Endoscopy
Cold snare endoscopic resection for large colon polyps: a randomised trial
Pohl H, Rex D, Barber J, et al. Cold snare endoscopic resection for large colon polyps: a randomised trial. Gut 2025; 74(11): 1804-1813. doi: 10.1136/gutjnl-2025-335075.
The role for cold-snare endomucosal resection (EMR) polypectomy in the resection of non-pedunculated colonic polyps >20 mm is uncertain. Current practice favours the use of hot EMR for these lesions. Cold EMR theoretically carries fewer risks, including lower rates of deep mural injury, bleeding, post polypectomy syndrome and perforation. This multi-centred USA and Canada-based randomised control trial (RCT) compared approaches.
From 2019-23, 660 patients (714 polyps) were randomised to hot or cold EMR strategy. Crossovers (i.e., endoscopists deciding to use the alternative method) were recorded. Primary outcome was the rate of adverse events (AEs) within 30 days. Secondary outcome was 6-month recurrence rate. Intention-to-treat and per-protocol analyses were conducted.
Rate of AEs did not differ significantly between the cold and hot EMR (2.1% vs. 4.3%, p=0.10). Five perforations occurred, all within the hot EMR group, managed endoscopically or conservatively. The rate of AEs for proximally located polyps was lower in the cold EMR group (1.4% vs. 4.4%, p=0.043). Recurrence was higher in the cold EMR group (28% vs. 14%, p<0.0001), reaching significance in subgroup analyses for adenomatous polyps and polyps >30-mm, but not for 20-29mm polyps or serrated lesions. This was despite instructions to maintain a wide resection margin of 3-mm. There was variation in recurrence between centres, which suggests operator-dependent factors.
Overall, the RCT did not demonstrate any significant safety advantage of cold EMR, with higher recurrence rates in the cold group. Further research will be needed to identify which polyps subtypes may favour a cold EMR strategy and on optimum cold resection techniques.
Choice of colon capsule or colonoscopy versus default colonoscopy in FIT positive patients in the Danish screening programme: a parallel group randomised controlled trial
Baatrup G, Bjørsum-Meyer T, Kaalby L on behalf of the CareForColon2015 study group, et al. Choice of colon capsule or colonoscopy versus default colonoscopy in FIT positive patients in the Danish screening programme: a parallel group randomised controlled trial. Gut 2025; 74: 1616-1623.
Although colonoscopy is the standard for colorectal cancer (CRC) screening, colon capsule endoscopy (CCE) provides an alternative. Separate to this, it is generally assumed that diminutive colorectal polyps are clinically less significant. This Danish multicentre randomised controlled study aimed to assess whether offering patients a choice between CCE and colonoscopy affected uptake rates and detection of advanced neoplasia, within a colorectal screening population.
From 2020 to 2022, 396,676 citizens aged 50–74 were invited; 11,075 were FIT (Faecal Immunochemical Test)-positive (threshold ≥20 µg hgb/g). The control group was offered colonoscopy only, while the intervention group could choose CCE or colonoscopy. Uptake was similar between groups (91.1% vs. 91.7%). In the intervention arm, 45.8% chose CCE, 11.4% colonoscopy, and 42.8% made no choice and underwent colonoscopy. However, 69.9% of CCE participants subsequently required colonoscopy due to incomplete exams or findings needing intervention.
Advanced neoplasia was defined as: intermediate-risk adenomas (3–4 adenomas <10 mm or one adenoma 10–19 mm, or more than 25% villous histology or high- grade dysplasia), high- risk adenomas (more than four adenomas or one adenoma >19 mm, or piecemeal resection) as per the Danish surveillance guidelines.
The detection of advanced neoplasia was similar in both groups 0.67% in the choice group versus 0.64% in controls (22.8% vs. 24.2% of FIT-positives). There were no complications.
Although CCE is minimally invasive and of equivalent accuracy, there is a significantly high reinvestigation rate increasing workload and costs, and therefore does not provide an advantage in FIT based screening programmes with high colonoscopy uptake.
Oesophagus
Mitochondrial dysfunction drives basal cell hyperplasia in eosinophilic oesophagitis
Morimoto M, Kawasaki K, McNamee N, et al. Mitochondrial dysfunction drives basal cell hyperplasia in eosinophilic oesophagitis. Gut 2025; 74(10): 1571-1588. doi: 10.1136/gutjnl-2024-334561.
Eosinophilic oesophagitis (EoE) is a chronic, food allergen–induced inflammatory disease of the oesophagus characterised by dysphagia, food impaction, and tissue remodelling. It is driven by a type 2 helper T-cell (Th2) immune response mediated by cytokines such as interleukin-13 (IL-13) and interleukin-4 (IL-4), which promote epithelial injury and basal cell hyperplasia (BCH) which is considered to be the histological hallmark of the disease.
In this study, Morimoto et al. identify mitochondrial dysfunction as a central mechanism underpinning epithelial remodelling in EoE. Using patient biopsies, mouse models, and oesophageal organoids, they demonstrate that IL-13 disrupts mitochondrial membrane potential, reduces oxidative capacity, and elevates reactive oxygen species, resulting in an energy deficit marked by activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of mammalian target of rapamycin complex-1 (mTORC1) signalling. Through clustered regularly interspaced short palindromic repeats interference (CRISPRi), depletion of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1A) (a key regulator of mitochondrial biogenesis) was sufficient to reproduce the BCH phenotype, establishing a causal link between mitochondrial impairment and epithelial hyperplasia.
Interestingly, omeprazole, a proton pump inhibitor (PPI) widely used as first-line EoE therapy, restored mitochondrial function and structure in both mouse and patient-derived organoid models, independent of acid suppression.
These findings redefine EoE as a disease of epithelial energy dysregulation and suggest that PPIs may act through mitochondrial protection. The study highlights mitochondrial pathways as potential therapeutic targets and highlights the value of patient-derived organoids for personalised treatment testing in EoE.
Gut Microbiota
Toxic microbiome and progression of chronic kidney disease: insights from a longitudinal CKD Microbiome Study
Laiola M, Koppe L, Larabi A, et al. Toxic microbiome and progression of chronic kidney disease: insights from a longitudinal CKD-Microbiome Study. Gut 2025: 74:1624–1637. doi: 10.1136/gutjnl-2024-33463
Chronic kidney disease (CKD) affects almost 9% of the global population and progresses through mechanisms that remain incompletely understood. Gut-derived uraemic toxins (UTs) such as indoxyl sulfate and p-cresyl sulfate have been implicated in worsening renal injury, but the link between gut microbiome changes, UT accumulation, and diet has not been fully explored.
Laiola et al. conducted a large, longitudinal, multiomics analysis within the French CKD-REIN cohort, profiling the gut microbiota of 240 non-dialysis CKD patients using shotgun metagenomics, alongside serum UT levels and detailed dietary data. 103 patients were re-evaluated after three years, and findings were validated in an independent Belgian cohort. Causality was tested through faecal microbiota transplantation (FMT) from CKD patients into antibiotic-treated CKD mice.
Compared with healthy controls, CKD patients exhibited significant microbiome alterations with enrichment of UT-producing bacterial species such as Enterocloster and Hungatella, correlating with higher circulating UT levels and lower estimated glomerular filtration rate (eGFR). Over time, microbial richness declined, including protective species, while toxin-producing species increased, mirroring disease progression and severity. Mice receiving stool from CKD donors developed higher serum UT levels and greater renal fibrosis, confirming a causal role of dysbiosis. Interestingly, this study also showed that adherence to a plant-based, low-protein, probiotic-rich diet was beneficial in modulating the gut microbiota and reducing the abundance of UT-producing species.
Although CKD remains incurable, this study highlights the gut microbiome as a modifiable contributor to UT production and disease progression. Although further clinical studies are required, these findings present a promising and hopeful avenue for therapeutic intervention through dietary or microbiota-targeted therapies, offering optimism for slowing CKD progression.
Hepatology
High-protein diets alleviate tumour growth and drug resistance by promoting AKT aggregation and turnover
Bu L, Zhang Y, Su Y, et al. High-protein diets alleviate tumour growth and drug resistance by promoting AKT aggregation and turnover. Gut 2025; 74: 1711-1727. doi: 10.1136/gutjnl-2024-334630
Dietary modifications have been advocated for cancer patients in previous literature, such as high protein diets (HPD) before or after chemotherapies, believed to lead repression of tumourigenesis. It is however not a well understood physiological mechanism, and as such, not currently standard of care.
Lang B et al. set out to investigate the underlying process of HPD as concomitant cancer therapy, in order to facilitate further research for treatment strategies in hepatocellular carcinoma (HCC). Through comparative chemotherapy with concomitant modified diet strategies and measurement of key oncogenic markers: viral murine thymoma oncogene homolog (AKT) and the Mechanistic Target of Rapamycin Complex 1 - Ribosomal protein S6 kinase beta 1 (mTORC1-S6K1) axis, researchers were able to demonstrate a nuanced physiological process that is key in liver tumourigenesis.
Utilising two syngeneic mouse models with mouse derived HCC and mammary tumour cell lines, treated with canonical first line chemotherapy under control diet and HPD. Results were in favour of HPD as the beneficial accompanying diet for both cancers, inducing a blunted tumour growth as well as sensitising these cancer types to chemo-drugs such as carboplatin and 5-fluororacil for HCC and doxorubicin for mammary cancer.
As a result of the HPD, there was a measurable increase in phosphorylation of pS6 which stimulates mTORC1 activity (a major sensor of amino acids, which regulates metabolic homeostasis and cell size), as well as a reduction in measurable AKT activity (also key in physiological metabolic homeostasis and closely linked to liver metabolic disorders). The combination of upregulated MTORC1-S6K1 axis and subsequent AKT activity attenuation in an amino-acid rich environment, results in tumour growth restriction and increased chemotherapeutic sensitivity.
Collectively, these results provide a better understanding of HPD benefits in HCC treatment strategies and promotes further research in this exciting field.
IBD
Integrated multimodel analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD
Gonzalez-Acera M, Patankar J, Erkert L, et al. Integrated multimodel analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD. Gut 2025; 74: 1602-1615. doi: 10.1136/gutjnl-2024-333729.
Mouse models have been central to shaping our understanding of inflammatory bowel disease (IBD) pathogenesis and informing the development of current therapies. However, no single model fully reproduces the complexity of human IBD, thereby limiting translational success. There remains an unmet need to better understand the mechanisms underpinning murine IBD models and their relevance to patients.
In this study, Gonzalez-Acera et al. address this gap by systematically characterising the mucosal transcriptomes of 13 distinct IBD mouse models—including infection-, barrier damage-, and immune modulation-driven models—all maintained under standardised conditions to enable robust comparative analysis. This revealed important insights. For instance, interferon-gamma response was upregulated across most murine models, whereas the downregulation of Notch and Wnt signalling was unique to acute and chronic TNBS (2,4,6-Trinitrobenzenesulfonic acid) colitis models. Comparing murine mucosal transcriptomes with those from multiple IBD patient cohorts, Gonzalez-Acera et al. identified both shared and model-specific molecular features. Major inflammatory pathways such as JAK–STAT (Janus Kinase- Signal Transducer and Activator of Transcription) signalling and Th17 (T helper cell 17) cell differentiation was widely conserved between IBD patients and murine models, whereas mitochondrial alterations and microvilli damage seen in human IBD were restricted to certain models. Distinct cytokine landscapes also emerged, with interleukin-17A (IL-17A) and oncostatin M dominating human IBD, while IL-1b (Interleukin-1 beta) and Tnf (tumour necrosis factor) were frequently upregulated in mice.
This comprehensive analysis demonstrates how individual murine models recapitulate specific aspects of human IBD. These insights, together with an interactive web explorer of their dataset, provide the IBD research community with an invaluable resource to guide the selection of preclinical models for mechanistic and translational studies.
Reviewers
Dr Anahita Sharma, ST6 Gastroenterology Registrar, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
Dr Mirashini Swaminathan, Gastroenterology Specialist Registrar, NHS University Hospitals of Liverpool Group, Liverpool, UK
Dr Daniela Toumazi, CT2 Internal Medicine Trainee, Broomfield Hospital, Mid and South Essex NHS Trust, Chelmsford, UK
Dr David Gomez, ST4 Gastroenterology, Royal Free London NHS Foundation Trust, London, UK
Dr John P Thomas, Chain-Florey Clinical Research Fellow, MRC Laboratory of Medical Sciences & Imperial College London, London, UK
Dr Vinoth Nadesalingam, Consultant Gastroenterologist, Bart’s Health NHS Trust, London, UK
BSG GUT Highlights is edited by Dr Philip J Smith, Honorary Consultant Luminal Gastroenterologist, Royal Liverpool Hospital, Liverpool University Hospitals NHS Foundation Trust, Mount Vernon, Liverpool, UK. Dr Smith is the Digital and Education Editor of GUT, Editor in chief of Frontline Gastroenterology and Associate Editor of BMJ Open Gastroenterology.
Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; internally peer reviewed.