To determine whether CPEB4 restrains VM and tumour adaptation to VEGF blockade in HCC.

We combined human and murine liver cancer models with genetic CPEB4 loss, xenografts, transcriptomic and ribosome profiling analyses and functional vascular assays.

CPEB4 loss enhanced tumour cell-intrinsic VM capacity and promoted formation of VM structures in vivo. CPEB4-deficient tumours displayed vascular remodelling with preservation of VM channels and endothelial vessels together with reduced hypoxia, apoptosis and necrosis. Under VEGF blockade, endothelial networks were impaired whereas VM activity persisted; notably, CPEB4-deficient tumour cells sustained vascular network organisation and tumour viability. Mechanistically, CPEB4 loss induced an epithelial-to-mesenchymal transition (EMT)-associated plasticity programme and enrichment of EMT-related signatures at the translational level, including increased ribosome occupancy of EMT-associated transcripts. Consistent with this, EMT regulators were enriched for cytoplasmic polyadenylation elements, suggesting post-transcriptional control.

CPEB4 acts as a tumour cell-intrinsic suppressor of VM in HCC. Its loss promotes an EMT-associated adaptive programme that reduces reliance on VEGF-driven angiogenesis and supports a mechanism of adaptive resistance to anti-angiogenic therapy.

To assess whether PA protects against CP and defines the underlying mechanisms.

We analysed the association between PA and CP risk in the UK Biobank cohort (>500 000 participants) and validated findings in an independent clinical cohort. In mice, experimental CP was induced and the effects of exercise interventions on pancreatic injury, fibrosis and immune responses were evaluated via histopathology, immunohistochemistry, flow cytometry, bulk and single-cell RNA-sequencing and proteomics.

In the UK Biobank, regular PA was independently associated with a lower risk of CP. This association was consistent across alcohol intake strata and disease subtypes. Consistently, physically active patients with CP exhibited milder clinical manifestations. In mice, exercise interventions, including both preconditioning and postdisease initiation, attenuated pancreatic injury, fibrosis and ferroptosis, with resistance exercise providing greater protection. Mechanistically, skeletal muscle-derived extracellular vesicles (EVs) induced by PA accumulated within inflamed pancreata and dampened mitochondrial DNA-driven innate immune activation while promoting inflammation-resolving states, at least in part through modulation of myeloid stimulator of interferon genes (STING) signalling. Importantly, inhibition of EV release partially attenuates these protective effects. Proteomic profiling identified PRDX6 as a muscle-derived vesicular factor that inhibits ferroptosis and, by binding to the zinc-thumb motif of cyclic GMP-AMP synthase, contributes to suppression of STING activation and inflammatory damage.

PA restrains CP progression by reprogramming pancreatic immune responses and ferroptosis pathways.

To explore the role of GPR15L in the pathogenesis of experimental colitis and IBD.

We studied how genetic deletion or overexpression of Gpr15l as well as rectal application of recombinant GPR15L alters the course of acute dextran sodium sulfate colitis and T cell transfer colitis. The impact of GPR15L on microbiota was explored with co-housing, littermate and faecal microbiota transfer studies, by 16S rRNA sequencing as well as anti-microbial assays and shotgun metagenomics. The expression of GPR15L was evaluated across three independent cohorts of patients with IBD and correlated to microbial diversity and flare-free survival.

GPR15L clearly mitigated experimental colitis, but this was independent of T cell recruitment and GPR15. Instead, we observed that the effects of GPR15L were mediated by altered microbiomes in the large intestine and, consistently, showed that GPR15L acts as an antimicrobial peptide under anaerobic conditions and shapes microbial communities towards a homeostatic phenotype. Rectal supplementation of GPR15L counteracted experimental colitis. In patients with IBD, GPR15L expression was decreased in active inflammation, correlated with microbial diversity and was associated with flare-free survival.

GPR15L is a host-defence peptide that plays a beneficial role in the pathogenesis of intestinal inflammation. It seems promising to further evaluate its potential as a future therapeutic approach in IBD.

To determine how TIAs influence PDAC progression and to define the immunometabolic mechanism involved.

We used orthotopic PDAC models and Kras(LSL-G12D/+);Trp53(LSL-R172H/+);Pdx1-Cre (KPC) mice, together with neutrophil lineage peroxisome proliferator-activated receptor gamma (PPAR) conditional knockout mice (PPAR(fl/fl)-S100A8(cre)). Tumour metabolomics, bulk RNA sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) were integrated with adipocyte and tumour-associated neutrophil (TAN) co-culture assays. Human relevance was assessed in a retrospective PDAC cohort (n=121) and validated in public transcriptomic datasets.

High TIA abundance correlated with poorer overall survival and an immune-suppressed tumour microenvironment (TME). In mouse models, adipocyte-enriched tumours showed reduced CD8⁺ T cell functions. Multiomics analyses highlighted the adipocyte-derived metabolite 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME) and supported its role in increasing TAN ferroptosis susceptibility. Mechanistically, 12,13-DiHOME enhanced PPAR-dependent ferritinophagy signalling in TANs, accompanied by increased ferroptosis and CXCL2 production. Genetic or pharmacologic disruption of this axis, CXCL2 neutralisation or CXCR2 blocking, attenuated tumour-promoting phenotypes and restored CD8⁺ T cell functions in vivo and in vitro.

These findings support an adipocyte-TAN immunometabolic circuit in PDAC, where TIA-derived 12,13-DiHOME promotes PPAR-dependent TAN ferroptosis and increases CXCL2, leading to impaired CD8⁺ T cell functions. Targeting this pathway may help mitigate immune suppression in PDAC.

Endoscopy-related musculoskeletal injuries (ERIs) affect up to two-thirds of endoscopists1 and this burden is likely to increase as procedures become longer and more complex. Although scientific societies have increasingly recognised ergonomics as an important component of endoscopic practice,2–5 formal training remains limited and much of the available evidence is extrapolated from surgical specialties. While many ergonomic challenges in GI endoscopy are related...]]> 2026-05-27T09:00:16-07:00 info:doi/10.1136/gutjnl-2026-338900 hwp:master-id:gutjnl;gutjnl-2026-338900 BMJ Publishing Group 2026-05-27 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2025-336392v1?rss=1 Autoimmune gastritis (AIG) has been traditionally recognised as a precursor to type I gastric neuroendocrine tumours and non-cardia gastric adenocarcinoma. However, emerging but scattered evidence suggests that its oncogenic footprint may extend beyond the gastric body to the cardia, gastro-oesophageal junction (GOJ) and oesophagus. In this review, we synthesise the available epidemiological and clinical studies linking AIG and its late manifestation, pernicious anaemia, to cardia/GOJ adenocarcinoma and oesophageal cancers. We discuss putative histopathological, immunological and other mechanisms, including corpus-predominant atrophy, intestinal metaplasia and vitamin B12 deficiency that may create a carcinogenic microenvironment not only in the distal stomach but also at the GOJ and beyond. We highlight diagnostic and epidemiologic challenges that have obscured these associations, including the difficulties in defining the gastric cardia, disentangling autoimmune versus other potential pathways and the under-recognition of AIG in routine practice. Finally, we outline a research agenda aimed at clarifying the malignancy risk across the stomach-cardia-oesophagus continuum, emphasising the need for well-phenotyped cohorts, biomarker-driven risk stratification and refined surveillance strategies. By reframing AIG as a potential hidden gateway to junctional and oesophageal malignancies, we argue that its true oncological significance may be broader than previously appreciated.

To investigate whether PTEN deficiency promotes resistance to ICB in MSS CRC.

An integrative analysis of clinical cohort and The Cancer Genome Atlas (TCGA) database was performed to establish the correlation between PTEN expression and therapeutic response. Single-cell RNA sequencing and flow cytometry were used to identify changes in the tumour immune microenvironment. Immunohistochemistry, mass spectrometry, co-immunoprecipitation and confocal microscopy were employed to dissect the non-canonical function of PTEN.

PTEN low expression was strongly associated with reduced CD8⁺ T-cell infiltration and poor survival in patients receiving ICB. Mechanistically, we identified a non-canonical function of PTEN that physically interacts with and stabilises KEAP1 via the C2 domain, shielding KEAP1 from p62-mediated degradation. Consequently, PTEN deficiency promoted KEAP1 degradation and subsequent NRF2 hyperactivation, which transcriptionally upregulated selective-autophagy machinery, thereby driving the selective lysosomal degradation of major histocompatibility complex (MHC)-I. This process abolished CD8⁺ T-cell recognition and effector functions, resulting in immune evasion. Crucially, pharmacological inhibition of NRF2 with ML385 restored cell surface MHC-I levels and sensitised PTEN-deficient tumours to anti-programmed cell death protein 1 therapy.

PTEN deficiency promotes immune evasion in MSS CRC via an NRF2-dependent axis that triggers autophagy-mediated degradation of MHC-I. Targeting NRF2 represents a promising strategy to enhance the efficacy of immunotherapy in PTEN-deficient MSS CRC.

To discover and characterise key regulators of hepatic lipotoxicity that drive MASH progression and to delineate their mechanistic and therapeutic relevance.

We integrated multiple RNA-seq datasets from murine and human MASH to identify candidate genes linked to disease-associated metabolic signatures. Functional and mechanistic studies were performed using primary hepatocytes, hepatocyte-specific transgenic and knockout mice and an AAV8-based post-onset knockdown model. Protein interactions and subcellular dynamics were evaluated using co-immunoprecipitation-mass spectrometry, structural modelling and colocalisation analysis. The small molecule of monooxygenase DBH like 1 (MOXD1) inhibitor candidates was screened by the artificial intelligence (AI) model, and their anti-MASH capacity was evaluated in vitro and in vivo.

We identified MOXD1 as a previously unrecognised gene tightly associated with MASH transcriptional programmes. Hepatocyte MOXD1 significantly exacerbated MASH phenotypes. Mechanistically, MOXD1 directly interacted with the ACOX1–PEX5 translocation complex, promoting ACOX1 trafficking to peroxisomes to block lipolysis, lipophagy. We further identified four key MOXD1 residues required for ACOX1 binding and resultant pro-MASH capacity. Importantly, based on the AI model and interacting details of MOXD1–ACOX1, we identified a small molecule rM15 that directly binds to MOXD1 and blocks its interaction with ACOX1. Notably, rM15 robustly protected against hepatocyte lipid accumulation and suppressed diet-induced MASH progression in vivo.

This study identifies MOXD1 as a previously unrecognised regulator of hepatic fatty-acid homeostasis and a key driver of MASH pathogenesis. Targeting the MOXD1–ACOX1 axis offers a promising therapeutic strategy for MASH.

To compare the clinical outcomes of urgent ERCP performed within 24 hours vs early ERCP performed within 24–48 hours in patients with mild to moderate acute cholangitis.

Single-centre, open-label, randomised controlled trial. The primary outcome was 30-day mortality. Secondary outcomes included organ failure at day 3 and day 30, in-hospital mortality, length of hospital stay, reintervention rates, readmission rates and post-ERCP adverse events. The sample size calculation was based on a superiority hypothesis, assuming event rates of 8% versus 19% in favour of urgent ERCP.

A total of 304 patients (mean age 55.58±14.10 years; 218 men) were randomised, with 152 assigned to urgent ERCP and 152 to early ERCP. Baseline characteristics were similar between the two groups. There was no significant difference in 30-day mortality between the urgent and early ERCP groups (3.95% vs 6.58%; hazard ratio 0.70, 95% CI 0.25 to 1.93; p=0.47). Likewise, there were no significant differences in in-hospital mortality (1.97% vs 3.28%; relative risk (RR) 1.67, 95% CI 0.40 to 7.20), organ failure at day 3 (9.2% vs 11.2%; RR 1.24, 95% CI 0.59 to 2.62), organ failure at day 30 (11.8% vs 17.1%; RR 1.54, 95% CI 0.80 to 2.94), reintervention rates or readmission rates. The median length of hospital stay was also similar between the groups (6.94 days vs 7.84 days). However, post-ERCP adverse events were more frequent in the urgent ERCP group than in the early ERCP group (17.1% vs 9.2%; RR 2.03, 95% CI 1.02 to 4.07) in the unadjusted analysis.

In patients with mild-to-moderate acute cholangitis, urgent ERCP within 24 hours was not superior to early ERCP within 24–48 hours with respect to mortality or organ failure and is associated with a higher rate of procedure-related adverse events.

NCT05920954.

To determine whether irreversible proteolytic cleavage of protease-activated receptor-2 (PAR₂) and its continued activity in endosomes amplify and sustain otherwise transient pronociceptive actions of histamine receptors to cause recurrent pain, the defining symptom of IBS.

We investigated PAR₂ and H₁R coexpression in nociceptors using RNAscope and assessed the consequences of coactivation using electrophysiological assays of nociceptor sensitisation and biophysical measurements of receptor and effector activity.

PAR₂ and H₁R were co-expressed by human and mouse dorsal root ganglion nociceptors. Intracolonic infusion of faecal supernatants from patients with IBS with elevated histamine and proteolytic activity enhanced mechanosensitivity of colonic nociceptors in mice. Antagonists of PAR₂ or H₁R abolished this response. Combined administration of subthreshold concentrations of trypsin and histamine replicated the effects of faecal supernatant and caused hyperexcitability of isolated nociceptors. Pre-activation with trypsin sensitised histamine-induced hyperexcitability in nociceptors from wild-type but not Par₂^–/– mice. Endocytosis inhibitors prevented this hypersensitivity, consistent with sustained endosomal signalling of PAR₂ and persistent nociceptor hyperexcitability. Trypsin amplified histamine-induced activation of H₁R and β-arrestin2 and Gαq effectors at the plasmalemma and in endosomes. Conversely, histamine did not sensitise trypsin-induced hyperexcitability of neurons, in line with the inability of histamine to induce sustained nociceptor hypersensitivity.

By amplifying and maintaining the otherwise transient actions of H₁R and possibly other pain receptors, persistent PAR₂ endosomal signalling makes a dominant contribution to IBS-related colonic pain.

To define features of the colonic microenvironment that distinguish LS carriers with and without a history of CRC from one another and from the general population.

We applied Expanded Cellular Indexing of Transcriptomes and Epitopes by sequencing, a multimodal single-cell platform, to profile tumour-free colonic cellular composition and transcriptome of LS carriers with and without a history of CRC compared with general population controls. We used flow cytometry, histology and mouse modelling to validate key observations.

We observed widespread remodelling in LS that included striking expansion of epithelial stem and progenitor cells, loss of fibroblast populations and changes in lymphocyte subsets. Although clonally expanded and terminally exhausted CD8 T cells were more prominent in individuals with a history of CRC, LS carriers without CRC displayed enrichment of cytotoxic mucosal-associated invariant T (MAIT) cells associated with CCL20 expression in epithelial progenitors, validated by orthogonal techniques including demonstration of a protective function in a murine model of CRC.

These findings define key features of the LS colonic microenvironment and suggest that MAIT cell enrichment contributes to immune surveillance against CRC, offering new insights into disease penetrance, risk stratification and prevention.

To assess gut microbiome taxonomic and functional associations with colorectal neoplasia presence, severity (non-advanced, advanced and CRC) and subtype and evaluate predictive potential in high-risk neoplasia.

Analysed cross-sectional stool metagenomes (pre-colonoscopy) from 1762 participants (97% White British) undergoing colonoscopy in the multicentre COLO-COHORT study. Neoplasia was classified per British Society of Gastroenterology surveillance guidelines. Linear mixed-effects models and random forest classifiers assessed taxonomic and functional associations, adjusting for dietary, clinical and lifestyle covariates.

Gut microbiome composition differences between individuals with and without neoplasia were statistically significant but minimal (R²=0.0008, p=0.03). A small number of species, including Mediterraneibacter faecis and Pseudoruminococcus massiliensis, and microbial pathways, including amino acid biosynthesis and β-lactam resistance, were modestly linked to neoplasia, particularly early lesions (q value <0.05). Associations were generally weak and attenuated after covariate adjustment. Predictive models combining the microbiome with clinical/demographic features modestly improved high-risk neoplasia classification (area under the curve=0.64 vs 0.58 for clinical/demographic features alone).

This large prospective cross-sectional study found weak and inconsistent associations between the gut microbiome and premalignant colorectal neoplasia, with no robust microbial signatures. Findings suggest that previously reported microbial shifts may emerge later in disease progression, potentially as a consequence rather than a cause of CRC. Longitudinal, multiomic studies disentangling temporal and causal pathways between the gut microbiome and neoplasia are required.

We evaluated the cccDNA and iDNA from liver tissues of 24 hepatitis B e antigen (HBeAg)(+) and 32 HBeAg(–) treatment-naïve chronic hepatitis B (CHB) participants in the North American Hepatitis B Research Network.

For cccDNA analysis, DNA was heat-denatured and digested by plasmid-safe ATP-dependent DNase to remove relaxed circular DNA and iDNA before real-time polymerase chain reaction. For iDNA detection, total DNA was subjected to HBV hybridisation-targeted next generation sequencing assay for identification of the HBV-host junction sequences. Comparisons of HBV cccDNA and iDNA with other virological biomarkers were assessed.

Intrahepatic cccDNA, serum HBV DNA, HBV RNA, hepatitis B core related antigen and quantitative hepatitis B surface antigen were higher in HBeAg(+) CHB. Intrahepatic hepatitis B core antigen staining was present in 87% HBeAg(+) but only 13% HBeAg(–) samples (p<0.0001). HBsAg staining was frequent in over 85% in both groups. 23 (95.8%) HBeAg(+) participants had ≤50% iDNA whereas 25 (78.1%) HBeAg(–) participants had >50% iDNA of total HBV DNA in their livers. For HBeAg(+) CHB, the iDNA integration sites were random with only 15.9% localised to the direct repeat 2 (DR2)-DR1 region. For HBeAg(–) CHB, 52.4% of the iDNA integrations were clustered at DR2-DR1. Microhomology-mediated end joining patterns of double-stranded linear DNA HBV integration was more frequent in HBeAg(+) livers.

HBeAg(–) CHB was associated with high HBsAg staining concentration despite low cccDNA levels suggesting that iDNA was the primary source of HBsAg. The high frequency of DR2-DR1 iDNA distribution in HBeAg(–) CHB suggests the selection advantage and clonal expansion of this integrant in the natural history of CHB.

To estimate the HCC burden attributable to HBV and HCV by country, region and globally.

We performed a systematic review and meta-analysis between 1 October 2014 and 31 December 2023 using studies that reported the prevalence of both HBV and HCV in at least 20 patients with HCC. Pooled prevalence estimates by country were calculated to estimate regional and global HBV and HCV attributable fractions (AFs) and HCC-attributable age-standardised incidence rates (ASIRs).

857 eligible publications from 81 countries or territories were included. HBV and HCV prevalence among patients with HCC varied substantially by country and region. HBV AF was highest in Eastern Asia (70%), with HBV-attributable ASIRs of >10 per 100 000 observed in Mongolia and Viet Nam and was lowest in Northern Europe (6%). HCV AF was highest in Northern Africa (77%), and HCV-attributable ASIRs of >10 per 100 000 were observed in Egypt and Mongolia. Patients with HBV-related HCC were younger than patients with HCV-related HCC. Globally, HBV and HCV AFs were 52% and 21%, corresponding to 345 434 and 134 418 HCC cases, respectively, in 2022. Alcohol and/or metabolic dysfunction-associated steatotic liver disease were present in more than 30% of HCC in certain countries of Europe and South America.

HBV and HCV contribute to approximately three-quarters of the global HCC burden. These data can inform viral hepatitis prevention strategies.

CRD42023397708.

Metabolic surgery has achieved major therapeutic goals, including long-term remission of type 2 diabetes mellitus (T2DM)1–3 and resolution of metabolic dysfunction-associated steatohepatitis.4 Procedures such as biliopancreatic diversion (BPD) and Roux-en-Y gastric bypass provide profound and durable improvements...]]> 2026-05-12T09:00:19-07:00 info:doi/10.1136/gutjnl-2025-337077 hwp:master-id:gutjnl;gutjnl-2025-337077 BMJ Publishing Group 2026-05-12 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2026-338954v1?rss=1 In GUT, Schroter et al provide experimental evidence that a population of non-conventional T cells characterised by expression of gamma delta () T cell receptors may help reduce the burden of hepatitis B virus (HBV)-infected hepatocytes in both chronic and acute HBV infection.1

T cells are a distinct and still enigmatic subset of T lymphocytes that, in contrast to classical αβ T cells—which recognise antigen in association with major histocompatibility complex (MHC) class I or class II molecules—use their T cell receptor (TCR) to perceive a broader array of foreign and self-derived antigens in an MHC-independent manner. Although the full repertoire of antigens recognised by T cells remains incompletely defined, their documented ability to respond to host-derived molecules such as phosphoantigens, CD1-associated lipids and stress-induced ligands including MICA, MICB and NKG2D ligands positions T cells at the interface between adaptive and innate-like immunity.2

However,...]]> 2026-05-11T09:00:25-07:00 info:doi/10.1136/gutjnl-2026-338954 hwp:master-id:gutjnl;gutjnl-2026-338954 BMJ Publishing Group 2026-05-11 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2025-337330v1?rss=1 Background

Hepatocellular carcinoma (HCC), one of the most prevalent cancers worldwide, has a high mortality owing to diagnostic challenges and therapeutic resistance. Lactate metabolism and protein lactylation play key roles in HCC progression; nevertheless, their regulatory mechanisms remain poorly understood.

This study aims to elucidate how lactate metabolism and protein lactylation contribute to HCC malignant progression by integrating multi-omics data, identifying key regulatory factors and exploring therapeutic strategies targeting this pathway.

Integrated multi-omics analysis identified AARS2–AP-2 as a key axis in HCC. Through mechanistic studies and virtual screening, we developed kukoamine A—a targeted inhibitor delivered via nanocarriers—demonstrating significant therapeutic potential.

AARS2 was identified as a key regulator linking lactate metabolism to HCC progression through lactylation modification. It catalyses AP-2 lactylation at K444, enhancing TRIM28 binding to promote K63-linked ubiquitination and nuclear translocation, thereby facilitating tumour progression. The inhibitor kukoamine A disrupts AARS2–AP-2 interaction and, when delivered via zeolitic imidazolate framework-8 nanocarriers, demonstrates improved liver targeting, potent antitumour activity and synergy with PD-1 blockade, offering new strategic avenues for HCC precision therapy.

AARS2 links lactate metabolism to HCC progression via lactylation. Kukoamine A nanotherapy targeting this axis shows synergistic efficacy with immunotherapy, advancing the prospects of precision oncology.

Our study aimed to construct a diagnostic model for CP and depict molecular landscape of CP based on EV long RNA (ExLR).

Candidate ExLRs were defined using prespecified expression-quality criteria and complementary discovery-stage screens, and a resampling-based consensus feature selection in the training cohort yielded a five-ExLRs panel for model construction. The ExLRs-based CP diagnostic model (ExLRCPdscore) was further confirmed in another two independent validation cohorts with different controls. To elucidate the biological architecture of CP through ExLR profiling, we integrated ExLR-seq, single-cell data and clinical information.

ExLRCPdscore constructed by random forest demonstrated excellent performance for detecting CP. Importantly, ExLRCPdscore could effectively detect early-stage CP, CP without alarm symptoms, CP without significant imaging findings and CP without risk factors. Using ExLR profiling and phenotypic data, we pinpointed MUC5B⁺ ductal cells exhibiting the strongest correlation with CP and derived an ExLR-based acinar-to-ductal metaplasia (ADM) score as a blood-based transcriptomic proxy of ADM-related programme. Integration of ExLR-seq and clinical information revealed significant associations between ADMscore and clinical characteristics, imaging findings and metabolic sequelae.

Our study is the first to report an ExLRs-based diagnostic model that demonstrates exceptional robustness in differentiating CP from healthy controls and non-pancreatic disease controls. ExLRs offer a promising tool for CP molecular characterisation and pathophysiological quantification.

To characterise gut microbiome alterations in EBV-associated NPC, evaluate microbiome-based diagnostic performance (alone and in combination with EBV markers), and explore associations between microbial features, EBV DNA burden, prognosis and the tumour microenvironment.

We conducted a large-scale shotgun metagenomic study including 516 patients with EBV-associated NPC and 263 healthy controls. Microbiome dysbiosis, functional pathways and associations with plasma EBV DNA were assessed. Species-level markers were used to build a random forest classifier for NPC diagnosis, and performance was evaluated alone and in combination with EBV-specific markers. Survival analyses were performed to identify microbial features associated with NPC-related mortality and relationships with an immune-suppressive tumour microenvironment were explored.

NPC was characterised by gut microbiome dysbiosis, including depletion of short-chain fatty acid–producing species and reduced butanoate metabolism, which were significantly associated with plasma EBV DNA. A random forest classifier based on species-level markers distinguished NPC from controls with an area under the curve (AUC) of 0.917; performance improved to an AUC of 0.984 when combined with EBV-specific markers. Specific microbial species were associated with NPC-related mortality and prognostic microbial features were linked to an immune-suppressive tumour microenvironment.

EBV-associated NPC is associated with distinct gut microbiome and functional alterations that correlate with plasma EBV DNA. Microbial markers show strong diagnostic potential, particularly when integrated with EBV-specific markers, and prognostic microbial features may be linked to an immune-suppressive tumour microenvironment, supporting a potential role of the gut microbiome in NPC tumourigenesis.

To develop and validate the Radiomics-based Early Detection MODel (REDMOD), an AI framework to identify subvisual radiomic signatures of pre-diagnostic PDA on standard-of-care CT.

REDMOD was trained on a multi-institutional cohort (n=969; 156 pre-diagnostic, 813 control) and tested on an independent set (n=493; 63 pre-diagnostic, 430 control), simulating a low prevalence (~1:6) early detection paradigm. The fully automated framework couples AI-driven segmentation with a heterogeneous ensemble architecture trained on a 40-feature radiomic signature derived from Synthetic Minority Over-sampling Technique (SMOTE)-balanced data. A tunable Youden Index-optimised classification threshold enables performance calibration without retraining. Validation included direct comparison with radiologists, longitudinal test–retest analysis and external specificity validation across two independent cohorts (n=539 and n=80).

On an independent test set (n=493), REDMOD identified occult PDA (AUC 0.82; 73.0% sensitivity) at a median 475-day lead time. This represented nearly twofold higher sensitivity than radiologists (38.9%; p<0.001), which grew to nearly threefold (68.0% vs 23.0%) at >24 months lead time. REDMOD showed strong longitudinal stability (90–92% concordance) and generalisable specificity across multi-institutional (81.3%; n=539) and public (87.5%; n=80) datasets. Mechanistic analyses confirmed predictive power derived principally from multi-scale wavelet-filtered textural features (90% of selected signature), which outperformed unfiltered features (AUC 0.82 vs 0.74; p=0.007) in capturing subvisual architectural disruptions.

REDMOD is an automated, mechanistically grounded, longitudinally stable, externally validated AI that surpasses radiologists for PDA detection at its visually occult pre-diagnostic stage. These attributes position it for prospective validation in high-risk cohorts, a necessary step towards shifting the paradigm from late-stage symptomatic diagnosis to proactive pre-clinical interception.

To elucidate the function of the deubiquitinase JOSD1 in modulating PTM crosstalk and its impact on tumour glycolysis, progression and immunotherapy response in HCC.

We combined multi-omics analyses with functional and mechanistic studies in cell lines, animal models and patient samples to characterise JOSD1 and its downstream pathways in HCC.

JOSD1 was identified as a gene associated with glycolysis and correlated with a poor prognosis. Its over-expression promoted malignant phenotypes and enhanced glycolytic flux. Mechanistically, the JOSD1-AARS1 axis cooperatively regulates the ubiquitination-lactylation crosstalk at the K251 residue of PGAM1, thereby stabilising PGAM1, enhancing its enzymatic activity and promoting lactate accumulation. This metabolic shift impaired CD8⁺ T cell infiltration and function, promoting immune suppression. Therapeutically, liver-targeted inhibition of JOSD1 effectively suppressed tumour progression and synergised with anti-PD-1 therapy, leading to prolonged survival.

The JOSD1-AARS1 axis regulates the ubiquitination-lactylation crosstalk on PGAM1, with JOSD1 acting as the critical upstream molecular switch that drives metabolic reprogramming and immune evasion in HCC. Targeting JOSD1 represents a promising therapeutic strategy to modulate tumour metabolism and improve immunotherapy efficacy.

We conducted a retrospective study of all HBV-related LTs in the UK (2010–2023) to review post-LT HBV prophylaxis, assess the impact of HBIG duration on HBV recurrence and overall survival and compare HBIG costs across protocols.

Significant variation in protocols among LT centres was observed. The majority of the 273 patients were high risk for HBV recurrence (81.7%). After LT, 85% received HBIG regardless of the risk for HBV recurrence and 54.6% of patients continued HBIG treatment with a median duration of 119 days (IQR 10–344). A total of 14 patients (5.1%) experienced HBV recurrence within 12 months following LT. Our multivariate analysis indicated that triple immunosuppression following LT had a significantly increased risk of HBV recurrence. Survival rates at 1, 5 and 7 years after LT were 98.2%, 88.3% and 80.6%, respectively. In the Cox regression analysis, only lower HBIG IV doses during the first week after LT were associated with 7-year mortality.

There is a vast discrepancy in HBIG usage across the UK. HBIG doses after LT and the risk of HBV recurrence groups do not influence outcomes. HBIG maintenance-free prophylaxis is therefore a feasible and cost-effective option for most patients. Further prospective studies should verify these findings and support wider adoption of HBIG-free strategies.

HCC events in this cohort were ascertained through prospective follow-up, medical record review or validated registries. In routine clinical practice, however, patients with higher FIB-4 or LSM values are more likely to be referred to hepatologists and to receive more frequent abdominal imaging .1 If high-risk patients underwent more intensive surveillance than low-risk patients—a realistic scenario in a...]]> 2026-04-21T09:00:15-07:00 info:doi/10.1136/gutjnl-2026-339053 hwp:master-id:gutjnl;gutjnl-2026-339053 BMJ Publishing Group 2026-04-21 Letter http://gut.bmj.com/cgi/content/short/gutjnl-2026-338214v1?rss=1 In response to Gupta and colleagues’ study on implementing an endoscopic submucosal dissection (ESD)-first algorithm for Barrett’s cancers >15 mm, we highlight critical concerns regarding selection bias, patient morbidity, and guideline adherence. We argue that the improved outcomes reported in the second study period may reflect a shift in case mix—diluted by morphologically favourable lesions—rather than the independent superiority of the strategy. Furthermore, from a risk–benefit perspective, the routine application of ESD exposes patients with dysplasia and T1a disease to a significantly higher risk of oesophageal strictures (22.6%) without demonstrating clear oncologic or survival superiority over endoscopic mucosal resection (EMR). We also raise concerns regarding the long-term oncological safety of patients with T1b diseasepatients who underwent non-curative resection without subsequent surgical salvage. Finally, we caution that lowering the ESD size threshold to 15 mm contradicts current international guidelines (typically >20 mm) and requires specific validation within this ‘"grey zone’." We advocate for a...]]> 2026-04-21T09:00:15-07:00 info:doi/10.1136/gutjnl-2026-338214 hwp:master-id:gutjnl;gutjnl-2026-338214 BMJ Publishing Group 2026-04-21 Letter http://gut.bmj.com/cgi/content/short/gutjnl-2026-338840v1?rss=1 Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related mortality worldwide.1 Many patients with HCC present at an advanced disease stage where the tumour has invaded major blood vessels or metastasised beyond the liver. Although immune checkpoint inhibitor (ICI) combinations have revolutionised treatment in these patients and are now the preferred first-line treatment, response rates remain low at 10–30%, with many patients developing acquired resistance.2 3 The liver’s unique immunotolerant microenvironment, characterised by abundant immunosuppressive cells, contributes substantially to this poor immunotherapy responsiveness.4 Among these, tumour-associated macrophages (TAMs) constitute the predominant immune population, comprising approximately 50% of tumour-infiltrating immune cells in HCC, and have emerged as critical drivers of immune evasion and ICI resistance.5 6 However, the heterogeneity and molecular mechanisms governing protumoral TAM subsets remain poorly defined.

In...]]> 2026-04-21T09:00:15-07:00 info:doi/10.1136/gutjnl-2026-338840 hwp:master-id:gutjnl;gutjnl-2026-338840 BMJ Publishing Group 2026-04-21 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2025-337595v1?rss=1 Background

Sympathetic signalling plays a critical role in the initiation and progression of various malignancies. However, its specific contribution to intrahepatic cholangiocarcinoma (iCCA) remains poorly understood.

This study aimed to investigate the effects and underlying mechanisms of sympathetic signalling on tumour and immune cells, and to explore the potential efficacy of targeting sympathetic pathways in iCCA characterised by perineural invasion (PNI).

Single-cell RNA sequencing was employed to elucidate the impact of PNI on iCCA. In vivo and in vitro experiments were conducted to decipher the molecular mechanisms. Preclinical models were used to investigate the therapeutic potential of targeting sympathetic signalling.

Tyrosine hydroxylase-positive sympathetic nerve fibres were detected in PNI⁺ iCCA, accompanied by elevated norepinephrine (NE). We constructed an atlas of PNI⁺ iCCA at single-cell transcriptional level, characterised by MDK overexpression and reduced infiltration of CD56^dimCD16⁺ natural killer (NK) cells. Mechanistically, NE was found to upregulate MDK expression via the ADRB2/PI3K-AKT/p65 axis, thereby promoting tumour progression of PNI⁺ iCCA. Furthermore, NE might induce NK cell ferroptosis by triggering an imbalance in glutamate/cysteine metabolism in PNI⁺ iCCA via ADRB2. Loss of sympathetic innervation in mice reduced NE concentrations and MDK expression, while increasing NK cell infiltration and inhibiting tumour growth. Preliminary results suggested that blockers of β-adrenergic receptors suppressed iCCA progression.

This study uncovers a novel neuro-immune-tumour axis in iCCA and provides a mechanistic rationale for targeting β-adrenergic signalling as a possible therapeutic strategy for PNI⁺ iCCA.

Advances in therapeutic endoscopy, including endoscopic submucosal dissection (ESD), peroral endoscopic myotomy (POEM) and endoscopic full-thickness resection (EFTR), have expanded minimally invasive treatment options for complex GI disease. However, these procedures carry an increased risk of iatrogenic perforation, with reported rates ranging from <0.01% for diagnostic colonoscopy to approximately 3% for therapeutic interventions such as ESD.1 2 While surgical repair was historically the standard treatment,...]]> 2026-04-15T09:00:20-07:00 info:doi/10.1136/gutjnl-2026-338174 hwp:master-id:gutjnl;gutjnl-2026-338174 BMJ Publishing Group 2026-04-15 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2026-338383v1?rss=1 Liver fibrosis represents a serious worldwide health issue with a prevalence of around 5% in general populations.1 The most relevant aetiologies of liver fibrosis include metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD) and chronic hepatitis B and C infections. Persisting liver fibrosis can lead to irreversible liver cirrhosis with fatal complications such as ascites, variceal haemorrhage and acute-on-chronic liver failure.

In liver fibrosis, all hepatic cell types undergo a pathological cell differentiation process, finally leading to stellate cell activation and extensive extracellular matrix synthesis. Attention has long been focused on the essential roles of hepatocytes and macrophages in the initiation and progression of liver fibrotic processes.2 3 However, comparatively little attention has been paid to endothelial cells. Liver sinusoidal endothelial cells (LSECs) are highly specialised cells that line the sinuses of the liver, where they are continuously exposed to the bloodstream and...]]> 2026-04-15T09:00:20-07:00 info:doi/10.1136/gutjnl-2026-338383 hwp:master-id:gutjnl;gutjnl-2026-338383 BMJ Publishing Group 2026-04-15 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2025-337640v1?rss=1 Background

Chronic hepatitis B virus (HBV) infection is characterised by immune dysfunction. While conventional T cell responses have been extensively studied, the role of T cells, innate-like cytotoxic lymphocytes enriched in the liver, remains incompletely understood.

To characterise T cell subsets in HBV infection and assess their association with viral control and antibody-dependent cellular cytotoxicity (ADCC).

Peripheral blood from patients with chronic (n=83) and acute (n=16) HBV infection, healthy controls (n=31), and cord-blood donors (n=3) was analysed using multiparameter flow cytometry, single-cell RNA sequencing and in vitro ADCC assays.

A distinct CD16⁺ T cell subset inversely correlated with hepatitis B core-related antigen (HBcrAg), a surrogate of intrahepatic viral replication. CD16⁺ T cells displayed a cytotoxic signature, whereas CD16^– cells showed inflammatory, non-cytotoxic profiles. On hepatitis B surface antigen-specific antibody stimulation, CD16⁺ T cells mounted potent ADCC responses, mainly mediated by V2⁺ cells expressing the activating receptor CD226, while V1⁺ cells preferentially expressed the inhibitory receptor TIGIT. Cytotoxic CD16⁺ V2⁺ T cells were present in both blood and liver. CD16⁺ T cells were expanded and highly functional in acute HBV but reduced and partially impaired in chronic infection. Neonatal cord-blood-derived T cells lacked CD16 expression and displayed limited ADCC potential.

CD16⁺ T cells mediate antibody-dependent antiviral immunity in HBV infection. Their inverse association with HBcrAg links T cell-mediated ADCC to viral control and highlights this pathway as a target for HBV cure strategies.

We aimed to identify whether modulating macrophage metabolism may facilitate mucosal healing without driving tumourigenesis.

Potential therapeutic targets associated with UC disease activity and relapse were assessed in multiple omics datasets and three clinical UC studies. The function and mechanism of macrophage pyruvate kinase M2 (PKM2) in UC progression were demonstrated by macrophage-specific PKM2 knockout mice, single-cell and spatial transcriptomic profiling, and human macrophage-colonic organoid coculture models.

Glycolysis was markedly upregulated in intestinal macrophages within damaged regions in UC patients, whereas PKM2 expression was associated with increased disease severity and a greater incidence of relapse. PKM2 depletion in macrophages enhanced intestinal barrier function and ameliorated colitis progression in mice. Mechanistically, PKM2 deficiency promoted monocyte differentiation into reparative Cadm1⁺ macrophages and enhanced Lgr5⁺ stem cell self-renewal via the PGE2/EP4 axis. Cross-species analysis revealed that human STAB1⁺ macrophages, which exhibit transcriptomic and metabolic similarities to mouse Cadm1⁺ macrophages, were positively associated with UC remission and spatial distribution of CD8⁺ T cells in colorectal cancer. Interestingly, macrophage PKM2 deletion greatly suppressed tumourigenesis in mice, accompanied by an increased abundance of Cadm1⁺ macrophages and enhanced CD8⁺ T-cell infiltration. Furthermore, targeting PKM2 in intestinal macrophages attenuated colitis progression in mice.

Therapeutic targeting of PKM2-dependent glycolysis in macrophages enhanced Cadm1⁺ macrophage-mediated mucosal healing without driving tumourigenesis.

The most recent Baveno VII guidelines recommend discontinuing PPIs after EVL unless there is a clear ongoing indication, although this recommendation is based on low-quality evidence and carries a weak strength of recommendation. 2026-04-14T09:00:16-07:00 info:doi/10.1136/gutjnl-2026-338098 hwp:master-id:gutjnl;gutjnl-2026-338098 BMJ Publishing Group 2026-04-14 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2025-337839v1?rss=1 Background

Spasmolytic polypeptide-expressing metaplasia (SPEM) arises in the gastric corpus in response to oxyntic atrophy, but its cellular origin and role in gastric cancer remain unclear.

To define the cellular origin of SPEM in the gastric corpus and its relationship to gastric dysplasia and cancer progression.

Tff2-CreERT2 knock-in mice were used for lineage tracing and genetic ablation to characterise Tff2⁺ corpus progenitor cells. Acute injury, chief cell ablation, H. pylori infection and Kras^G12D activation models were applied. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed on human gastric tissues to validate differentiation trajectories.

Highly proliferative Tff2⁺ progenitors were localised to the corpus isthmus and generated multiple secretory lineages including chief cells, but lacked long-term self-renewal. Following acute injury or chief cell loss, Tff2⁺ progenitors rapidly expanded to form transient SPEM. Genetic ablation of Tff2⁺ progenitors abolished SPEM formation, whereas ablation of Lgr5-DTR- or Gif-rtTA–labelled chief cells enhanced SPEM derived from Tff2⁺ progenitors. on H. pylori infection or Kras^G12D activation, Tff2⁺ progenitors progressed to SPEM and dysplasia. Kras activation in Tff2⁺ progenitors promoted direct progression to dysplasia through acquisition of stem cell–like properties. In contrast, Kras-mutant SPEM and chief cells failed to progress to dysplasia. Human scRNA-seq and spatial transcriptomics revealed distinct differentiation trajectories from isthmus proliferating cells to SPEM or gastric cancer.

Tff2⁺ corpus progenitors represent a common cellular origin for SPEM and gastric dysplasia, challenge the conventional stepwise model of gastric carcinogenesis and indicate divergent differentiation programmes from Tff2⁺ progenitors.

Leveraging the heterogeneity of cancer-associated fibroblasts (CAFs) within the tumour microenvironment, this study aims to identify and evaluate candidate biomarkers to support patient stratification and improve prediction of therapeutic responses.

We applied a multiomic approach integrating single-cell RNA sequencing, computational cell deconvolution and protein-level assessment from patient tumours, complemented by in vitro and in vivo preclinical models, to characterise stromal populations linked to CRC progression and treatment resistance.

Retrospective analysis of over 3000 patient samples across multiple cohorts identified a distinct subset of CAFs expressing collagen triple helix repeat containing 1 (CTHRC1). CTHRC1(+) CAFs were associated with increased transforming growth factor-beta (TGF-beta) signalling and poor clinical outcomes in early and advanced disease stages. CTHRC1(+) CAFs enabled stratification of both mismatch repair-deficient/microsatellite instability (dMMR/MSI) and mismatch repair-proficient/microsatellite stability (pMMR/MSS) tumours into immune-inflamed and poorly immunogenic subtypes. Retrospective analysis of several clinical trials revealed that CTHRC1(+) CAFs are linked to resistance to immune checkpoint inhibitors in MSI and MSS tumours, suggesting therapeutic potential for combining TGF-beta blockade with immunotherapy.

CTHRC1-expressing CAFs represent clinically relevant biomarkers that link molecular profiling with diagnostic pathology. Our findings support the potential incorporation of CTHRC1(+) CAF assessment into routine histopathological workflows, pending prospective validation, and suggest a framework for stroma-informed CRC stratification, particularly in patients with stroma-rich, treatment-resistant tumours and pMMR/MSS with limited therapeutic options.

Evaluate the impact of the portal milieu on neutrophils in ACLD with portal hypertension.

We conducted a prospective study of patients undergoing transjugular intrahepatic portosystemic shunt placement. Paired blood samples were obtained from the portal vein (PV) and superior vena cava (SVC); the neutrophil phenotype was assessed by spectral flow cytometry; plasma was analysed by cytokine quantification, reporter assays and metabolomics. Effects of tryptophan supplementation on neutrophil function and phenotype were tested in isolated neutrophils.

Patients with ALD but not non-ALD showed highly activated CD10^highCD11b^high neutrophils in the portal circulation. PV plasma induced this phenotype in SVC neutrophils. Analysis of portal plasma revealed no differences in cytokines or toll-like receptor (TLR)/nucleotide-binding oligomerisation domain-containing protein (NOD) ligands but decreased local tryptophan concentrations in patients with ALD. In vitro supplementation of tryptophan ameliorated activation of isolated neutrophils.

Our findings identify portal tryptophan as a local regulator of neutrophil activation in ACLD. The link between low tryptophan levels and heightened neutrophil reactivity, especially in ALD, underscores the role of the gut–liver metabolic crosstalk in immune modulation and highlights a potential therapeutic target for mitigating neutrophil-driven liver injury.

We aim to identify bacteria that inhibit colorectal cancer (CRC) progression and enhance immunotherapy efficacy.

The abundance of bacteria in CRC patients was evaluated in our in-house cohorts and validated in published datasets. The effect of candidate bacterium with anti-PD-1 therapy was determined in two syngeneic mouse models of MC38 (microsatellite instability-high) and CT26 (microsatellite stable, MSS), transgenic Apc^min/+ mice and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC tumourigenesis model. Immune landscape changes were identified by multicolour flow cytometry and immunohistochemistry staining. Metabolomic profiling was performed on stool, serum and tumour tissues.

Bifidobacterium catenulatum was significantly depleted in stool samples of 110 CRC patients compared with 112 healthy controls, which was further validated in 3 published metagenomic datasets comprising 198 CRC patients and 176 normal subjects. Oral administration of B. catenulatum inhibited tumour growths in multiple CRC models including MC38 and CT26 syngeneic models, Apc^min/+ mice and AOM/DSS-induced CRC. Notably, B. catenulatum synergised with anti-PD-1 therapy through enhancing intratumoural CD8⁺ T cell infiltration in MSS CRC models of Apc^min/+ mice and CT26 allografts. B. catenulatum-derived acetate was identified as the functional metabolite. Mechanistically, acetate directly bound to MCT-4 in CD8⁺ T cells and activated mitogen-activated protein kinase signalling. Pharmacological and genetic MCT4 ablation abolished acetate-mediated CD8⁺ T cell activation in vitro.

B. catenulatum suppresses colorectal tumourigenesis through generating acetate, which also improves anti-PD-1 efficacy through activating CD8⁺ T cells in MSS CRC. B. catenulatum is a potential adjuvant to improve immunotherapy against CRC.

The study aims to determine the role of the STAT1 rG4 binding protein candidate CARPIN1 in IFN signalling and to elucidate how HBV infection drives CARPIN1 expression.

Employing an integrated platform, complemented by HBV-infection models, humanised liver mice and paired liver biopsies, we found that cell cycle associated protein 1 (CAPRIN1) facilitates stress granule formation and stabilises STAT1 rG4, thereby repressing STAT1 translation. Quantitative assays confirm an inverse relationship: IFN non-responders exhibit high CAPRIN1 and low STAT1, whereas IFN responders display the opposite profile. Mechanistically, HBV polymerase functions as a transcription factor that drives CAPRIN1 expression. CAPRIN1 knockdown in vitro and in vivo restores STAT1 abundance and sensitises cells to IFN, whereas re-expression establishes IFN resistance. Ribonucleoprotein immunoprecipitation-Mass spectrometry, electrophoretic mobility shift assay, luciferase reporter assays, ribosome profiling and circular dichroism analyses collectively demonstrate that CAPRIN1 selectively binds STAT1 rG4, halting ribosomal scanning and suppressing STAT1 protein production. IFN-resistant cells mirror these findings, displaying elevated CAPRIN1 and diminished STAT1.

CAPRIN1 is elevated in IFN non-responders and further upregulated during HBV infection/replication. By facilitating stress granule formation and stabilising STAT1 rG4 structure, CAPRIN1 blocks ribosomal scanning and suppresses STAT1 translation. We therefore designate CAPRIN1 as a critical rheostat that calibrates the amplitude of IFN responses during innate immunity and adjuvant IFN-α therapy.

We aimed to measure artificial sweeteners and emulsifier polysorbate-80 (P-80) in patients with CD and assess their associations with disease activity.

1461 biosamples from 487 subjects (245 CD and 242 controls) across Australia, Hong Kong and Chinese Mainland were analysed for aspartame, sucralose, saccharin and P-80 levels in stool, urine and serum. CD activity was assessed using Crohn’s Disease Activity Index and faecal calprotectin. A generalised linear model (GLM) with P-80 and sweeteners distinguished active CD from inactive CD.

Patients with CD had higher sweetener levels compared with controls across cohorts (all p<0.0001). P-80 underwent predominantly hydrolytic and oxidoreductive degradation in CD and controls, respectively, while its native form was undetectable. CD-associated P-80 metabolites positively correlated with urinary sweeteners in patients with CD. In vitro, CD-associated P-80 metabolites increased gut permeability, enabling translocation of sweeteners across the epithelium. Sweeteners and specific CD-associated P-80 metabolites were higher in active CD. The GLM built using sweeteners and P-80 metabolites distinguished active CD from inactive CD, achieving an area under the curve (AUC) of 0.86 in the discovery cohort and average AUC of 0.94 in two independent validation cohorts from Australia and Chinese Mainland.

This is the first human study to demonstrate distinct P-80 metabolism in patients with CD compared with controls. Dietary sweeteners and P-80 metabolites showed significant correlations with disease activity, suggesting their potential utility as non-invasive biomarkers for CD activity assessment.

To elucidate the role of Selenoprotein P (Sepp1)-mediated selenium metabolism in driving the accumulation and immunosuppressive function of senescent-like neutrophils in HCC, and its impact on tumour immune evasion.

We performed integrative single-cell RNA sequencing analyses in HCC mouse models, coupled with functional, metabolic and epigenetic assays to characterise neutrophil subpopulations and dissect the regulatory pathways linking Sepp1 and selenium metabolism to neutrophil senescence-associated reprogramming and tumour progression.

We identified a distinct subpopulation of senescent-like tumour-infiltrating neutrophils marked by hepatic depletion of Sepp1, elevated Cdkn1a, S100a8/9 and Vegfa. Loss of tumour-derived Sepp1 impaired selenium uptake via Lrp8-mediated transport, suppressing intracellular selenium metabolism and hydrogen selenide production. This led to S-adenosylmethionine accumulation and increased histone H3 protein of trimethylation of lysine 4 histone modification, driving a prosenescence chromatin landscape. Selenium supplementation reversed these effects, restoring Sepp1 expression, reducing neutrophil senescence-associated reprogramming and reinvigorating anti-tumour immunity. Moreover, selenium synergised with anti-programmed cell death 1 therapy to suppress tumour growth.

Sepp1 is a key regulator of neutrophil senescence-associated reprogramming and immune suppression in HCC through selenium-dependent epigenetic remodelling. Targeting senescent-like neutrophils via selenium supplementation holds therapeutic promise to enhance immunotherapy efficacy in liver cancer.

To investigate the association between antibiotic and non-antibiotic drugs with microbiome-modulating activity on new occurrences of CDI.

We conducted a Swedish population-based case–control study from 2006 to 2019 including 42 921 cases matched with 355 159 population controls on age and sex, obtained from multiple linked Swedish registries. The effect of antibiotic and non-antibiotic use within 30 days from the index date on CDI occurrence was estimated using multivariable conditional logistic regression additionally with a lasso penalty. Models were adjusted for age and sex by design and for Charlson Comorbidity Index and concomitant drug use, providing adjusted ORs (aORs) with 95% CIs.

Antibiotics with the greatest CDI risk were lincosamides (aOR=31.4, 95% CI 27.9 to 35.3), combinations of penicillins (aOR=19.8, 95% CI 15.9 to 24.5), sulfonamides and trimethoprim, and cephalosporins, though no association for tetracyclines. Among non-antibiotic drugs, we found decreased risks of CDI for lipid-modifiers (aOR=0.8, 95% CI 0.8 to 0.8) and aspirin (aOR=0.8, 95% CI 0.7 to 0.8) and increased risks for antidiarrhoeals (aOR=7.3, 95% CI 6.8 to 7.8), corticosteroids (aOR=2.4, 95% CI 2.3 to 2.5), proton-pump inhibitors (PPIs) (aOR=1.8, 95% CI 1.7 to 1.8), nervous system drugs, constipation drugs, histamine H2-receptor antagonists, antidepressants, and beta blockers, but no significant risk for non-steroidal anti-inflammatory drugs.

We found varying effects of antibiotics on CDI, providing evidence for ongoing efforts in prudent prescribing decisions and antimicrobial stewardship. We confirmed PPI as a main risk factor for CDI and provided new evidence for other non-antibiotic drugs as potentially important risk factors considering their high prescription prevalence.

To develop and validate a multimodal prognostication model for HCC that allows for a precise assessment of survival outcomes of HCC patients receiving TACE therapy.

This study enrolled 1448 HCC patients, including a TACE cohort (n=1349), a biomarker subset from a randomised trial (n=41), a single-cell RNA sequencing cohort and The Cancer Genome Atlas (TCGA) HCC cohort (n=50). Pre-treatment contrast-enhanced CT images were used to construct deep learning and conventional radiomic models. The early-fusion and late-fusion models (LFMs) were compared, and a clinical-radiologic model (CRM) was formed by integrating the better-performing LFM with clinical variables. Using TCGA data and single-cell transcriptomic profiles, the differences between high-score and low-score groups in tumour immune microenvironment, cellular functional states and key signalling pathways were investigated.

The CRM effectively stratified patients’ survival across multiple independent cohorts and achieved more granular risk stratification than the existing clinical models. Multi-omic analyses revealed that in the LFM high-score group, myelocytomatosis oncogene was activated, epithelial-mesenchymal transition enhanced, glycolysis upregulated and hypoxia pathway activated. Single-cell transcriptomic data confirmed that virtually all cell types in high-risk patients scored high in hypoxia, and cytotoxic T cells had a reduced cytotoxic activity.

The CRM model can non-invasively predict the prognosis of HCC patients treated by TACE therapy.

The standard of care for resectable oesophageal cancer includes neoadjuvant chemotherapy followed by oesophagectomy.1–3 Advances in systemic therapy have resulted in histopathologic tumour regression...]]> 2026-03-24T09:00:15-07:00 info:doi/10.1136/gutjnl-2025-337307 hwp:master-id:gutjnl;gutjnl-2025-337307 BMJ Publishing Group 2026-03-24 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2026-338551v1?rss=1 Clinical Presentation

A 49-year-old woman had a rectal lesion detected during a screening colonoscopy and was referred to our institution for further evaluation. Her medical history included cervical intraepithelial neoplasia and a family history of breast cancer in her mother. Laboratory tests and tumour markers were within normal limits, including carcinoembryonic antigen (2.0 ng/mL) and carbohydrate antigen 19–9 (2.9 U/mL). Abdominal CT revealed no masses or lymphadenopathy.

Colonoscopy revealed a 15 mm lesion with slight central redness in the rectosigmoid colon (figure 1a). After spraying with indigo carmine dye, the lesion appeared as a thickened, submucosal tumour (SMT)-like elevation (figure 1b). Magnifying narrow band imaging revealed findings that were mostly consistent with normal mucosa; however, an area of amorphous structure was identified (figure 1c). Magnifying endoscopy with 0.05% crystal violet staining revealed that most of the lesion was covered with normal pits seen in normal mucosa. However,...]]> 2026-03-23T09:00:25-07:00 info:doi/10.1136/gutjnl-2026-338551 hwp:master-id:gutjnl;gutjnl-2026-338551 BMJ Publishing Group 2026-03-23 Editor's quiz: GI snapshot http://gut.bmj.com/cgi/content/short/gutjnl-2026-338664v1?rss=1 Tica et al1 report that pre-pregnancy maternal and paternal adiposity are associated with increased odds of metabolic dysfunction-associated steatotic liver disease (MASLD) in adult offspring, and that biparental overweight/obesity confers particularly elevated risk (OR 3.73), with 67% mediated through cumulative excess body mass index (BMI) between ages 7 years and 17 years. This life-course perspective enriches understanding of intergenerational MASLD risk. We would like to offer some methodological comments that may refine interpretation of the reported associations.

First, the FibroScan performance data suggest differential outcome measurement across adiposity strata. Supplemental table 3 shows that XL probes were used in 5.7% of participants with a normal liver but in 51% of those with MASLD, indicating a striking imbalance in probe type by case status. Steatosis was defined using a single controlled attenuation parameter (CAP) threshold of 275 dB/m applied to both M and XL probes, although CAP performance and optimal cut-offs...]]> 2026-03-23T09:00:24-07:00 info:doi/10.1136/gutjnl-2026-338664 hwp:master-id:gutjnl;gutjnl-2026-338664 BMJ Publishing Group 2026-03-23 Letter http://gut.bmj.com/cgi/content/short/gutjnl-2026-338313v1?rss=1 We read with great interest the recent article by Huo et al published in Gut,1 entitled ‘Long-term prognosis of lean MASLD: evidence from three population-based prospective cohorts.’ Using three prospective cohorts comprising both Western and Asian populations, the authors consistently demonstrated that lean individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) had a significantly increased risk of all-cause mortality and liver-related events compared with those with non-lean MASLD. Together with previous cohort studies,2 3 these findings support the notion that lean MASLD is not a benign condition, highlighting the need for improved identification of this subgroup and for more tailored surveillance or management strategies.

Despite the strengths of this study, including its large sample size and long follow-up duration, several important limitations warrant consideration. First, in both the UK Biobank (UKB) and China Kadoorie Biobank (CKB) cohorts, hepatic steatosis was defined using a Fatty Liver...]]> 2026-03-23T09:00:24-07:00 info:doi/10.1136/gutjnl-2026-338313 hwp:master-id:gutjnl;gutjnl-2026-338313 BMJ Publishing Group 2026-03-23 Letter http://gut.bmj.com/cgi/content/short/gutjnl-2025-337436v1?rss=1 Background

The gut-liver axis plays a critical role in liver disease progression; however, how gut microbial ecology and function vary across disease stages remains unclear.

To define stage-specific microbial and functional signatures and evaluate their diagnostic potential.

We analysed faecal samples from 1168 individuals spanning healthy controls, fatty liver, hepatitis, cirrhosis and hepatocellular carcinoma by 16S rRNA sequencing, with a subset (n=141) profiled by shotgun metagenomics. To increase statistical power and enable external validation, 2376 publicly available metagenomic datasets, including 734 liver-related, were integrated. Machine learning-based multicohort analysis was used to identify microbial biomarkers, assess risk factors and classify disease stages.

Microbial diversity declined and a low-richness enterotype expanded with disease severity. Machine learning revealed a discordance in hepatitis, which lacked taxonomic markers but was defined by a conserved functional signature of biosynthetic upregulation. In contrast, advanced stages featured consistent markers like Ligilactobacillus and Veillonella, with strain-level evidence confirming oral-gut transmission. Functional profiling delineated a metabolic continuum from anabolic precursor synthesis in hepatitis to virulence factor production in cirrhosis and putrefactive metabolism in carcinoma. Comparative analysis confirmed that these signatures were distinct from those in non-liver metabolic and oncologic disorders. Importantly, the expansion of oral-derived Veillonella spp and the low-richness enterotype were significantly associated with increased mortality.

This large-scale study delineates stage-dependent ecological and functional remodelling of the gut microbiome across liver diseases. These findings highlight the potential of microbiome-based markers for non-invasive diagnosis and prognostic risk stratification in liver diseases.

To test whether PSC-UC neoplasia is driven by transferable microbiota-mediated inflammation linked to secondary BA loss.

Surveillance colonoscopies (2012–2022) from PSC-UC (n=251) and UC-only (n=8839) were compared for segmental endoscopic/histological activity and dysplasia. We generated multidrug resistance protein 2 (MDR2)^–/– x interleukin (IL)-10^–/– double-knockout (DKO) mice and used germ-free (GF) derivation, faecal microbiota transplantation (FMT), antibiotic conditioning and cohousing with shotgun metagenomics and liquid chromatography–tandem mass spectrometry BA profiling.

PSC-UC showed greater inflammatory activity and a right-shifted dysplasia burden versus UC-only. Under specific-pathogen-free conditions, DKO mice developed early right-predominant colitis and multifocal dysplasia progressing with age. DKO communities were depleted of 7α-dehydroxylation capacity with near absence of deoxycholic and lithocholic acids and no enrichment of canonical bacterial genotoxins. GF DKO mice were protected, whereas live DKO donor FMT reinstated severe colitis and dysplasia; sterile-filtered stool supernatant was inactive. IL-10^–/– donor FMT or cohousing attenuated colitis and increased recipient secondary BA, whereas wild-type/MDR2^–/– donor transfers were non-colitogenic. In GF DKO mice, direct deoxycholic acid repletion caused hepatotoxicity.

PSC-UC neoplasia associates with transmissible microbiota-dependent inflammation and secondary BA deficiency. Controlled restoration of BA-transforming microbial functions, rather than indiscriminate secondary BA replacement, is a rational translational direction.

We aimed to investigate uptake of extrinsic fatty acids (FAs) in tumours and their relevance for CRC lipid metabolism and progression.

Total FAs were quantified using gas chromatography-mass spectrometry in non-diseased mucosa and tumour tissue from patients with CRC of a discovery cohort (n=152), validated in an independent cohort (n=28) and associated with clinical, genomic and microbiome data. The genetic mouse tumour model Apc^1638N was used to track the flux of stable isotope-labelled FAs in tumours from the intestinal lumen. The relationship between FA uptake and tumour progression was investigated in 2D and 3D cell models.

Extrinsic long chain PUFAs, including arachidonic acid, accumulate in CRC, particularly in right-sided tumours, and in tumours of Apc^1638N mice. The CRC-specific FA profiles were independent of sex, molecular subtypes, early-disease or late-disease onset. The absorption of FAs from the intestinal lumen in tumours was confirmed in specific pathogen-free Apc^1638N mice. In the absence of the microbiome, in germ-free Apc^1638N mice, fewer tumours were developed, and survival was increased. Inhibition of FA import or β-oxidation reduces cancer cell proliferation.

Extrinsic FAs accumulate in CRC, verifying a central role of arachidonic acid-derived inflammatory mediators, but also suggesting a relevance of dietary FAs for cancer cell proliferation. It will be intriguing to explore to what extent targeting this flux pathway together with the interrelated microbiome opens new therapeutic avenues for CRC in humans.

This study aims to explore the intracellular and intercellular consequences of sustained, tumour-derived IL-6 signalling.

We generated CRISPR-activated IL-6^high patient-derived iCCA cell models and characterised them using RNA-sequencing and secretome analysis. Therapeutic vulnerabilities were determined with high-throughput drug screening, while the impact of tumour-conditioned media on the phenotype and function of circulating immune cells was assessed with high-dimensional flow cytometry. Spatial transcriptomic analysis (Visium HD) was performed on 14 resected tumours to quantify tumour-derived IL6 expression, cell type composition and ligand-receptor interactions in the tumour microenvironment.

Chronic IL-6 signalling drives distinct transcriptional programmes, metabolic vulnerabilities and immunomodulatory effects. IL-6^high tumour cells confer sensitivity to nicotinamide phosphoribosyltransferase inhibition, leading to disrupted mitochondrial fitness and selective IL-6 downregulation. Chronic IL-6 signalling also alters the tumour secretome, which modulates immune cell composition and impairs cellular function, including the suppression of MER proto-oncogene tyrosine kinase-mediated macrophage efferocytosis. Spatial transcriptomic analysis confirms that tumour IL6 expression correlates with myeloid cell depletion, cancer-associated fibroblast (CAF) enrichment and enhanced tumour-CAF communication.

These findings uncover a multifaceted role for IL-6 in shaping tumour-intrinsic, microenvironmental and macroenvironmental features, revealing novel molecular mechanisms and potential therapeutic vulnerabilities in iCCA.

To elucidate the immune and epigenetic mechanisms regulating VM and identify strategies to overcome VM-driven PDAC progression.

Histopathology, three-dimensional tissue clearing, spatial transcriptomics and single-cell RNA sequencing were combined to map VM distribution and its immune contexture. Tissue microarrays, co-culture assays and xenograft models were used to assess tumour-associated macrophage (TAM) contributions. Extracellular vesicle (EV) proteomics and mechanistic studies identified cargo molecules and signalling pathways. DOT1L (disruptor of telomeric silencing 1-like) inhibitor EPZ-5676 and vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib were used for therapeutic validation.

VM was abundant in PDAC, increased with tumour stage and was preferentially surrounded by TAMs. M2-like TAMs promoted tube formation, invasion and tumour growth, while blockade of TAM-derived EVs abolished these effects. EV proteomics identified caveolin-1 (CAV1) as a key cargo correlating with VM density and TAM infiltration. Mechanistically, EV-delivered CAV1 interacted with DOT1L, promoted DOT1L EV loading and drove H3K79 methylation-dependent autophagy-related 5 (ATG5) transcription, sustaining VM and invasive phenotypes. Notably, while DOT1L inhibition suppressed VM and tumour progression, it paradoxically induced compensatory endothelial angiogenesis. Combined DOT1L and VEGFR blockade overcame this compensatory feedback, achieving superior tumour control without toxicity.

TAM-derived EVs drive VM through a CAV1-DOT1L-ATG5 axis. We identify a compensatory link between VM and angiogenesis and demonstrate that dual targeting of these two vascular modalities offers a promising therapeutic strategy for PDAC.

To determine whether TSR follows a non-linear prognostic pattern and to develop an artificial intelligence (AI)-powered framework for standardised TSR assessment and prognosis prediction in hepatocellular carcinoma (HCC).

We integrated whole-slide image (WSI) data with clinical variables across a retrospective cohort (n=392) and The Cancer Genome Atlas dataset (n=168). Restricted cubic splines were used to interrogate non-linear hazard dynamics, with biological validation via transcriptomics and immunohistochemistry. An AI-driven foundation model framework was developed for TSR quantification and multimodal prognostic modelling.

Our analysis unveiled an inverted U-shaped non-linear relationship between TSR and mortality, identifying a risk initiation threshold at 0.188 and a peak at 0.268. Transcriptomics analysis indicated that this high-risk phenotype is characterised by active tumour proliferation, stromal activation and tumour microenvironment crosstalk. Technically, AI-derived TSR showed strong correlation with expert assessment (R² >0.9). Furthermore, we developed a novel ‘Token-Guided Multimodal Fusion’ architecture to integrate WSI, TSR and clinical variables as high-dimensional tokens directly into the computational logic. Consequently, our multimodal framework demonstrated prognostic accuracy (area under the curve >0.80) compared with unimodal baselines.

This study redefines TSR assessment, shifting from manual estimation to high-dimensional semantic reasoning. By identifying the non-linear prognostic mechanics of the stroma, our token-guided framework offers a biologically interpretable solution for HCC. We suggest that the future of computational pathology may lie not in simple quantification, but in the semantic fusion of human domain knowledge with AI reasoning.

We aimed to investigate whether specific gut microbial species are associated with muscle strength and to explore underlying mechanisms linking the gut microbiota to muscle health.

We conducted metagenomic analyses in cohorts of younger and older adults extensively phenotyped for muscle strength. Associations were tested between bacterial taxa and performance measures. Causality was assessed by oral supplementation of candidate species in antibiotic-treated mice. Metabolomic profiling and muscle phenotyping were performed to elucidate mechanisms.

The relative abundance of Roseburia inulinivorans, but not other Roseburia species, was positively associated with multiple strength measures including handgrip, leg press and bench press in humans. Supplementation of R. inulinivorans in mice significantly enhanced forelimb grip strength, whereas other Roseburia species had no effect. Metabolomic analyses revealed that R. inulinivorans reduced amino acid concentrations in the caecum and plasma, while activating the purine and pentose phosphate pathway in muscle. These changes coincided with increased muscle fibre size and a shift from type I to type II fibres. Accordingly, we observed that the relative abundance of R. inulinivorans is lower in older adults compared with young adults.

R. inulinivorans emerges as a species-specific modulator of muscle strength, linking gut microbiota to muscle metabolism and function. These findings support its potential as a probiotic candidate for nutraceutical interventions targeting age-related muscle-wasting diseases.

NCT02365129.

In this study, we aimed to identify potent inhibitors of HEV replication.

We developed a rapid, image-based screening platform based on a full-length HEV fluorescence reporter virus and screened a nucleotide/nucleoside analogue library. The identified lead candidate was validated in authentic hepatocyte culture systems, as well as in a gerbil infection model.

Bemnifosbuvir (BEM), previously characterised as a nucleotide analogue with activity against other RNA viruses, efficiently suppressed HEV replication in vitro and in vivo in a dose-dependent manner, with minimal cytotoxicity at effective concentrations. Combining BEM with ribavirin, the off-label drug given to patients with chronic HEV, resulted in an additive antiviral effect against HEV. We found that HEV-3 remains susceptible to inhibition by BEM over an extended treatment period, reducing concerns about the rapid development of viral resistance. Importantly, BEM significantly reduced HEV viral loads and liver inflammation in a gerbil infection model.

Given BEM’s favourable safety profile in preclinical and clinical settings, our results suggest investigating its efficacy in patients with chronic HEV infection.

We aimed to describe AIG features and quantify the risk of gastric adenocarcinoma and type 1 gastric neuroendocrine tumours (NETs).

Retrospective study across eight tertiary centres in Europe, Türkiye, Latin America, the USA and Japan. Adults with histologically confirmed AIG were included. Clinical and follow-up data were collected to estimate adenocarcinoma and NET incidence and associated factors.

1240 patients were included (female:male 2:1; median age 59, IQR 48–67; median follow-up 68 months, IQR 36–108). Macrocytic anaemia predominated in Europe (45.6%), microcytic anaemia in Türkiye (56.1%) and Latin America (64.7%). Autoimmune comorbidities were most frequent in Latin America (67.7%). 36 (2.9%) gastric adenocarcinomas and 132 (10.6%) NETs occurred. No incident adenocarcinomas were reported in Latin America or Japan cohorts. Crude incidence rates ranged from 1.15 to 1.47 for adenocarcinoma and 0.70 to 1.62/100 person-years for NETs. Factors associated with adenocarcinoma included age >65 years (OR 4.50, 95% CI 2.18 to 9.27), intestinal metaplasia (OR 1.51, 95% CI 1.16 to 1.97), gastrin-17 >1316 pg/mL (OR 15.52, 95% CI 3.61 to 66.71) and prior proton pump inhibitor (PPI) (OR 5.74, 95% CI 2.13 to 15.47). For NETs, prior PPI (OR 2.69, 95% CI 1.12 to 6.46), smoking (OR 2.45, 95% CI 1.75 to 3.42), intestinal metaplasia (OR 2.88, 95% CI 1.38 to 6.01) and gastrin-17 >1316 pg/mL (OR 3.25, 95% CI 1.42 to 7.45), were associated with higher odds, while Helicobacter pylori eradication was associated with lower odds of NETs (OR 0.25, 95% CI 0.07 to 0.88).

AIG presentation and neoplastic risks differ by region, warranting further research and potentially region-specific follow-up strategies.

This study aims to identify metabolic and intrinsic metabolism of PC associated with early recurrence.

We analysed resected primary tumours from patients with PC with early (E-Rec) and late (L-Rec) recurrence using an integrated multiomics workflow and spatial metabolomics. Multiplex immunofluorescence quantified carnitine shuttle system (CSS) heterogeneity, and functional in vitro assays alongside in vivo models evaluated pharmacological inhibition of carnitine transport in combination with chemotherapy or immunotherapy.

Multiomics analysis revealed SLC6A14 was a key CSS-related gene driving early recurrence of PC. Spatial metabolomics showed elevated carnitine levels in cancer-associated fibroblasts (CAFs) from L-Rec and in tumour cells from E-Rec. Mechanistically, cancer cells used carnitine secreted from PPAR⁺ CAFs via SLC6A14 uptake, activating the AMPK/PPARα/CPT1B signalling cascade to enhance fatty acid β-oxidation. In vivo experiments demonstrated that pharmacological inhibition of carnitine transport by meldonium, tetrahydropalmatine or quinidine suppressed tumour growth and sensitised tumours to chemotherapy and immunotherapy.

PC cells exploit carnitine secreted by PPAR⁺ CAFs via SLC6A14-mediated uptake to promote tumour recurrence. Targeting the CSS, particularly in combination with chemotherapy or immunotherapy, represents a promising avenue for mitigating recurrence in PC.

We aimed to elucidate the role and mechanism of macrophage STING in CHB-MASLD comorbidity.

Human and mouse liver tissues were used to assess STING expression levels. Myeloid-specific STING knockout and hepatocyte-specific STING knock-in mice were used to explore the effects of STING in comorbidity. Tohoku Hospital Pediatrics (THP)-1 and HepG2.2.15/HepG2-NTCP co-cultured cells were stimulated with palmitic acid (PA) for 12 hours in vitro for mechanism research. Markers for STING, autophagy and endoplasmic reticulum stress (ERS) were assessed using western blot analysis, immunohistochemistry and immunofluorescence assays. The liver organoids were used for validation.

CHB-MASLD comorbidity in mice decreased HBV replication but accelerated liver inflammation and fibrosis, linked to aberrant STING upregulation in macrophages. HBV synergised with lipotoxicity to disrupt Rab7 expression and function in macrophages, impairing STING degradation via autophagic-lysosomal and endosomal-lysosomal pathways. Pathological STING accumulation had dual effects: cytosolic STING enhanced antiviral activity (TANK-binding kinase 1-interferon regulatory factor 3-interferon beta) and promoted inflammation (nuclear factor kappa-B/NOD-like receptor family pyrin domain-containing 3 (NLRP3)). Extracellular vesicles transported STING to hepatocytes, triggering ERS (PKR-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (CHOP)), further activating NLRP3 and exacerbating injury. Therapeutically, restoring Rab7 facilitated STING degradation, attenuating pathology.

In CHB-MASLD comorbidity, impaired Rab7 function leads to aberrant STING accumulation in macrophages, suppressing HBV replication but paradoxically accelerating liver disease progression. Targeting Rab7 to degrade excessive STING represents a novel therapeutic strategy.

This study evaluates prospective associations between pre-pregnancy biparental adiposity and offspring MASLD in adulthood.

We included 1933 offspring from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) to assess the associations between parental pre-pregnancy body mass index (BMI) and odds of offspring MASLD at age 24 years. MASLD was defined as hepatic steatosis on transient elastography and ≥1 cardiometabolic risk factors. We evaluated causal mediation by childhood adiposity measures.

At age 24 years, 10.4% of offspring had MASLD. Pre-pregnancy maternal and paternal obesity were independently associated with an increased odds of offspring MASLD. Each 1 kg/m² increase in maternal BMI increased the odds of MASLD by 10% (Odds Ratio [OR] 1.10, 95% CI 1.06 to 1.14), while each 1 kg/m² increase in paternal BMI raised the odds by 9% (OR 1.09, 95% CI 1.04 to 1.13). Biparental overweight or obesity was associated with 3.73 times the odds of offspring MASLD (OR 3.73, 95% CI 2.43 to 5.73) compared with parents with a normal BMI, with 67% of this association mediated by cumulative excess childhood BMI, a defined area under the curve for BMI Z score >1 for ages 7–17 years.

Excess parental adiposity pre-pregnancy was associated with a higher odds of offspring MASLD, mediated by cumulative excess childhood BMI, highlighting the potential of life course interventions to reduce the risk of MASLD in future generations.

To identify key drivers that reprogramme PDAC mitochondrial function and its role in remodelling the immunosuppressive tumour microenvironment (TME) during PDAC liver colonisation.

Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screening, in vivo mouse model screening and in vitro anoikis-resistant cell selection were employed to identify key drivers during PDAC liver colonisation. PDAC organoids, metabolic flux analysis, single-cell RNA sequencing, spatial metabolomics and glutathione S-transferase (GST) pull-down assay were used to explore the regulation of mitochondrial fission process protein 1 (MTFP1) on PDAC liver colonisation and unravel the underlying mechanism.

We revealed MTFP1, a protein that plays an important role in cell viability and mitochondrial dynamics, as a driver of PDAC liver colonisation. Mechanistically, MTFP1 is recognised as a novel ATP synthase modulator through its interaction with numerous ATP synthase subunits, thereby enhancing oxidative phosphorylation (OXPHOS). Increased mitochondrial fission and subsequent redox signalling (ROS production) upregulates solute carrier family A1 member 5 (SLC1A5) expression by activating the PI3K/AKT/c-MYC pathway, competing for glutamine uptake and impaired antitumour responses of CD8⁺ T cells. By performing virtual screening, we identified KPT 9274 (ATG-019) as an effective inhibitor of MTFP1. Limitation of glutamine uptake in PDAC cells or MTFP1 inhibition reverses the immunosuppressive TME and reduces liver colonisation of PDAC.

Our data demonstrate that the enhanced MTFP1 expression leads to an upregulated glutamine-OXPHOS axis in PDAC liver colonisation. This metabolic shift is triggered by the ROS/PI3K/AKT/c-MYC/SLC1A5 pathway. Targeting MTFP1 may be a potential therapeutic strategy for PDAC patients with liver metastasis.

To investigate the relationship between plasma OA and HTG-AP-associated ALI and to explore the mechanism by which OA disrupts endothelial barrier through PIEZO1-mediated impairment of fatty acid oxidation (FAO).

This study used clinical sample analysis, an HTG-AP mouse model and OA-stimulated human umbilical vein endothelial cells. The association between OA and ALI was evaluated, and PIEZO1 was identified as a potential OA target through calcium imaging, transcriptomics and the Human Protein Atlas. Genetic/pharmacological interventions, lipidomics, Seahorse assays and barrier function tests were used to characterise FAO impairment and barrier disruption. NR4A1 regulation of CPT1A was investigated through transcriptomic and ChIP assays. Finally, the pathway’s function was validated in mice with endothelial-specific Piezo1 knockdown.

Clinical and animal data showed elevated plasma OA in HTG-AP, positively associated with ALI incidence and severity. Multidimensional data identified PIEZO1 as a key target mediating OA-induced endothelial dysfunction. Mechanistically, OA activated and upregulated PIEZO1, which suppressed NR4A1 expression, leading to downregulation of CPT1A and impaired FAO, ultimately disrupting the endothelial barrier. Endothelial-specific Piezo1 knockdown significantly alleviated HTG-AP-associated ALI in mice.

OA promotes endothelial barrier dysfunction and exacerbates HTG-AP-associated ALI via the Piezo1/NR4A1/CPT1A axis by impairing FAO, offering a novel mechanistic insight and identifying potential therapeutic targets for HTG-AP-associated ALI.

We aimed to develop mouse models of sporadic and hereditary DGC by inactivation of Cdh1 in the mouse stomach.

We generated tamoxifen-inducible Cre/loxP mouse models of DGC driven by the Cd44 promoter with a tdTomato reporter. Two models were developed, one with Cdh1-knockout alone (Cd44-Cre/tdTom^loxP/loxP/Cdh1^loxP/loxP (Cdh1-KO)) and a second more aggressive model with combined Cdh1 and Trp53 knockout (Cd44-Cre/tdTom^loxP/loxP/Cdh1^loxP/loxP/Trp53^loxP/loxP (Cdh1-KO/Trp53-KO)).

Cdh1 inactivation alone led to multiple foci of in situ (pTis) signet ring cells (SRCs) within 1 week of induction and intramucosal DGC (stage pT1a) within 2 months. By 9 months, 50% of mice had developed advanced (pT3) DGC. The morphology of most gastric carcinomas was comparable to human DGC, exhibiting poorly cohesive SRC and poorly differentiated cells. Additional Trp53 knockout accelerated cancer development, resulting in pT3 DGC within 3 months. From this point, Cdh1-KO/Trp53-KO mice frequently developed thymic lymphomas and soft tissue sarcomas. DNA sequencing did not find evidence of additional genetic events necessary for cancer progression in either model. Organoids derived from Cdh1-KO and Cdh1-KO/Trp53-KO mice showed a disrupted morphology with SRCs displaced out of the epithelial plane. Transcriptional changes associated with processes including cell-to-cell adhesion, interaction with the actin cytoskeleton and NF-B signalling were observed.

Inactivation of Cdh1 alone in Cd44-expressing cells is sufficient to induce DGC in mice. Tumour growth is significantly accelerated by concurrent Trp53 inactivation.

This study aimed to investigate the role of the endothelial GTPase RAP1A in sinusoidal capillarisation and liver fibrosis.

Liver fibrosis models were induced by HFHCD, CDAHFD, CCl₄ or DDC treatment. EC-specific Rap1a knockout (Rap1a^EC) mice were generated by breeding Rap1a^fl/fl mice with Cdh5-Cre mice. Therapeutic intervention was performed using the RAP1 activator 8-pCPT-2'-O-Me-cAMP. LSEC capillarisation, along with the extent of liver fibrosis and inflammation, was evaluated.

RAP1A expression in LSECs was downregulated in all murine fibrosis models, as well as in primary LSECs undergoing spontaneous capillarisation during in vitro culturing. Young Rap1a^EC mice exhibited spontaneous capillarisation, which progressed to liver fibrosis with age. Endothelial Rap1a deficiency exacerbated sinusoidal capillarisation and liver fibrosis in CCl₄-/DDC-treated mice. Mechanistically, RAP1A loss promoted RAF1 degradation via the ubiquitin-proteasome pathway, enhancing nuclear translocation of Notch intracellular domain (NICD) and activating Notch signalling. Pharmacological activation of RAP1A attenuated LSEC capillarisation and mitigated liver fibrosis in CCl₄-/DDC-induced models.

Endothelial Rap1a deficiency aggravates capillarisation and liver fibrosis by activating Notch signalling through RAF1 degradation. These findings indicate that Rap1a is essential for maintaining LSEC homeostasis and represents a potential intervention target for liver fibrosis.

We elucidate the role of trogocytosis-related CLDN18.2 in CD8⁺ T cells and pancreatic ductal adenocarcinoma (PDAC) progression.

We constructed humanised hCD34⁺, Trp53^R172HKras^G12DPdx1-cre (KPC), Cldn18.2 knockout (KO), and patient-derived xenograft/organoid mouse models. Flow cytometry, immunofluorescence, single-cell RNA-sequencing and immunoprecipitation-mass spectrometry (IP-MS) were performed.

CLDN18.2⁺CD8⁺ T cells indicated poor pancreatic cancer prognosis and immunotherapeutic resistance. CD8⁺ T cells acquired CLDN18.2 from tumour cells via trogocytosis, inhibiting their activation and cytotoxicity. "Dressed" CLDN18.2 suppressed glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8⁺ T cells. Mechanically, trogocytosis-related CLDN18.2 induced GSK3β/CK1α-mediated β-catenin phosphorylation, promoting β-catenin ubiquitination and proteasome degradation in CD8⁺ T cells. CLDN18.2 interacted with β-catenin’s N-terminal domain via its C-terminal domain, further strengthening the interaction between β-catenin and CK1α. Moreover, CLDN18.2⁺CD8⁺ T cells preferentially ‘homed’ to the bone marrow through the CXCL12/CXCR4 axis, skewed haematopoietic stem cell myeloid differentiation and induced systemic immune senescence via IL1α. Notably, preclinical mouse studies showed PC18.1 peptide sensitised immunotherapy and suppressed PDAC progression by disrupting the CLDN18.2/β-catenin interaction in CD8⁺ T cells.

Trogocytosis-related CLDN18.2 inhibited the glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8⁺ T cells by promoting the ubiquitin-proteasomal degradation of β-catenin in PDAC. Therefore, targeting trogocytosis-related CLDN18.2⁺CD8⁺ T cells may be a promising therapeutic strategy to inhibit PDAC progression.

This study aimed to identify tumour cell-intrinsic regulators that promote immune evasion and ICB resistance in PDAC.

Multi-omics analysis and clinical cohort studies identified protein disulfide isomerase family A member 6 (PDIA6) as a regulator of the immune microenvironment. Flow cytometry, multiplex immunohistochemistry, electron microscopy and Glutathione S-Transferase (GST) pulldown assays confirmed that PDIA6 repressed PRKR-like endoplasmic reticulum kinase (PERK) activation and immunogenic cell death (ICD). Chromatin immunoprecipitation confirmed that KRAS^G12D and YY1 modulated PDIA6 transcription. LSL-Kras ^G12D/+ ;LSL-Trp53 ^R172H/+ ;Pdx-1-Cre (KPC) mouse models showed that PDIA6 inhibition improved ICB response.

Multi-omics screening identified PDIA6 as a biomarker of CD8⁺ T-cell paucity and poor prognosis in patients with PDAC. High PDIA6 levels predicted poor ICB response in the PDAC cohorts. PDIA6 inhibition reprogrammed the immunosuppressive tumour microenvironment and hindered mouse PDAC growth in the presence of CD8⁺ T-cell, which is attributed to enhanced ICD. PDIA6 interacted with cysteine 453 of PERK, abrogating the disulphide bond-mediated dimerisation and activation of PERK, an ICD inducer. Oncogenic KRAS^G12D potently upregulated PDIA6 via YY1-mediated transcriptional activation. We identified a small-molecule inhibitor of PDIA6, PACMA31, and demonstrated that targeting PDIA6 with PACMA31 improved ICB efficacy in a PDAC mouse model with KRAS mutations.

PDIA6, driven by KRAS^G12D, alleviates ICD and promotes immune evasion, functioning as a predictive biomarker to screen ICB-sensitive patients and a therapeutic target to improve ICB efficacy in PDAC with KRAS mutations.

We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME.

We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways.

We identified a conserved syndecan 1 (SDC1) ⁺ CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1⁺ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis.

Our study establishes SDC1⁺ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

We aimed to identify plasmablast-derived HBsAg-specific mAbs, evaluate their antiviral activities and resolve their structure for binding to native HBsAg.

A previously vaccinated volunteer was enrolled in this study, who was boosted with a dose of recombinant hepatitis B vaccine and donated the blood sample. Activated plasmablasts were sorted from fresh peripheral blood mononuclear cells and mAbs were expressed. Their gene features, cross-genotypic binding activities and antiviral functions in vitro and in vivo were comprehensively analysed. The cryo-electron microscopy (cryo-EM) was used to determine the structure of representative mAb bound to the native HBsAg.

In this study, we cloned a series of HBsAg-specific mAbs directly from clonally expanded plasmablasts from a vaccinated individual. Most of the mAbs displayed cross-reactivities of binding to different genotype HBsAg proteins and antiviral functions such as neutralisation and antibody-dependent cellular phagocytosis. These human anti-HBsAg mAbs, especially SY-4-class and SY-23-class, could be good candidates for antibody drugs. The cryo-EM structure of SY-23 bound to the dimeric HBsAg was determined, revealing its binding mechanism and unprecedented structural detail of the major antigenic loop (AGL) of HBsAg.

Overall, our work has uncovered the diverse gene features and varied anti-HBV activities of plasmablast-derived mAbs, providing a series of antibody drug candidates and the long-sought-after atomic model of AGL has paved the way for a wholistic characterisation of the AGL’s dynamic conformation during HBV infection and immune response.

We aim to investigate the mechanisms of other bacteria influencing GC progression and metastasis.

Integrated intratumoural microbiome-metabolome analysis identified GC-associated microbes and metabolites. We then demonstrated the pro-metastatic role of Acinetobacter baumannii (A. baumannii, Ab) and its metabolite nicotinic acid (NA) using genetic, molecular and in vivo approaches.

The abundance of A. baumannii was significantly increased in GC tissues, correlating with advanced tumour stage and intratumoural NA levels. Fluorescence in situ hybridisation confirmed its colonisation in GC tumours. In co-culture systems, A. baumannii increased NA levels, enhancing nicotinamide adenine dinucleotide (NAD) metabolism and increasing 1-Methylnicotinamide accumulation in tumour cells. Mutagenesis of the bacterial NA synthase gene pncA confirmed that A. baumannii excreted an NA-dependent pro-metastasis effect. Mechanically, A. baumannii promotes GC metastasis by reprogramming tumour cell glucose metabolism, reducing oxidative phosphorylation while enhancing glycolysis and activating the hypoxia-inducible factor-1 pathway in GC cells through metabolites both in vivo and in vitro.

This study elucidates the role of A. baumannii in enhancing NAD metabolism in GC cells through NA synthesis, consequently promoting GC metastasis. These findings establish a microbiota-metabolism axis as a mechanistic foundation for developing targeted therapeutic strategies against GC metastasis.

Here, we identify a novel gut-brain neural circuit that promotes stroke recovery via kynurenic acid (KYNA) signalling.

In a training cohort (30 patients with acute ischaemic stroke (AIS) and 30 controls), untargeted metabolomics profiled intestinal metabolites and the key metabolite KYNA was validated in an independent cohort (100 patients with AIS and 100 controls) using targeted metabolomics and assessed for its 3-month prognostic value. In stroke mouse models, KYNA was administered to evaluate therapeutic effects. Mechanistic studies combined neuronal calcium imaging, enteric neuron receptor manipulation, vagotomy, neuronal tracing, electrophysiology and immunofluorescence to delineate the KYNA-mediated gut-brain neural circuit regulating stroke recovery.

Our study demonstrates a significant reduction of intestinal KYNA in patients with AIS and validates its prognostic value for neurological recovery at 3 months poststroke in both the training and validation cohorts. Oral KYNA supplementation markedly improves poststroke cerebral injury by activating G protein-coupled receptor 35 (GPR35) on enteric neurons, initiating vagal nerve signalling. Mechanistically, KYNA-GPR35 interaction activates vagal afferents, transmitting signals through the nucleus tractus solitarius to hippocampal and hypothalamic regions. This GPR35-vagus nerve signalling pathway, further validated with the selective GPR35 agonist Zaprinast, confers neuroprotection by shifting microglial polarisation towards the anti-inflammatory M2 phenotype and enhancing neuronal α7 nicotinic acetylcholine receptor activity.

KYNA acts through an intestinal GPR35-vagus neural pathway to influence stroke recovery, highlighting this gut-brain signalling axis as a promising therapeutic avenue.

To identify a central hub of visceral pain in IBS-D and elucidate the mechanism by which repetitive transcranial magnetic stimulation (rTMS) confers analgesic effects.

Combined functional MRI with visceral sensitivity assessments was used to pinpoint hyperactive brain regions of patients with IBS-D. Mechanistic studies were conducted in a well-established IBS mouse model. A clinical trial was performed to validate the therapeutic potential of rTMS in patients with IBS-D.

Clinical observations identified hyperexcitability of the medial prefrontal cortex (mPFC) as strongly correlated with visceral pain in patients with IBS-D. In IBS mice, visceral pain was driven by the hyperactivity of mPFC glutamatergic (mPFC^Glu) neurons, which received nociceptive inputs from the anterior cingulate cortex via an NR2A-dependent mechanism. Low frequency (lf)-rTMS of the mPFC sustainably alleviated visceral pain in IBS mice by inhibiting mPFC^Glu neurons and restoring normal synaptic plasticity. Building on these findings, a clinical trial validated that a 2-week course of mPFC-targeted lf-rTMS in patients with IBS-D effectively alleviated visceral pain and improved bowel habits, effects associated with reduced mPFC activity and sustained for at least 8 weeks.

Hyperexcitability of the mPFC drives chronic visceral pain in patients with IBS-D and lf-rTMS provides analgesia by suppressing this hyperactivity, offering a novel, mechanism-based neuromodulation strategy for IBS-D treatment.

To map lymph node metastasis (LNM) patterns and assess surgical outcomes in a large multicentre cohort of patients with AEG undergoing radical resection.

The Chinese League of Adenocarcinoma of Esophagogastric Junction (CLAEG) registry, initiated in 2022 across 44 high-volume Chinese centres, prospectively enrolled AEG patients. This analysis included 2044 radical resections, with LNM assessed by station, stratified by Siewert type and neoadjuvant therapy. Surgical outcomes were compared between total versus proximal gastrectomy and laparoscopic versus open resection.

Most tumours were Siewert type II (64.6%) or III (33.4%). LNM was substantially higher in abdominal than mediastinal stations; category-1 nodes (metastasis, >10%) comprised stations 1, 2, 3, 4, 7, 8a, 9 and 11p. The LNM rates for mediastinal stations were 2.77% (No. 110), 0.71% (No. 111) and 0.68% (No. 112). Patients who received neoadjuvant therapy had lower LNM rates, indicating nodal downstaging. Among those undergoing gastrectomy, patients who underwent total gastrectomy had a lower postoperative complication rate than those who underwent proximal gastrectomy (14.8% vs 21.0%; p=0.001) and achieved more extensive lymphadenectomy. Compared with open surgery, patients who underwent laparoscopic resection experienced faster postoperative recovery without higher complication rates (16.5% vs 17.3%). No perioperative mortality occurred.

The CLAEG study shows that abdominal lymphadenectomy should be prioritised in AEG, with neoadjuvant therapy, total gastrectomy and laparoscopy associated with favourable short-term outcomes.

We aimed to elucidate the functional role and underlying mechanism of NOP2/Sun RNA methyltransferase 6 (NSUN6), an m⁵C methyltransferase, in shaping the TME of pancreatic ductal adenocarcinoma (PDAC).

The clinical significance of NSUN6 was assessed in human PDAC cohorts. The impact of NSUN6 on antitumour immunity was evaluated using murine PDAC models. Single-cell RNA sequencing was employed to characterise the TME landscape of PDAC. RNA bisulfite sequencing and RNA sequencing were used to identify NSUN6 targets. The synergistic effects of C-C motif chemokine ligand 2 (CCL2) blockade combined with immune checkpoint blockade (ICB) therapy were investigated.

NSUN6 deficiency significantly enhanced macrophage accumulation and polarisation toward immunosuppressive phenotypes, thereby impairing CD8⁺ T cell-mediated antitumour immunity in PDAC. Mechanistically, NSUN6 deficiency downregulated KDM5A expression in an m⁵C-dependent manner, resulting in transcriptional activation of CCL2. Elevated CCL2 secretion promoted the accumulation and polarisation of protumorous macrophages, fostering an immunosuppressive TME and inducing resistance to ICB. Notably, CCL2 blockade reversed protumorous macrophage infiltration and restored ICB sensitivity in Nsun6-deficient murine PDAC models. Clinical analysis further revealed a positive correlation between NSUN6 expression and favourable immune responses in ICB-treated cohorts.

NSUN6 deficiency drives immune suppression through the m⁵C-KDM5A-CCL2 axis in PDAC. Targeting the NSUN6-CCL2 axis represents a promising strategy to sensitise PDAC to ICB therapy.

This study aimed to achieve consensus on the risk of CRC in individuals with MASLD.

A Delphi survey was conducted by a multidisciplinary panel of 35 international experts from diverse medical fields across Asia, Europe, North America, South America, Oceania and Africa. Experts evaluated 17 statements across three domains: epidemiology, pathogenesis and management.

Consensus was achieved on all 17 statements. MASLD is associated with an increased risk of CRC, and metabolic burden further increases this risk. Furthermore, the severity of MASLD is associated with worse outcomes in patients with MASLD and CRC. The gut–liver axis and gut dysbiosis play key roles in the development of MASLD and CRC, while leptin and adiponectin may also be involved. Weight loss with lifestyle interventions, early CRC screening, bariatric surgery and use of GLP-1 receptor agonists are highlighted as potential risk-reduction strategies.

The expert panel emphasises the need for greater clinical vigilance for CRC among individuals with MASLD. This consensus supports a paradigm shift towards earlier, risk-adapted screening and integrated metabolic management to reduce the burden of CRC in the MASLD population.

The specific impacts of steatosis grade and cardiometabolic burden on HCC risk among patients with MASLD remain unclear.

We enrolled 700 patients who underwent biannual HCC surveillance after HCV cure. Steatosis was graded by vibration-controlled transient elastography using controlled attenuation parameter cut-offs of 248–267, 268–279 and ≥280 dB/m, corresponding to S1, S2 and S3, respectively. Cardiometabolic risk factors (CMRFs) were assessed at the time of viral cure. Cumulative HCC incidence was compared across steatosis grades and cardiometabolic burdens using the log-rank test. Multivariable Cox proportional hazards models with Akaike Information Criterion-based selection evaluated the effects of steatosis grade, cardiometabolic burden and individual CMRFs on HCC risk, expressed as adjusted HRs (aHRs) with 95% CIs. Fine-Gray subdistribution hazard models were used for sensitivity analyses.

Cumulative HCC incidence differed significantly across steatosis grades (p=0.035) but not across cardiometabolic burdens (p=0.62). In multivariable analysis adjusted for age, sex, liver stiffness and alpha-fetoprotein, advanced steatosis remained independently associated with HCC risk (S3 vs S1: aHR 2.15, 95% CI 1.25 to 3.69, p=0.005). Among individual CMRFs, pre-diabetes or type 2 diabetes was significantly associated with HCC risk (aHR 2.33, 95% CI 1.38 to 3.94, p=0.002). Fine-Gray analyses confirmed these associations.

Advanced hepatic steatosis and glycaemic abnormalities, rather than overall cardiometabolic burden, are independently associated with increased HCC risk after HCV cure.

To identify genes and mechanisms involved in gut motility, providing a foundation for clinical translation.

We performed a multiancestry genome-wide association study (GWAS) meta-analysis of SF in 268 606 European and East Asian individuals. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS signals were fine-mapped and functionally annotated to prioritise candidate genes and pathways. Findings implicating thiamine metabolism were followed-up with dietary interaction analyses in UK Biobank (UKB).

SF heritability was comparable in Europeans (7.0%) and East Asians (5.6%). We observed strong genetic correlations with gastrointestinal and psychiatric disorders (r_g=0.18–0.47), and causal effects on IBS. Novel correlations with cardiovascular traits (r_g=0.12–0.14) were supported by drug signature enrichment analyses. We identified 21 independent loci, including 10 novel signals implicating bile acid synthesis (KLB) and cholinergic signalling (COLQ). Fine-mapping converged on vitamin B1 metabolism, highlighting single-variant causal effects at SLC35F3 (a thiamine transporter) and XPR1 (phosphate exporter essential for thiamine activation). In 98 449 UKB participants, thiamine intake was positively associated with SF (p<0.0001), and a combined SLC35F3/XPR1 genotype score significantly modulated this effect (p<0.0001).

We identify therapeutically tractable mechanisms involved in the control of gut motility, including a previously unrecognised role for vitamin B1. These findings warrant mechanistic and clinical studies to evaluate their translational potential in IBS and other dysmotility syndromes.

The PREdiCCt study was designed to examine demographic, clinical and dietary factors associated with disease flare among patients with IBD in self-reported remission.

Multicentre, prospective cohort study conducted across 47 UK centres. Patients with Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBDU) in self-reported remission were prospectively followed up. The baseline diet was assessed using a validated food frequency questionnaire. The primary outcome was time to patient-reported flare (captured by monthly IBD-Control) and objective flare (clinical flare plus C-reactive protein >5 mg/L and/or faecal calprotectin (FC) >250 µg/g with treatment escalation). Associations were evaluated using Cox frailty models adjusted for demographic, clinical and biochemical variables, including baseline FC.

Between November 2016 and March 2020, 2629 participants (1370 CD; 1259 UC/IBDU) were enrolled and followed up for a median of 4.1 years (IQR 3.0–5.0). Baseline FC was strongly associated with patient-reported flares (FC ≥250 µg/g: adjusted HR (aHR) 2.22; FC 50–250 µg/g: aHR 1.52 (reference <50 µg/g)) and objective flares (FC ≥250 µg/g: aHR 3.25; FC 50–250 µg/g: aHR 1.98). In UC, higher total meat intake was associated with increased risk of objective flares (highest versus lowest quartile: aHR 1.95, 95% CI 1.07 to 3.56). No consistent associations were observed for ultraprocessed foods, fibre or polyunsaturated fatty acids and flare.

Higher habitual meat intake was associated with increased risk of objective flare in UC, suggesting diet may contribute to flare susceptibility in specific patient groups.

NCT03282903.

This study aims to elucidate the role of ADAR1-imposed RNA editome in HSC activation and to determine the therapeutic potential of targeting ADAR1 for liver fibrosis.

ADAR1 expression was measured in fibrotic human and mouse livers, as well as in primary human and mouse HSCs. Adar1 loss-of-function effect was evaluated in Adar1^f/f/Cre-ER, Adar1^HSC and Adar1^iHSC mice, whereas viral infection with Ad-Adar1 was employed in gain-of-function studies. Adar1^HSCIfih1^–/–- and Adar1^HSCIfnar^HSC mice were used for mechanistic studies. An ADAR1 inhibitor and HSC-selective RNAi were used for therapeutic evaluations.

ADAR1 is decreased in human and mouse fibrotic livers and activated HSCs. HSC-specific ablation or pharmacological inhibition of ADAR1 ameliorated HSC activation and liver fibrosis. In contrast, forced expression of ADAR1, but not its editing-deficient mutant, exacerbated HSC activation. Mechanistically, ADAR1 ablation accumulated double-stranded RNA and activated HSC-intrinsic innate immunity in a melanoma differentiation-associated gene 5-dependent manner. Interferon-β was identified as a key antifibrotic effector via the activation of the JAK1/2 pathway. RNA editome analysis revealed the Col3a1 3’ UTR as a novel ADAR1 editing target, leading to increased collagen production.

ADAR1-imposed RNA editome suppresses HSC-intrinsic innate immunity and promotes collagen production, leading to aggravated HSC activation and liver fibrosis. Targeting ADAR1 with its pharmacological inhibitor or HSC-selective RNAi shows great promise in treating liver fibrosis.

This study aimed to explore the therapeutic potential and underlying mechanisms of GSK3β pathway disruption in PDAC with enriched nuclear GSK3β levels.

We investigated the activation and function of GSK3β and its downstream transcription factor NFATc1 in tumour recurrence, growth and resistance using human PDAC tissues, patient-derived organoids and tumour cells, PDAC explants, cell lines and murine models. GSK3β signalling was disrupted using genetic and pharmacological approaches. Live-cell imaging, proliferation, homologous recombination (HR) repair and comet assays, messenger RNA sequencing and chromatin immunoprecipitation were used to explore GSK3β-NFATc1 signalling-mediated target gene regulation in DNA repair, growth and resistance.

Nuclear GSK3β accumulates in a subset of resected PDAC and promotes proliferation and DNA repair through NFATc1. The GSK3β^high/NFATc1^high subtype accounts for 14% of resected PDAC and is associated with rapid tumour recurrence and poor survival. The GSK3β-NFATc1 signalling pathway contributes to cisplatin resistance by inducing BRCA genes transcription, which facilitates HR-mediated DNA double-strand breaks (DSBs) repair. Disruption of the GSK3β-NFATc1 axis impairs HR-driven DSB repair, increasing cisplatin sensitivity in vitro and in preclinical PDAC models.

We have identified a highly aggressive GSK3β^high/NFATc1^high subtype that predicts early recurrence, poor survival and cisplatin resistance in PDAC. This subtype reveals new treatment vulnerabilities suggesting that patients with PDAC may benefit from stratification-based tailored treatment strategies.

This study aimed to identify and functionally characterise the critical premalignant cell states that arise from this heterogeneity, to define novel biomarkers and targets for early intervention.

Public and in-house scRNA-seq data of pancreatic tumour models were analysed to identify key subpopulations in early cellular heterogeneity. Genetic perturbation in KrasG12D-driven models was performed to assess functional impact. Mechanistic studies used TurboID proximity proteomics, epigenetic profiling and metabolic assays. Clinical relevance was validated in human PDAC cohorts.

We identified LY6D as a marker of a distinct, gastric-like cell state that emerges early and persists throughout tumourigenesis. The LY6D⁺ population exhibits conserved stemness and a unique, pan-stage dependency on oxidative phosphorylation (OXPHOS). Genetic ablation of Ly6d specifically impaired the gastric lineage and delayed tumourigenesis, while its overexpression enhanced tumourigenic and metastatic potential. Mechanistically, the glycosylphosphatidylinositol (GPI)-anchored LY6D protein scaffolds a lipid raft-associated kinase network that drives FOSL1-dependent epigenetic-transcriptional reprogramming. In human PDAC, LY6D⁺ cells harbour stemness and Epithelial-Mesenchymal Transition (EMT) signatures, and high LY6D expression is an independent prognostic marker of poor survival.

Our work defines the LY6D⁺ gastric-like cell state as a key driver linking early pre-malignant heterogeneity to PDAC initiation and progression. LY6D represents a pan-stage therapeutic target and a candidate biomarker for early detection and therapeutic targeting.

To investigate the role of RNA binding protein ZFP36 ring finger protein like 1 (ZFP36L1) in regulating hepatocyte fate and its contribution to the progression of ALD.

We selectively deleted ZFP36L1 in mouse hepatocytes to assess its impact on ALD progression, transcriptional reprogramming, senescence and direct mRNA targets. In parallel, we analysed human liver explants to evaluate ZFP36L1 in relation to hepatocyte senescence, disease severity and zinc-dependent regulation.

Deletion of ZFP36L1 exacerbated experimental ALD and activated transcriptional programmes driving ductal transdifferentiation, inflammation and senescence. Mechanistically, ZFP36L1 directly destabilised cyclin-dependent kinase inhibitor 1A (Cdkn1a)(p21) and jagged canonical notch ligand 1 (Jag1) mRNAs, thereby suppressing hepatocyte senescence and JAG1-NOTCH signalling. In human liver explants, ZFP36L1 activity declined in parallel with increasing hepatocyte senescence and ALD severity and was closely associated with impaired zinc-dependent signalling. Manipulation of zinc availability altered ZFP36L1 activity and expression of its direct targets.

These findings uncover a zinc-dependent ZFP36L1-regulon that governs hepatocyte fate by repressing p21- and JAG1-driven senescence and NOTCH activation and highlight ZFP36L1 as a promising therapeutic target in ALD.

We aimed to propose a framework for identifying high-risk participants for prevention trials by reporting the outcomes of the pre-PIONIR screening stage.

Faecal calprotectin was measured in asymptomatic FDRs aged 6–38 years; those with persistent elevation, defined as >70 µg/g in at least two separate tests, were offered panenteric video capsule-endoscopy or ileocolonoscopy.

Of 950 FDRs approached, 331 (35%) agreed to be screened: 63 (19%) had persistently elevated calprotectin, of whom 42 underwent further evaluation. Nine (2.7%) had endoscopic appearance compatible with presymptomatic CD, 22 (6.6%) had non-specific macroscopic mucosal changes and 11 (3.3%) had normal mucosa despite elevated calprotectin, suggesting probable histological inflammation. The 33 participants in the two latter groups were defined as ‘potential pre-CD’ (17.9% of all screened after adjusting for missing values). Calprotectin >225 µg/g predicted presymptomatic CD (area under the receiver operating characteristic curve 0.97 (95% CI 0.94 to 1.0; p<0.001; sensitivity 89%, specificity 94%). Of those with a single elevated calprotectin value, 22% normalised on repeat testing with significant variability (intraclass correlation coefficient 0.72 (95% CI 0.57 to 0.82)).

Approximately one in five asymptomatic FDRs had persistently elevated calprotectin, which was able to differentiate those with presymptomatic CD. The findings highlight calprotectin’s utility in identifying at-risk individuals during the potential pre-CD stage for enrolment in prevention trials.

This study aims to identify pharmaceutical targets whose inhibition suppresses pancreatic ductal adenocarcinoma (PDAC) or potentiates KRAS inhibition, focusing on molecular vulnerabilities specific to KRAS-mutant PDAC.

We integrated genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR-associated Protein 9) dropout screens, large-scale genomic dependency datasets and pharmacological screens to identify molecular vulnerabilities in KRAS-mutant PDAC. Conditional knockout mouse models were used to assess the essentiality of candidate genes in pancreatic cancer. RNA sequencing, metabolomics/proteomics analysis and stable isotopic tracing were employed to investigate mechanisms underlying inosine monophosphate dehydrogenase 2 (IMPDH2) vulnerability. Additionally, proteolysis-targeting chimaera compounds targeting IMPDH2 were developed and evaluated in patient-derived organoid and xenograft models.

Integrated screens revealed de novo guanine nucleotide biosynthesis (DNGB) as a vulnerability in KRAS-mutant PDAC, with IMPDH2 being the critical gene. Unexpectedly, IMPDH2 expression and activity are not driven by the KRAS vertical pathway. Consequently, IMPDH2 inhibition induces irreversible guanine nucleotide depletion that cannot be compensated for by mutant KRAS. Inducing guanine nucleotide depletion via targeting IMPDH2 for degradation inhibits PDAC and augments KRAS inhibitor efficacy in vitro and in vivo.

These findings provide a rationale for developing combination therapies targeting KRAS and DNGB, highlighting the potential of purine nucleotide imbalance as a biomarker to guide the application of these therapies.

Systematic data on the endoscopic management and outcomes of large, laterally spreading duodenal adenomas involving the papilla are limited, and most reports describe piecemeal endoscopic mucosal resection.1 These lesions are also managed surgically, despite the considerable morbidity (30%–40%) and mortality (1%–4%) associated with resection in this anatomically complex region.2 The largest retrospective comparative study evaluating endoscopic papillectomy (EP)...]]> 2026-01-06T09:00:31-08:00 info:doi/10.1136/gutjnl-2025-336411 hwp:master-id:gutjnl;gutjnl-2025-336411 BMJ Publishing Group =3 cm) laterally spreading duodenal tumours involving the papilla: a multicentre retrospective study]]> 2026-01-06 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2025-337596v1?rss=1 We read with interest the article by Santacroce about personalised medicine in eosinophilic oesophagitis (EoE) and the identification of novel therapeutic targets.1 While dietary approaches are first-line treatment options for EoE, pathomechanisms are not well understood.2 Studies have shown that milk is the leading culprit category.3 4 It remains elusive if changes in dairy production are associated with EoE development. A dominant point mutation in beta casein occurred in ancestors to modern type cattle with a change from A2 milk (non-mutated) to A1/A2 milk (at least one point mutation, proline to histidine at position 67).5 Nothing is known about the allergenicity of standard versus A2 milk and its implications in EoE pathogenesis.

This was a prospective analysis of patients included in the Swiss EoE cohort study combined with an experimental in vitro study (IRB approval: EKNZ2015-388/CER-VD148-14, BASEC2024-01668). We offered patients with...]]> 2026-01-06T05:18:20-08:00 info:doi/10.1136/gutjnl-2025-337596 hwp:master-id:gutjnl;gutjnl-2025-337596 BMJ Publishing Group 2026-01-06 Letter http://gut.bmj.com/cgi/content/short/gutjnl-2025-336549v1?rss=1 Message

Organ preservation has emerged as a therapeutic objective in low rectal cancer management, particularly for patients achieving complete or near-complete response following neoadjuvant chemoradiotherapy. While radical surgery remains the standard recommendation in current guidelines, watch-and-wait (WW) strategies are increasingly used. We report 28 cases managed with endoscopic full-thickness resection of the scar and adjacent tissue as an alternative, all with R0 resection. Histology showed ypT0, ypT1 and ypT2 in 17, 5 and 6 cases. Among ypT2 cases, one received salvage surgery, while five received adjuvant radiochemotherapy. All patients remained recurrence-free over a median 25-month follow-up. Major low anterior resection syndrome occurred in one patient.

Neoadjuvant chemoradiotherapy combined with total mesorectal excision remains the standard treatment for locally advanced rectal cancer and has been shown to reduce local recurrence and improve survival,1 2 as recommended by international guidelines including National Comprehensive Cancer Network，European Society...]]> 2026-01-06T05:18:20-08:00 info:doi/10.1136/gutjnl-2025-336549 hwp:master-id:gutjnl;gutjnl-2025-336549 BMJ Publishing Group 2026-01-06 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2025-336744v1?rss=1 Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with limited therapeutic options. Despite promising immunotherapy, response rates remain suboptimal. Tumour-associated macrophages (TAMs) constitute a pivotal component of the immunosuppressive HCC microenvironment, yet TAM heterogeneity and contributions to tumour progression and immunotherapy resistance remain poorly defined.

To identify and characterise critical TAM subsets in HCC and evaluate their potential as therapeutic targets.

Integrated multiomics analysis of hepatocellular carcinoma (HCC) clinical specimens was performed and validated across independent cohorts. Single-cell RNA sequencing identified tumour-associated macrophage (TAM) subpopulations. Functional characterisation employed whole-body and macrophage-specific CD48 knockout mice, adoptive transfer experiments and co-culture systems. Mechanistic studies used immunoprecipitation-mass spectrometry, immunofluorescence colocalisation and pathway analysis. Therapeutic efficacy was evaluated using anti-CD48 monotherapy and combination with anti-programmed cell death protein 1 (PD1) in orthotopic HCC models.

CD48⁺ TAMs were identified associating with accelerated tumour progression, immunotherapy resistance and poor clinical outcomes. These TAMs exhibited protumorous phenotypes, driving immunosuppression and promoting extracellular matrix remodelling. Genetic CD48 ablation attenuated HCC progression while promoting CD8⁺ T-cell function. Adoptive transfer of CD48-deficient macrophages validated tumour-suppressive effects. Mechanistically, matrix metalloproteinase-14 (MMP14) was identified as a novel cis-interacting partner for CD48, functioning independently of the canonical CD48–CD244 axis. This interaction activated RAP1 GTPase, triggering Yes-associated protein (YAP) nuclear translocation and YAP-signal transducer and activator of transcription 3 (STAT3) complex formation to upregulate immunosuppressive genes. Anti-CD48 antibodies effectively inhibited tumour progression and demonstrated synergistic effects with anti-PD1 therapy.

CD48 represents a novel immune checkpoint on TAMs critical for HCC progression and immunotherapy resistance. Targeting CD48 may overcome immunosuppression and increase therapeutic efficacy in HCC.

This International Consensus, developed by 32 experts from 14 countries through a structured Delphi process based on the PICO framework and GRADE methodology, provides evidence-based recommendations across five domains: epidemiology and pathogenesis; clinical features; diagnosis; medical therapy; and surgical management.

Key statements define diverticulosis as the presence of diverticula without symptoms and diverticular disease as diverticula associated with symptoms or complications. High dietary fibre intake is protective whereas smoking, obesity and the use of non-steroidal anti-inflammatory drugs, corticosteroids, opioids or immunotherapy increase risk. Imaging is essential in suspected acute diverticulitis: ultrasound may be appropriate in experienced hands, while CT remains preferred for complicated cases. Diverticulosis itself requires no treatment. In symptomatic uncomplicated diverticular disease, dietary fibre, selected probiotics, mesalazine and rifaximin may help relieve symptoms. Routine antibiotic use is not recommended for acute uncomplicated diverticulitis, and elective surgery should be individualised, prioritising quality of life considerations over episode count.

These Consensus statements aim to standardise and optimise the diagnosis, management and prevention of diverticular disease across diverse healthcare systems, while highlighting research priorities such as microbiome characterisation, genetic risk profiling and long-term outcomes of selective antimicrobial and surgical strategies.

We aim to elucidate the immune alterations and underlying mechanisms driving liver regeneration following ALPPS.

The cohort study included single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on remnant liver tissues from ALPPS patients. Neutrophil infiltration was validated by flow cytometry and histological analyses in the world’s largest ALPPS clinical cohort and mouse ALPPS models. Functional validation, including neutrophil depletion, matrix metalloproteinase 9 (MMP9) inhibition and CD177 blockade, as well as Cd177 knockout and CD177⁺ neutrophil infusion in vivo.

scRNA-seq revealed substantial neutrophil infiltration following stage 1 ALPPS. Depletion of neutrophils impaired liver regeneration. Among subsets, CD177⁺ neutrophils were metabolically active with enhanced neutrophil extracellular traps formation and secreted MMP9. MMP9 inhibition disrupted extracellular matrix (ECM) degradation and hepatocyte growth factor alpha (HGF-α) release, impairing regeneration. CD177⁺ neutrophils interacted with endothelial cells via CD177–PECAM1 to facilitate transmigration, while hepatic stellate cell-derived CXCL8 promoted neutrophil chemotaxis via CXCL8–CXCR1/2. Cd177 deficiency attenuated neutrophil infiltration and regenerative growth, while CD177⁺ neutrophil infusion restored regeneration, which was abolished in Cd177^–/^– mice.

CD177⁺ neutrophils drive liver regeneration by promoting endothelial transmigration, ECM degradation and HGF-α release. These findings reveal a neutrophil-mediated mechanism driving surgical liver regeneration and support the potential of CD177⁺ neutrophil infusion to establish a proregenerative hepatic environment for therapeutic strategies in liver failure.

We performed expression profiling in human MASLD-HCC samples (n=29 pairs of tumour and adjacent normal tissues). Advanced in vivo genetic lineage tracing coupled with single-cell RNA sequencing was used to characterise CD133⁺ CSCs in preclinical models. To establish causality, we developed a hepatocyte-specific CD133-overexpressing mouse model of MASLD-HCC. We identified CD133 protein interactors by mass spectrometry. A novel strategy combining CD133-targeted small interfering RNA (siRNA) nanoparticles with first-line therapy was assessed in clinically relevant MASLD-HCC models.

CD133⁺ CSCs were significantly enriched in human MASLD-HCC tumours and positively correlated with established markers of malignancy. In vivo genetic lineage tracing in mice revealed that CD133⁺ cells exhibit hallmark CSC properties, including self-renewal, tumour-initiating capacity and multipotent differentiation, as compared with CD133^– counterparts. Hepatocyte-specific CD133 overexpression in mice accelerated MASLD-HCC tumourigenesis. Mechanistically, CD133 interacts with myosin heavy chain 9 (MYH9) to stabilise active β-catenin, thereby propagating Wnt/β-catenin signalling that drives CSC phenotypes and tumourigenic potential. Therapeutically, genetic ablation of CD133⁺ cells or systemic delivery of CD133-siRNA nanoparticles potently sensitised MASLD-HCC to sorafenib and lenvatinib, significantly improving outcomes in MASLD-HCC.

This study established CD133⁺ CSCs as critical mediators through the CD133-MYH9/β-catenin axis in MASLD-HCC. Targeting CD133 enhances multikinase inhibitor efficacy, offering a promising therapeutic strategy for MASLD-HCC.

To identify predisposing events driving fistula formation.

Rectal biopsies from patients with CD with or without PFD (CD+PFD and CD, respectively; n=31) were collected and subjected to single-cell RNA sequencing. Functional analyses were conducted using peripheral CD3⁺ T cells, intestinal tissue explants, primary fibroblasts and two-dimensional epithelial monolayer cell cultures.

The rectal mucosa of patients with CD+PFD is imprinted with cellular and transcriptomic alterations specific to PFD and independent of luminal inflammation, potentially driven by tumour necrosis factor-like ligand 1A (TL1A) activation in CD4⁺ T cells. We identified lymphotoxin beta (LTB or its functional heterotrimer LTα₁β₂) as a novel mediator downstream of TL1A that, along with interleukin (IL)-22, induces a PFD-associated signature in rectal fibroblast and epithelial cells, respectively. This signature includes an increased abundance of fibroblasts, an induction of matrix-degrading enzymes, transcriptomic rewiring of the lamina propria S1 fibroblasts and an anti-bacterial and immune responses in epithelial cells. Notably, the induction of LTα₁β₂ and IL-22 occurs independently of tumour necrosis factor (TNF) signalling, revealing a new TL1A-LTα₁β₂/IL-22 axis that remains active under anti-TNF therapy.

Our findings revealed unique cellular alterations in the rectum of patients with CD+PFD, highlighting the previously unrecognised involvement of TL1A in mediating this signature and supporting the need for exploring the role of TL1A inhibition as a therapeutic approach for PFD.

This study aimed to evaluate the safety profile of anti-PD-1 antibody (αPD-1), as well as its impact on hepatitis B surface antigen (HBsAg) and immune responses in a larger cohort of CHB patients.

In this prospective, open-label study, virally suppressed patients with CHB on nucleos(t)ide analogue (NA) were assigned to receive either 24-week NA monotherapy (n=62) or αPD-1 (half-dose sintilimab) add-on therapy (n=59), with both groups subsequently receiving NA monotherapy for an additional 12-week observation period.

93.6% of adverse events (AEs) were grade 1 or 2. Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase were the most common AEs, and they represented the only severe AEs. αPD-1 add-on therapy induced greater HBsAg reductions (mean decline: –0.720 vs –0.034 log₁₀ IU/mL, p<0.001) and higher HBsAg loss rates (6.1% vs 0%, p=0.166) than NA monotherapy at week 24. Notably, significant HBsAg decline and seroclearance exclusively occurred in the initial 12 weeks of αPD-1 treatment. HBsAg levels did not rebound at 12 weeks after discontinuation of αPD-1 therapy. After αPD-1 therapy, the numbers of HBsAg-specific, HBpol-specific, HBx-specific and HBeAg/HBcAg-specific IFN- spots all increased (p<0.05), while frequencies of HBsAg-specific B cells remained stable. Furthermore, ALT elevation and enhanced HBsAg-specific T-cell responses following αPD-1 therapy correlated with HBsAg decline (p<0.05).

In virally suppressed CHB patients on NA therapy, 24-week half-dose sintilimab treatment demonstrated a favourable safety profile. This regimen can facilitate HBsAg reduction and even HBsAg loss, while concurrently enhancing HBV-specific T-cell responses. These findings support αPD-1 as a potential therapeutic alternative for CHB.

NCT05769816.

We aimed to investigate the predictive value of HBV RNA and HBV mutants on HBsAg seroconversion in patients with chronic HBV infection from childhood to adulthood.

We recruited 700 children (409 males and 291 females) with initially hepatitis B e antigen (HBeAg)-positive chronic HBV infection. With the mean initial visit age of 7.28 years (95% CI 7.03 to 7.62 years), they were followed for 15 912 person-years at our institution. Serum samples collected after HBeAg seroconversion in HBeAg seroconverters were analysed for circulating HBV RNA, HBsAg, HBV core-related antigen, HBV DNA levels and the percentage of HBV mutants.

23 subjects (3.29%) experienced HBsAg seroconversion following antiviral therapy, while another 27 (3.86%) achieved spontaneous HBsAg seroconversion in this cohort. The annual probability of HBsAg seroconversion is 0.32% (95% CI 0.30% to 0.33%) per person-year across the entire cohort. After HBeAg seroconversion, the spontaneous annual HBsAg seroconversion rate is 0.47% (95% CI 0.42% to 0.51%) per person-year, and it rises to 1.30% (95% CI 1.10% to 1.51%) per person-year in subjects who had previously received antiviral agents before HBeAg seroconversion. Undetectable circulating HBV RNA and the percentage of A2131C mutants <10% after HBeAg seroconversion are significant predictors of HBsAg seroconversion in both univariate and multivariate survival analyses.

In this long-term chronic HBV cohort, we elucidated both the natural course and antiviral-related HBsAg seroconversion. Undetectable circulating HBV RNA and percentage of A2131C mutants <10% after HBeAg seroconversion are novel and independent predictors of HBsAg seroconversion.

We investigated whether baseline or longitudinal changes in humoral immunity correlated with outcome of discontinuing prolonged NA treatment.

Global memory B cells (MBC) and T follicular helper cells (Tfh) were analysed by flow cytometry. HBs (small surface)/HBc (core)-MBC were quantified by ex-vivo bait staining and function assessed by cultured ELISpots (enzyme-linked immunosorbent spots). Immune parameters assessed at end-of-treatment (EOT), 12 and 48 weeks after treatment withdrawal (and at 4–8 years in a subset) were correlated with intrahepatic and longitudinal serum viral markers and alanine transaminase (ALT).

Individuals on prolonged NA had comparable frequencies of HBc-MBC and HBs-MBC, although the latter were PD-1^hi and functionally defective. Following treatment withdrawal, increases in class-switched HBc-MBC were frequently temporally linked with hepatic flares. Subjects achieving HBsAg loss had an increase in activated global MBC detectable at EOT that become more marked by week 48, accompanied by significant increases in plasmablasts. HBs-MBC in those with HBsAg loss showed significant reductions in PD-1, trends to increased activation (CD71) and function and a more robust correlation with Tfh, compared with HBsAg persistence. MBC changes were maintained 4–8 years after HBsAg seroconversion.

Differences in global and HBs-specific B cell immunity associate with HBsAg loss, whereas HBc-MBC temporally associates with flares, following withdrawal of prolonged NA treatment. Our results underscore the need to further explore the potential of B cell targets for monitoring and enhancing HBV functional cure in larger cohorts.

Investigate the causal role of BAs produced by 7αDH+ gut bacteria in CRC.

We performed feeding studies in a porcine model of CRC combined with multi-omics analyses and gnotobiotic mouse models colonised with 7αDH+ bacteria or a genetically modified strain to demonstrate causality.

Western diet exacerbated the CRC phenotype in APC^1311/+ pigs. This was accompanied by increased levels of the secondary BA deoxycholic acid (DCA) and higher colonic epithelial cell proliferation. The latter was counteracted by the BA-scavenging drug colestyramine. Metagenomic analysis across multiple human cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in faeces of patients with CRC. Addition of these specific 7αDH+ bacteria (C. scindens/Extibacter muris) to defined communities of gut bacteria led to DCA production and increased colon tumour burden in mouse models of chemically or genetically induced CRC. A mutant strain of Faecalicatena contorta lacking 7αDH caused fewer colonic tumours in azoxymethane/dextran sodium sulfate treated mice and triggered less epithelial cell proliferation in human colon organoids compared with wild-type F. contorta.

This work provides functional evidence for the causal role of secondary BAs produced by gut bacteria through 7αDH in CRC under adverse dietary conditions, opening avenues for future preventive strategies.

Here, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumour microenvironment.

Hepatocyte-specific phosphatase and tensin homologue (Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametrical flow cytometry were performed to analyse the immune landscape alterations. Untargeted metabolomics was conducted to elucidate the hepatic metabolism dysregulation.

PCK1 is downregulated in tumour tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumour-infiltrating CD8⁺ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8⁺ T cells and activate the p38 mitogen-activated protein kinase pathway by directly interacting with the BTB and CNC homology 1 transcription factor, ultimately leading to CD8⁺ T cells dysfunction. Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD-1 treatment increases the antitumour capability of CD8⁺ T cells and suppresses MASH-HCC development.

This study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8⁺ T cell dysfunction via 12-HETE-p38 signalling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD-1 immunotherapy in MASH-HCC.

We aim to investigate the role of hepatic macrophage and its therapeutic potential in human PBC and murine autoimmune cholangitis.

Phenotypic analysis of hepatic macrophages in patients with PBC and dnTGFβRII mice model was performed by single-cell RNA sequencing, flow cytometry and immunohistochemistry. Depletion of hepatic macrophages and inhibition of MoMs were performed in murine autoimmune cholangitis. Lyz2-Cre-mediated Atg5 knockout mice and co-culture experiments were applied to explore the role and mechanism of macrophage autophagy in autoimmune cholangitis. Therapeutic intervention was performed using nanoparticle-capsuled small interfering RNA against Atg5.

Kupffer cells from patients with PBC and dnTGFβRII mice upregulate genes associated with inflammatory responses and exhibit increased autophagy. Further, macrophage-specific knockout of Atg5 leads to reduction of inflammation and bile duct damage. We propose that the mechanism of this modulation is secondary to decreased activation of pathogenic CD8⁺ T cells. Indeed, Kupffer cells maintain CD8⁺ T cell tolerance through expression of inducible nitric oxide synthase (iNOS) and generation of NO. Increased autophagy resulted in degradation of iNOS in Kupffer cells and abrogated their suppressive activity against CD8⁺ T cells. Finally, we report that targeted downregulation of Kupffer cell autophagy in vivo using cationic lipid-assisted nanoparticles encapsulating siRNA against Atg5 leads to reduction of liver inflammation and bile duct damage.

Macrophage autophagy promotes autoimmune cholangitis and strongly supports this pathway as a potential therapeutic target.

In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies.

We developed a murine model of cirrhosis through chronic administration of carbon tetrachloride for up to 20 weeks. We investigated both the intestinal epithelial and vascular compartments and performed single-cell transcriptomic profiling of myeloid cells isolated from cirrhotic mice and from individuals with compensated and decompensated cirrhosis.

Our findings indicate that bacterial translocation in cirrhosis is the result of failure at multiple checkpoints, including aberrant epithelial cell death, vascular barrier damage and dysfunction of gut-vascular macrophages. In a preclinical model of cirrhosis, macrophages exhibited increased levels of monocyte-attracting chemokines, reduced bacterial clearance and impaired interactions with blood vessels. Importantly, depleting vascular-lining macrophages resulted in bacterial translocation to systemic sites, even in the absence of experimental liver disease. Transcriptional profiling of macrophages from duodenal biopsies of patients with cirrhosis indicated similar dysregulation of pathways supporting blood vessels and elevated expression of chemokines.

This study emphasises the critical role of intestinal macrophages in preventing the dissemination of luminal bacteria and highlights the multifaceted breakdown of the intestinal barrier in cirrhosis and the importance of the gut-vascular barrier.

For platforms lacking true single-cell resolution, data unmixing and deconvolution rely on the references from single-cell atlases, resulting in degrading precision of cell-type annotation as compared to the reference data sets.2 Thus, such single-cell prediction-based...]]> 2025-11-05T20:50:16-08:00 info:doi/10.1136/gutjnl-2025-337322 hwp:master-id:gutjnl;gutjnl-2025-337322 BMJ Publishing Group 2025-11-05 Letter http://gut.bmj.com/cgi/content/short/gutjnl-2025-336251v1?rss=1 Background

Peg-interferon (peg-IFN) plays an increasingly important role in HBV cure strategies, either in combination with novel antivirals, as a lead-in or as consolidation treatment.

We aimed to provide estimates of hepatitis B surface antigen (HBsAg) decline and clearance that can be achieved with peg-IFN addition to nucleos(t)ide analogue (NA) therapy.

This is a post hoc meta-analysis of individual participant data from eight clinical trials involving chronic hepatitis B patients on NA therapy who received peg-IFN add-on. The primary endpoint was HBsAg loss at end of follow-up (EOF, 6–12 months after end of peg-IFN). Secondary analyses focused on HBsAg decline.

581 patients were included. At the start of peg-IFN therapy (SOT), 44% were hepatitis B envelope antigen (HBeAg) positive, mean HBsAg level was 3.03 log10 IU/mL (HBsAg<100: 12%; 100–1000: 28%; ≥1000: 60%), and planned duration of peg-IFN was 48 weeks in 496 patients (85%).

At EOF, 50 (8.6%) patients achieved HBsAg loss (HBsAg<100/100–1000/≥1000: 37.7/9.8/2.3%, p<0.001) Findings were consistent across ethnicities (Caucasian: 30.0/8.7/3.6%; Asian: 39.3/9.2/2.2%). In patients with SOT HBsAg≥1000 IU/mL, levels <1000 and <100 were achieved in 29.7% and 8.9% at 24 weeks and in 47.5% and 16.3% at 48 weeks of peg-IFN therapy, respectively.

Peg-IFN add-on results in HBsAg loss in 18% of patients with SOT HBsAg<1000 IU/mL, and in 38% if SOT HBsAg<100 IU/mL. Among patients with higher HBsAg levels, peg-IFN could be used to reduce HBsAg to below thresholds associated with response to novel compounds.

This study elucidates the role and mechanism of A20 in AIH progression and its therapeutic potential.

A20 expression was analysed in patient sample and AIH mouse model. A20 function was explored in mice with hepatocyte-specific A20 knockout and overactivation and wild type controls. Liver samples were assessed by histology, immunoblot and electron microscopy. Proteomics, mass spectrometry, co-immunoprecipitation and site-specific mutation experiments were used to elucidate underlying mechanisms. AdipoRon was used to identify the effects of pharmacological induction of A20 on AIH.

A20 expression is reduced in livers of individuals with AIH. In experimental AIH, hepatocyte-specific A20 depletion aggravates hepatic inflammation and fibrosis, enhances ferroptosis of hepatocytes and increases sensitivity to ferroptosis inhibitors, while A20 overexpression ameliorates AIH pathology and reduces hepatocyte ferroptosis. Mechanistically, A20 is found to interact with KEAP1 and mediate its K48-linked polyubiquitination degradation, promoting NRF2 accumulation and nuclear translocation to enhance antioxidant and antiferroptosis effects. Pharmacological induction of A20 confers protective effects in AIH. The clinical correlation among A20, KEAP1, NRF2 and ferroptosis is validated in human AIH samples.

Our findings elucidate a previously unrecognised A20-KEAP1-NRF2 axis that orchestrates hepatocyte ferroptosis in AIH. Targeting A20 may provide a promising therapeutic strategy for AIH.

ESD enables en bloc resection of early gastrointestinal malignancies with histopathological margin assessment. ESD achieves lower recurrence rates than endoscopic mucosal resection (EMR) and offers lower morbidity and mortality than surgery.1–4 However,...]]> 2025-10-28T22:56:19-07:00 info:doi/10.1136/gutjnl-2025-336937 hwp:master-id:gutjnl;gutjnl-2025-336937 BMJ Publishing Group 2025-10-28 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2025-336677v1?rss=1 Recent Gut publications have emphasised the importance of optimising biopsy strategies and improving risk stratification for gastric cancer, including the RE.GA.IN. consensus,1 long-term natural history studies in Helicobacter pylori-infected individuals,2 and recent advances in precision risk assessment after H. pylori eradication.3 However, no agreement was reached on the role of the incisura angularis (IA) for the assessment of gastritis, and its sampling—previously required by the Updated Sydney System4—was left as optional.

To create an evidence-based background for further studies, we performed a systematic review to assess the influence of the IA biopsy on the stratification of patients with gastritis by quantifying the impact of an AI biopsy on Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia (OLGIM)5 stages.

This systematic review was conducted in accordance with the Cochrane Collaboration Handbook for Systematic Reviews of Interventions6...]]> 2025-10-28T22:56:19-07:00 info:doi/10.1136/gutjnl-2025-336677 hwp:master-id:gutjnl;gutjnl-2025-336677 BMJ Publishing Group 2025-10-28 Letter http://gut.bmj.com/cgi/content/short/gutjnl-2025-335449v1?rss=1 Objective

The impact of nucleos(t)ide analogues (NAs) therapy on the long-term outcomes in chronic HBV infection individuals outside 2025 European Association for the Study of the Liver (EASL) strongly recommended treatment indications remains uncertain. We aimed to assess the association between NAs therapy and the risks of cirrhosis and hepatocellular carcinoma (HCC) in Chinese chronic HBV infection individuals outside these criteria.

We analysed data from 30 784 chronic HBV infection individuals across 12 centres in China. We categorised individuals outside 2025 EASL strongly recommended treatment criteria into four groups: (1) hepatitis B e antigen (HBeAg)-positive, high replicative (age <30, HBV DNA ≥8 log₁₀IU/mL, normal alanine aminotransferase (ALT), no/mild fibrosis, no family history of liver cancer); (2) HBeAg-positive, impending phase transition (typically age ≥30, HBV DNA ≥6 log₁₀IU/mL, normal ALT, no advanced fibrosis); (3) HBeAg-negative, low replicative (HBV DNA <3.3 log₁₀IU/mL, normal ALT, no/mild fibrosis); (4) HBeAg-negative, high replicative, low-risk (HBV DNA 3.3–4.3 log₁₀IU/mL, normal ALT, no/mild fibrosis). The primary endpoints were the incidence of cirrhosis and HCC.

Up to 5 years of follow-up (117 814 person-years), we documented 635 incident cirrhosis and 164 HCC cases. In multivariable analyses, NA therapy significantly reduced risks of cirrhosis (HR 0.18, 95% CI 0.11 to 0.32) and HCC (HR 0.03, 95% CI 0.01 to 0.21) in Group 1, and cirrhosis (HR 0.50, 95% CI 0.41 to 0.61) and HCC (HR 0.25, 95% CI 0.16 to 0.41) in Group 2. No significant associations were observed in Groups 3 and 4. Findings were consistent in propensity score matching analyses.

NAs therapy was associated with reduced risks of cirrhosis and HCC in HBeAg-positive individuals with high replicative or impending phase transition phenotypes, supporting the expansion of chronic HBV infection treatment criteria.

To guide vaccine development, we assessed whether natural protection against observed HCV reinfection among MSM was associated with a distinct humoral immune profile.

From a prospective cohort of HIV-positive MSM with acute HCV infection (MOSAIC, Dutch MSM Observational Study of Acute Infection with hepatitis C), we selected 13 cases who became HCV-reinfected (R) and 18 controls who remained free of observed reinfections (non-reinfected, NR) in 0.5–9.5 years after primary infection clearance, matched for calendar year of primary infection. At time point T₁ (29 days before to 78 days after primary clearance) and T₂ (3–6 months before R subjects’ first reinfection), we evaluated serum antibody responses against HCV’s E1E2 envelope glycoprotein. Based solely on E1E2-binding antibody levels and Fc-gamma receptor (FcR)/C1q engagement at T₁, we divided participants into subgroups using latent profile analysis.

HCV-neutralising responses were observed mainly at T₁ (9/18 NR and 3/13 R participants). The NR group could be distinguished from the R group at T₁ by higher levels of E1E2-binding antibodies that bound FcRs/C1q. Among four identified latent profiles, HCV reinfection prevalence was lowest in the profile defined by moderate to high levels of E1E2-binding antibodies (IgM/IgG/IgG1/IgG3) and FcR/C1q engagement. This profile exhibited a relatively broad, potent HCV-neutralising capacity and the broadest epitope specificity.

We propose broad, potent serum Fc-mediated effector functions and neutralisation and a broad anti-E1E2 antibody epitope specificity as ingredients of HCV-protective immunity towards which vaccination approaches should aim.

We aimed to elucidate critical cellular interactions and molecular mechanisms underlying aggravated HIRI in aged livers to uncover therapeutic targets.

Single-cell RNA sequencing and spatial transcriptomics were performed on liver tissues from humans, rats and mice across ages to define key cell types and intercellular signalling. HIRI and liver transplantation animal models, primary cell co-cultures and adeno-associated virus-mediated gene knockdown were used to prove cellular function and mechanisms. Neutralising antibody was used to assess therapeutic efficacy.

Integrated analyses revealed a significant enrichment of senescent liver sinusoidal endothelial cells (LSECs) in aged livers, with the most prominent age-associated increase in crosstalk with hepatocytes, thereby promoting inflammation. Further investigation demonstrated increased transcriptional activity of myeloid ecotropic viral integration site 2 (MEIS2) in senescent LSECs, driving interleukin (IL)-1α expression via promoter binding and the IL-1α–IL1R1 axis subsequently activated NF-B signalling in hepatocytes, enhancing inflammatory cytokine production. Interestingly, LSECs were also most strongly influenced by hepatocytes during liver ageing, as hepatocyte-derived TNF-α further enhanced MEIS2 transcriptional activity in LSECs, establishing a proinflammatory positive feedback loop. Furthermore, we confirmed that neutralising IL-1α effectively alleviated HIRI in aged livers.

Our findings identify the crosstalk between LSECs and hepatocytes in aged livers aggravating HIRI via MEIS2/IL-1α/IL1R1/TNF-α axis, suggesting that IL-1α neutralising antibody can be exploited as a promising therapeutic strategy for aged HIRI.

What is your suspected cause of the condition?

Colonic biopsy pathology identified...]]> 2025-09-05T09:00:25-07:00 info:doi/10.1136/gutjnl-2025-336583 hwp:master-id:gutjnl;gutjnl-2025-336583 BMJ Publishing Group 2025-09-05 Editor's quiz: GI snapshot http://gut.bmj.com/cgi/content/short/gutjnl-2025-336452v1?rss=1 Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related death worldwide, and the incidence is predicted to further increase substantially within the next 20 years in all regions of the world.1 HCC surveillance in individuals at risk, including patients with liver cirrhosis as well as patients with HBV infection or metabolic dysfunction associated steatohepatitis, aims at early diagnosis of HCC, allowing for curative treatment such as resection or liver transplantation. In addition, locoregional therapies such as radiofrequency ablation, microwave ablation, transarterial chemoembolisation or radiotherapy are valuable treatment options in intermediate cancer stages. A large proportion of patients, however, are diagnosed in an advanced cancer stage, with multiple liver lesions or even extrahepatic metastases. These patients require systemic therapy. During the last few years, checkpoint-inhibitor based immunotherapy has become the first-line therapy for advanced HCC.2 While immunotherapy has prolonged...]]> 2025-09-05T09:00:24-07:00 info:doi/10.1136/gutjnl-2025-336452 hwp:master-id:gutjnl;gutjnl-2025-336452 BMJ Publishing Group 2025-09-05 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2025-336108v1?rss=1 Colorectal cancer (CRC) represents a major global health issue, ranking as the third most common tumour and the second leading cause of cancer-related mortality worldwide.1 Distant metastasis is the primary cause of fatality for patients with cancer. CRC often presents as metastatic disease at diagnosis, and up to 70% of patients who undergo curative surgery of the primary tumour will eventually develop metastases. The liver is the most common site for CRC metastatic spread. Despite significant progress in surgical interventions and treatments, a large number of patients with CRC have inoperable liver metastases or experience recurrence after surgery. To develop new therapeutic strategies and improve the management of advanced CRC, a deep understanding of the metastatic process is of utmost importance.

In recent decades, we have learnt that the tumour microenvironment (TME) plays a central role in every phase of oncogenesis and tumour development. The reciprocal and dynamic communication...]]> 2025-08-25T17:37:22-07:00 info:doi/10.1136/gutjnl-2025-336108 hwp:master-id:gutjnl;gutjnl-2025-336108 BMJ Publishing Group 2025-08-25 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2024-334233v1?rss=1 Gastric cancer peritoneal metastasis (GCPM) remains a formidable clinical challenge, characterised by poor prognosis and limited therapeutic options. Despite the transformative impact of immune checkpoint blockade (ICB) therapy across various cancer types, its efficacy in GCPM remains restricted, primarily due to profoundly immunosuppressive mechanisms within the tumour microenvironment (TME).1 2 Li et al recently conducted a single-cell transcriptomic analysis of tumour samples from a phase II trial evaluating ICB (sintilimab) combined with chemotherapy in patients with GCPM.2 Their study established a comprehensive single-cell transcriptional atlas, revealing a novel mechanism driving ICB resistance.2 They identified a unique stroma–myeloid niche dominated by THBS2⁺ matrix cancer-associated fibroblasts (mCAFs) and SPP1⁺ tumour-associated macrophages (TAMs), within resistant tumours, forming an immunosuppressive hub mediated via complement signalling.2 Specifically, THBS2⁺ mCAFs secreted complement component C3, engaging its receptor, C3aR (encoded by C3AR1) on macrophages. This C3–C3aR signalling...]]> 2025-08-22T02:16:19-07:00 info:doi/10.1136/gutjnl-2024-334233 hwp:master-id:gutjnl;gutjnl-2024-334233 BMJ Publishing Group 2025-08-22 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2025-335915v1?rss=1 Hepatocellular carcinoma (HCC) remains a major global health concern. According to GLOBOCAN 2022, primary liver cancer ranks as the sixth most common cancer and the third leading cause of cancer-related deaths, with approximately 865 269 new cases and 757 948 deaths in 2022.1 Without intensified screening and treatment, global HBV-related deaths are projected to rise by roughly 39% between 2015 and 2030.2

Current treatment guidelines fromthe American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) are mainly based on serum HBV DNA, alanine aminotransferase (ALT) levels and liver histology.3 4 A key challenge in HBV management is the so-called ‘indeterminate’ or ‘gray zone’ in which patients who do not meet current antiviral treatment guidelines but may still harbour considerable risk.5 6 Our previous study showed that HBV replication per se...]]> 2025-08-18T23:15:08-07:00 info:doi/10.1136/gutjnl-2025-335915 hwp:master-id:gutjnl;gutjnl-2025-335915 BMJ Publishing Group 2025-08-18 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2025-336200v1?rss=1 Message

Artificial intelligence (AI) has proven effective in assessing bowel preparation adequacy, but its role in guiding personalised laxative dosing is untested. In this prospective, multicentre, endoscopist-masked randomised trial, 1650 participants were assigned to AI-assisted or conventional groups using self-evaluation (SE) by patients during a 3 L split-dose polyethylene glycol (PEG) regimen. The AI group used significantly less PEG (mean difference –496.1 mL; p<0.001) while maintaining similar bowel cleanliness, polyp detection rates (PDR) and withdrawal times. Right colon scores were slightly higher, with less nausea and bloating reported in the AI group. AI-assisted assessment (AIA) offers an effective personalised approach to colonoscopy and warrants evaluation with other regimens.

Colonoscopy plays a vital role in early detection of colorectal cancer (CRC), with adequate bowel cleansing being essential for mucosal visualisation.1 Our team previously developed an AIA tool capable of real-time evaluation of rectal effluent images, providing instant feedback and...]]> 2025-08-12T23:13:20-07:00 info:doi/10.1136/gutjnl-2025-336200 hwp:master-id:gutjnl;gutjnl-2025-336200 BMJ Publishing Group 2025-08-12 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2025-335441v1?rss=1 Message

The strategy of discarding diminutive colonic polyps (≤5 mm) has been discussed for many years. However, despite their exceedingly low risk of malignancy, implementation has remained limited, with minimal impact on clinical practice. More recently, computer-assisted optical diagnosis (CADx) has been introduced to support and potentially enable broader adoption of this approach. We prospectively assessed patient acceptance and examiner-based quality control in 95 out of 102 patients (93.1%) who consented to this approach, involving a total of 149 polyps. Of these, 143 polyps were reviewed by three examiners blinded to CADx diagnoses and the results were compared with CADx diagnoses. Resect-and-discard accuracy was 83.5% excluding sessile serrated lesions (SSLs), while treating SSLs as neoplastic or hyperplastic yielded 75.9% and 84.3%, respectively. Excluding SSLs, the diagnose-and-leave negative predictive value was 92.3%. Surveillance interval recommendations based on CADx and expert review, aligned with current guidelines, achieved 100% concordance, ensuring appropriate follow-up.

Portal hypertension is the major driver of complications of cirrhosis, and a HVPG of more than 10 mm Hg is considered indicative of clinically significant portal hypertension.1 Although HVPG is generally regarded as the gold standard and is considered safe, it is not widely...]]> 2025-07-23T09:00:23-07:00 info:doi/10.1136/gutjnl-2025-335661 hwp:master-id:gutjnl;gutjnl-2025-335661 BMJ Publishing Group 2025-07-23 Endoscopy news http://gut.bmj.com/cgi/content/short/gutjnl-2025-336092v1?rss=1 Albumin is a multifunctional protein with pleiotropic activity that is produced almost exclusively in the liver. From many studies in several patient groups, it has become clear that in patients with liver disease, there is a reduction both in the quality and quantity of the circulating albumin, impacting negatively its functionality.1 Clinically, these alterations may lead to changes in oncotic pressure, immune status and the ability to deal with infection and inflammation, carrying a potential negative impact on patient outcomes. Therefore, there have been many studies in patients with liver disease for the last 50 years that have shown that albumin infusion can restore the oncotic pressure and thereby manage hypotension and oedema and finally provide volume expansion to support end organ blood flow and function. These have led to guideline-based indications for the acute or short-term use of human albumin solution for the management of patients with...]]> 2025-07-22T10:38:03-07:00 info:doi/10.1136/gutjnl-2025-336092 hwp:master-id:gutjnl;gutjnl-2025-336092 BMJ Publishing Group 2025-07-22 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2025-334965v1?rss=1 The suitability and tolerability of oats has been a long-standing controversy in the management of coeliac disease (CD). In Europe and the USA, pure oats are recommended for their nutritional benefits, palatability and desire by the patients with CD, whereas Australia and New Zealand have excluded oats from gluten-free diets due to safety concerns. In Gut, the research group of Jason Tye-Din publishes a unique and ground-breaking study on the immune reaction and tolerability of oats in CD.1 It is well known and studied that the ‘gluten-like’ proteins of wheat, rye and barley are harmful in CD—but what about the close cousin oats? There is an issue of contamination of oats with other cereals, and the patients have been well educated to rely on uncontaminated oats—but is this really the whole story? This commentary delves into these findings and their implications for dietary guidelines and clinical practice.

The investigators...]]> 2025-07-21T09:00:17-07:00 info:doi/10.1136/gutjnl-2025-334965 hwp:master-id:gutjnl;gutjnl-2025-334965 BMJ Publishing Group 2025-07-21 Commentary http://gut.bmj.com/cgi/content/short/gutjnl-2025-336308v1?rss=1 We read with great interest the recent article by van der Schee et al in Gut.1 This study shows that endoscopic intermuscular dissection (EID) with active surveillance is safe and effective. It is a useful organ-preserving strategy for patients with low to intermediate-risk rectal deep submucosal invasive cancer. These findings challenge the necessity of radical surgery in all such cases. We commend the authors for their important contribution. However, we would like to raise two concerns and suggest areas that warrant further investigation: (1) the potential adverse impact of EID on subsequent surgical procedures and (2) the optimal anatomical indication for EID.