Intestinal inflammation
24-Nor-ursodeoxycholic acid improves intestinal inflammation
Zhu C, Boucheron N, Al-Rubaye O, et al. 24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting TH17 pathogenicity and transdifferentiation. Gut 2025; 74(7): 1079-1093. doi: 10.1136/gutjnl-2024-333297.
There has been an increasing appreciation for the potential importance of bile acids and their effect on inflammatory pathways both in intestinal inflammation as well as cholestatic liver disease. As a result, there has been focus on bile acids as potential novel therapeutic targets for both liver and intestinal involvement, particularly in patients with primary sclerosing cholangitis (PSC). However, the mechanisms of bile acids and how they may affect inflammation have remained poorly described.
In this publication, Zhu et al., sought to assess the effect of 24-Nor-ursodeoxycholic acid (norUDCA) on T-helper type 17 cells, and their role on inflammation. This was first assessed using an adoptive cell transfer mouse model. With further mechanistic studies to investigate using flow cytometry and several additional metabolomic assays. Key findings were then validated using a humanised NSG mouse model – where NSG refers to NOD/SCID/IL-2rγ (Non-Obese Diabetic/Severe Combined Immunodeficiency/Interleukin-2 receptor gamma) all being knocked out. Two weeks after transfer, mice were fed with either chow or norUDCA-supplemented diet for 2 weeks
NorUDCA suppressed TH17 effector function and enriched regulatory T cell (Treg) abundance. By mitigating intraepithelial TH17 pathogenicity, norUDCA decreased the generation of proinflammatory T helper cells. The effects of norUDCA appeared to be through metabolic conditioning of anti-inflammatory regulatory T cells, and also seemed to work in a humanised NSG model reconstituted with peripheral blood mononuclear cells from patients with PSC.
These data highlight the multiple functions and importance of bile acids. These findings also support targeting bile acids as a potentially attractive therapeutic avenue for both intestinal and hepatobiliary inflammation.
Endoscopy
Rectal diclofenac versus indomethacin for prevention of post-ERCP pancreatitis (DIPPP)
, et al, Rectal diclofenac versus indomethacin for prevention of post-ERCP pancreatitis (DIPPP): a multicentre, double-blind, randomised, controlled trial. Gut 2025; 74(7): 1094-1102. doi: 10.1136/gutjnl-2024-334466.
Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a common complication, occurring in up to 10% of patients, with higher risks in certain subgroups. Nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac and indomethacin are recommended for prophylaxis, but their comparative efficacy remains unclear. A multicentre, double-blind, randomised controlled trial (DIPPP, NCT03947861) across nine Chinese tertiary centres compared 100 mg rectal diclofenac versus 100 mg rectal indomethacin for preventing post-ERCP pancreatitis (PEP). The study enrolled 1204 patients (aged 18–90) with native papilla undergoing ERCP, randomised 1:1 to receive either drug before the procedure. The primary outcome was the incidence of PEP, with secondary outcomes including other ERCP-related complications.
The trial was terminated early for futility following a scheduled interim analysis. Baseline characteristics were balanced. PEP occurred in 8.8% (53/600) of the diclofenac group and 6.1% (37/604) of the indomethacin group (relative risk 1.44, 95% CI 0.96–2.16, p=0.074), showing no significant difference. In high-risk patients (e.g., sphincter of Oddi dysfunction, prior PEP, difficult cannulation, multiple pancreatic duct injections), PEP rates were 14.2% (35/247) vs. 9.8% (26/266) for diclofenac vs. indomethacin (p=0.124); low-risk rates were 5.1% (18/353) vs. 3.3% (11/338) for diclofenac vs. indomethacin (p=0.227). Other complications, like bleeding and infection, were similar. Subgroup analyses showed consistent results across sex, age, procedural difficulty, and pancreatic duct instrumentation.
These findings confirm that both NSAIDs are equally effective for prophylaxis, supporting their interchangeable use in clinical practice to reduce PEP risk, particularly in high-risk patients, while highlighting the value of interim analyses for trial efficiency.
Multicentre randomised controlled trial of a self-assembling haemostatic gel to prevent delayed bleeding following endoscopic mucosal resection (PURPLE Trial)
Drews J, Zachäus M, Kleemann T, et al. Multicentre randomised controlled trial of a self-assembling haemostatic gel to prevent delayed bleeding following endoscopic mucosal resection (PURPLE Trial). Gut 2025; 74(7): 1103-1111. doi: 10.1136/gutjnl-2024-334229.
This multicentre, randomised controlled trial evaluated whether prophylactic application of a haemostatic gel (Purastat) reduces the risk of clinically significant delayed bleeding (CSDB) following endoscopic mucosal resection (EMR) of large colorectal (≥20 mm) and duodenal (≥10 mm) lesions. Conducted across 15 German centres, the trial enrolled 234 patients who underwent hot-snare EMR and were randomised to either gel application or no gel post-procedure. The primary endpoint was CSDB within 30 days, defined by objective clinical and laboratory criteria.
The study was terminated early for futility after an interim analysis, with 94.4% of the planned sample recruited. CSDB occurred in 11.7% of patients in the gel group and 6.3% in the control group (p=0.227), showing no statistically significant difference. Subgroup analyses for colorectal and duodenal EMR similarly demonstrated no benefit of gel application. Furthermore, the haemostatic gel had no observed effect on wound healing assessed during follow-up endoscopy 8-10 weeks later.
Roughly half of all patients received endoscopic haemostasis (clipping and/or coagulation) before randomisation, but even in those who did not, the gel did not significantly reduce bleeding rates. Adverse events were similar between groups, and the gel was well tolerated.
Drews et al., conclude that prophylactic use of Purastat haemostatic gel does not prevent delayed bleeding after large EMR in the colon or duodenum. These findings suggest that gel application should not be routinely used for bleeding prevention in this context.
Neurogastroenterology
Characterisation of MRGPRX2+ mast cells in irritable bowel syndrome
Decraecker L, Cuende Estévez M, Van Remoortel S, et al. Characterisation of MRGPRX2+ mast cells in irritable bowel syndrome. Gut 2025; 74(7): 1068-1077. doi: 10.1136/gutjnl-2024-334037.
The pathophysiological basis of irritable bowel syndrome (IBS) is yet to be elucidated. In this study, Decraecker et al. test the theory that mast cell activation, through a ‘pseudoallergic’ pathway distinct from the canonical IgE-mediated pathway, is implicated in a subtype of patients with IBS with visceral hypersensitivity. These pathways are mediated by the mast cell G-protein receptor coupled family (MRGPR), which are stimulated by a wide number of compounds, including drugs, toxins and endogenous molecules such as substance P.
The group has previously demonstrated a 10.7-fold increased expression of the specific receptor MRGPRX2 (Mas-related G-protein coupled receptor member X2) in colonic specimens of a subset of patients with IBS. The researchers compare the expression and functional characteristics of MRGPRX2 in rectal biopsies obtained from patients with IBS against those from healthy controls. They also undertake functional studies of MRGPRX2 in healthy colonic specimens.
In healthy colonic specimens, Decraecker et al. demonstrate that MRGPRX2 agonists—such as compound 48/80, substance P (SP), and MRG-733—induce significant mast cell degranulation and TRPV1 (transient receptor potential cation channel subfamily V member 1) sensitisation in the submucosal plexus, indicating a potential mechanism for nociceptor sensitisation.
Exposure to MRGPRX2 agonists in the IBS rectal specimens induced heightened mast cell de-granulation compared to the rectal specimens of healthy controls, despite no difference in MRGPRX2 frequency or receptor expression. This enhanced responsiveness suggests intracellular sensitisation mechanisms or a pre-activated mast cell phenotype in IBS. Furthermore, supernatants from the IBS biopsies showed elevated MRGPRX2 agonistic activity, particularly due to increased levels of substance P. This mechanistic insight supports the development of MRGPRX2 antagonists or modulators as treatment targets.
Hepatology
Bioprinting functional hepatocyte organoids derived from human stem cells to treat liver failure
Li G, He J, Shi J, et al. Bioprinting functional hepatocyte organoids derived from human chemically induced pluripotent stem cells to treat liver failure. Gut 2025; 74(7): 1150-1164. doi: 10.1136/gutjnl-2024-333885.
Regenerative medicine shows great potential as a therapeutic approach in liver failure. In this article, Li et al., developed chemically re-programmed human induced pluripotent stem cells to generate 3D-bioprinted hydrogel-embedded hepatocyte organoids (3D-hCiPSCs-HOs), that lead to amelioration of disease parameters of when transplanted into in-vivo liver failure models.
Firstly, Li et al., characterised and optimised the hCiPSC-hepatocyte differentiation process, spheroid/organoid formation and bioprinting of organoids. Using RT-qPCR, immunofluorescence, fluorescence-based assays, staining and simple microscopy, each of these steps were optimised based on cell viability, functionality and gene/protein expression. The final 3D-hCiPSC-HOs exhibited higher or equivalent hepatocyte-specific gene expression, with corresponding protein expression, albumin and urea synthesis and CYP3A4 (Cytochrome P450 3A4) activity, compared to pre-printed organoids and comparable to primary human hepatocytes.
Subsequently, 3D-hCiPSC-HOs transplanted into two mice models of liver failure (carbon tetrachloride (CCl4) and Fah-/-) lead to reduction of tissue inflammatory/fibrotic gene expression, improvement in serum liver function tests and albumin levels, histology and survival compared to sham procedure, 3D-printed A549 cells and blank transplant, at different time points. Extracted 3D-hCiPSC-HOs from Fah-/- mice showed maintained structural integrity and viability and angiogenesis coinciding with Dextran and CD31 staining, at day 60 post-transplant. Furthermore, hepatic gene expression was maintained along with presence of bile duct markers expression, suggesting tissue re-organisation, de-novo angiogenesis and bio-tolerance.
Li et al., conclude that 3D-hCiPC-HOs are a feasible and effective approach in treatment of liver failure in their pre-clinical work, whereby future aspects should be focused on improving biocompatibility of hydrogels, mechanical integrity, scalability and ultimately, clinical translation.
Reviewers
Dr Nurulamin Noor, Clinical Lecturer in Gastroenterology, University of Cambridge and Cambridge University Hospitals, Cambridge, UK
Dr Gaurav Nigam, NIHR Clinical Research Fellow, University of Oxford and Oxford University Hospitals, Oxford, UK
Dr Anahita Sharma, Gastroenterology Registrar, Department of Gastroenterology, Arrowe Park Hospital, Wirral, UK
Dr Brian Ho, Honorary Clinical Research Fellow and Gastroenterology Registrar, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
Dr Keith Pohl, JAG Fellow and Gastroenterology Registrar, Torbay and South Devon NHS Foundation Trust, Torquay, 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.