Tian J, Chen W, He J. Esophageal cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. 2021 Oct 31;33(5):535-547. doi: 10.21147/j.issn.1000-9604.2021.05.01. PMID: 34815628; PMCID: PMC8580797.

3. Asghar MS, Khan NA, Kazmi SJH, Hassan M, Rasheed U, Jawed R, Yaseen R, Naqvi SAA. Clinical, epidemiological, and diagnostic characteristics of esophageal carcinoma in a Pakistani population. Ann Saudi Med. 2021 Mar-Apr;41(2):91-100. doi: 10.5144/0256-4947.2021.91. Epub 2021 Apr 1. PMID: 33818145; PMCID: PMC8020643.

Introduction

The impact of antral preservation versus antral resection in sleeve gastrectomy remains a subject of debate due to its potential effects on weight loss, metabolic outcomes, and gastrointestinal function. This meta-analysis aims to provide a comparative assessment of these surgical techniques.

Aims & Methods

The Meta-Analysis aims to provide a comprehensive analysis between ​these two surgical techniques.
A systematic review and meta-analysis were conducted using 10 studies published between 2014 and 2025 that compared sleeve gastrectomy with antral preservation versus antral resection. The primary outcomes included excess weight loss (EWL) at different time points, while secondary outcomes assessed metabolic parameters (C-peptide, GLP-1, HbA1c), gastric emptying, gastroesophageal reflux disease (GERD), and resolution of comorbidities.

Results

A total of 10 studies were included. Patients undergoing antral resection exhibited greater excess weight loss at 6 and 12 months (MD: -4.50, 95% CI: -5.98 to -3.02; MD: -6.11, 95% CI: -7.74 to -4.47, respectively; p<0.00001), though the difference diminished by 24 months (MD: -3.37, 95% CI: -7.04 to 0.30; p=0.07). No significant differences were observed in overall GERD incidence (RR: 1.00, 95% CI: 0.75–1.33) or complications (RR: 1.00, 95% CI: 0.74–1.42). Metabolic outcomes showed marginal differences, with C-peptide (SMD: 0.02, 95% CI: -0.38 to 0.42) and GLP-1 (SMD: -0.22, 95% CI: -0.90 to 0.47) exhibiting minimal changes between groups.

Conclusion

Antral resection in sleeve gastrectomy is associated with superior short-term weight loss, but long-term differences remain inconclusive. Metabolic outcomes and postoperative complications appear comparable between techniques. Further randomized controlled trials with extended follow-up are warranted to refine surgical recommendations.

References

Disclosure

The author(s) declare no conflict of interest

Introduction

Graves’ disease (GD) and ulcerative colitis (UC) are two distinct autoimmune disorders with increasing evidence of shared pathophysiological mechanisms. While previous epidemiological studies have reported a higher risk of IBD among individuals with GD, the association between GD and UC specifically remains controversial. In particular, the causal direction, genetic liability, and molecular mediators underlying this relationship are not well defined.

Aims & Methods

We conducted a multi-layered investigation to clarify the relationship between GD and UC. First, a large-scale prospective analysis using the UK Biobank cohort was performed to assess the association between GD and subsequent UC risk, with adjustments for demographic, lifestyle, and clinical covariates utilizing COX proportional hazard models. Second, two-sample Mendelian randomization (MR) analyses were conducted using publicly available genome-wide association study (GWAS) datasets to infer potential causal links. Finally, we performed protein mediation analysis integrating plasma proteomic data to identify potential intermediate proteins and pathways mediating the effect of GD on UC.

Results

Observational analysis revealed that patients with GD had a significantly elevated risk of developing UC. Stratified analysis further revealed that this association was more pronounced among male and obese individuals. The association remained significant even after adjusting for key covariates including medication use, psychological disorders, air pollution exposure, and sunlight exposure. Genetic-level analysis using Mendelian randomization confirmed a potential causal relationship between AITD and UC. This association was independently validated in MR sensitivity analyses. Through mediation analysis based on plasma proteomic data, 28 UC-related proteins were identified as potential mediators of the AITD–UC relationship. Among them, proteins such as Arachidonate 15-lipoxygenase B (ALOX15B) were significantly enriched in the high-risk group. Collectively, six pathways likely represent the core signaling axes through which GD promotes UC pathogenesis, highlighting potential targets for mechanistic and therapeutic exploration.

Conclusion

This study provides robust clinical, genetic, and molecular evidence for a link from GD to UC, mediated through specific immunopathogenic proteins and pathways. These findings offer novel insights into shared autoimmunity and may inform biomarker-driven strategies for early identification and targeted prevention of UC in patients with GD.

References

Ferrari SM. The association of other autoimmune diseases in patients with Graves' disease (with or without ophthalmopathy): Review of the literature and report of a large series. Autoimmun Rev. 2019 Mar;18(3):287-292.
Ordás I. Ulcerative colitis. Lancet. 2012 Nov 3;380(9853):1606-19.
Xian W. Graves Disease and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization. J Clin Endocrinol Metab. 2023 Apr 13;108(5):1075-1083.
Burisch J. Incidence of Immune-Mediated Inflammatory Diseases Among Patients With Inflammatory Bowel Diseases in Denmark. Clin Gastroenterol Hepatol. 2019 Dec;17(13):2704-2712.e3.

Disclosure

The authors declare no conflicts of interest.