Gut最新文献

{"title":"Correction: Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver cancer","authors":"BMJ Publishing Group Ltd and British Society of Gastroenterology","doi":"10.1136/gutjnl-2024-333238corr1","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333238corr1","url":null,"abstract":"Rösner T, Rupp C, Lechler C, et al . Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver cancer. Gut 2025;74:1653-1666. In the published article, figures 2–4 do not appear in the correct order. The correct figures are below: Figure 2 RPK liver tumours develop from hepatocytes (HEP). (A) Survival of male RPK mice after injection of AAV-TBG-Cre or tam in RPK lines targeting HEP (red) or bile duct cells (green) in …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"158 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to: ‘Differentiating gastroparesis from functional dyspepsia is no longer sufficient’ by O’Grady et al","authors":"Michael Camilleri, Nicholas J Talley","doi":"10.1136/gutjnl-2025-336998","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336998","url":null,"abstract":"We thank Drs O’Grady and colleagues for their interest1 in our commentary ‘Are functional dyspepsia and gastroparesis really ‘interchangeable’ diseases?’2 and their comment agreeing that improvement in tests of gastric emptying (GE) is highly desirable. Their plea for moving the field to understanding mechanisms and validating actionable biomarkers3 with the objective of personalising therapy4 is certainly consistent with our long track record. Consistent with the quest for pathophysiological characterisation of patients with symptoms considered to be arising in the stomach and duodenum, we previously published data on 1287 patients evaluated in the clinical practice using the …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"32 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between liver sinusoidal endothelial cells and hepatocytes via IL-1α–IL1R1 axis exacerbates ischaemia/reperfusion injury in aged livers","authors":"Yasong Liu, Tingting Wang, Feng Zhang, Xuying Liu, Zhongying Hu, Jiebin Zhang, Haitian Chen, Jiaqi Xiao, Qiang You, Zhengqi Wu, Jia Yao, Yingcai Zhang, Shuhong Yi, Hua Li, Qi Zhang, Yang Yang, Rong Li, Jun Zheng","doi":"10.1136/gutjnl-2025-335964","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335964","url":null,"abstract":"Background With population ageing, elderly patients account for a growing proportion of hepatic surgery recipients. Hepatic ischaemia-reperfusion injury (HIRI) is a major cause of postoperative liver dysfunction, particularly in aged livers, yet its mechanisms remain poorly understood. Objective We aimed to elucidate critical cellular interactions and molecular mechanisms underlying aggravated HIRI in aged livers to uncover therapeutic targets. Design 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. Results 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-κB 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. Conclusion 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. Data are available upon reasonable request. The data sets analysed during the current study are available from the corresponding author on reasonable request. This study did not use any unique codes, and all analyses were performed in R and Python using standard protocols from previously published packages. All primers and other nucleic acid sequences are provided in the [online supplemental Table 1][1]. [1]: #DC16","PeriodicalId":12825,"journal":{"name":"Gut","volume":"54 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale multiomic analysis identifies non-coding somatic driver mutations and nominates ZFP36L2 as a driver gene for pancreatic ductal adenocarcinoma","authors":"Jun Zhong, Aidan O’Brien, Minal B Patel, Daina Eiser, Michael Mobaraki, Irene Collins, Li Wang, Konnie Guo, ThucNhi TruongVo, Ashley Jermusyk, Sudipto Das, Maura O’Neill, Courtney D Dill, Andrew D Wells, Michelle E Leonard, James A Pippin, Struan F A Grant, Tongwu Zhang, Thorkell Andresson, Katelyn E Connelly, Jianxin Shi, H Efsun Arda, Jason W Hoskins, Laufey T Amundadottir","doi":"10.1136/gutjnl-2025-335152","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335152","url":null,"abstract":"Background The identification and characterisation of somatic cancer driver mutations in the non-coding genome remains challenging. Objective To broadly characterise non-coding driver mutations for pancreatic ductal adenocarcinoma (PDAC). Design Using mutation calls from whole-genome sequence data in PDACs and genome-scale maps of accessible gene regulatory regions in normal-derived and tumour-derived pancreatic samples, we analysed enrichment of non-coding mutations in gene regulatory regions relevant to normal-derived and tumour-derived pancreatic contexts. Functional follow-up of potential driver mutations was performed using chromatin interaction analyses, massively parallel reporter assays (MPRA) and targeted analysis of selected non-coding somatic mutations (NCSMs). Results We first created genome-scale maps of accessible chromatin regions (ACRs) and histone modification marks (HMMs) in pancreatic cell lines and purified pancreatic acinar and duct cells. Integration with whole-genome mutation calls from 506 PDACs revealed 314 ACRs/HMMs significantly enriched with 3614 NCSMs. Chromatin interaction analysis identified 416 potential target genes and MPRA revealed 178 NCSMs impacting reporter activity (19.45% of those tested). Targeted luciferase validation confirmed negative effects on gene regulatory activity for NCSMs near ZFP36L2 and CDKN2A . For the former, CRISPR interference identified ZFP36L2 as a target gene (16.0–24.0% reduced expression, p=0.023–0.0047), and growth inhibition after overexpression of ZFP36L2 (4.1–14.1-fold reduction, p=6.0×10–4 − 3.2×10–3) implicates a possible tumour suppressor function. Conclusion Our integrative approach provides a catalogue of potential non-coding driver mutations and nominates ZFP36L2 as a novel PDAC driver gene with a likely tumour suppressor function. Data are available in a public, open access repository. Data may be obtained from a third party and are not publicly available. Data are available in a public, open access repository or may be obtained from a third party and are not publicly available. All data sets created as part of this work or used in this study and available through third parties, are listed in the Online Methods section under the Data availability section.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"11 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host-microbiome determinants of insulin resistance in obesity: alone we go faster, together we go further!","authors":"Andre Marette, Genevieve Pilon","doi":"10.1136/gutjnl-2024-333855","DOIUrl":"10.1136/gutjnl-2024-333855","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1759-1760"},"PeriodicalIF":25.8,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ISG15-CREB1 ISGylation: a stellate cell brake in liver fibrosis.","authors":"Maria Arechederra,Ruchi Bansal","doi":"10.1136/gutjnl-2025-336503","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336503","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"16 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Galectin-4 drives anti-PD-L1/BVZ resistance by regulating metabolic adaptation and tumour-associated neutrophils in hepatocellular carcinoma.","authors":"Wenxin Xu,Yufei Zhao,Jialei Weng,Mincheng Yu,Qiang Yu,Peiyi Xie,Shaoqing Liu,Lei Guo,Bo Zhang,Yongfeng Xu,Yongsheng Xiao,Huichuan Sun,Qinghai Ye,Hui Li","doi":"10.1136/gutjnl-2025-336374","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336374","url":null,"abstract":"BACKGROUNDThe combination of atezolizumab and bevacizumab (ATZ/BVZ) therapy has significantly advanced therapeutic approaches for hepatocellular carcinoma (HCC). However, less than 30% of patients achieve durable responses, highlighting the urgent need to understand mechanisms underlying resistance.OBJECTIVEThis study aimed to elucidate the mechanisms of resistance to ATZ/BVZ therapy in HCC and identify druggable targets associated with resistance, thus improving the treatment efficacy of ATZ/BVZ-resistant HCC.DESIGNWe employed single-cell RNA sequencing and a prospective clinical cohort (NCT04649489) to identify and characterise potential genes that contribute to ATZ/BVZ therapy resistance. Multiple preclinical HCC models and a coculture system were constructed, and cytometry by time-of-flight technology was used to further explore the relevant molecular mechanism.RESULTSElevated baseline serum galectin-4 levels correlated with resistance to ATZ/BVZ therapy and unfavourable prognosis in HCC. Galectin-4 overexpression nullified ATZ/BVZ therapy efficacy through promoting metabolic adaptation and fostering an immunosuppressive tumour microenvironment characterised by reduced infiltration and impaired cytotoxicity of CD8+ T cells and accumulation of PD-L1+ tumour-associated neutrophils. Mechanistically, galectin-4 inhibited proteasomal degradation of lactate dehydrogenase A (LDHA) by competitively decreasing tripartite motif containing 28 binding, thereby enhancing glycolysis and amplifying HIF-1α-mediated C-X-C motif chemokine ligand 6 (CXCL6) expression. Genetic knockdown or pharmacological inhibition of galectin-4 reversed metabolic adaptation and immune exclusion, and restored sensitivity to anti-PD-L1/BVZ therapy in preclinical models.CONCLUSIONActivation of the galectin-4/LDHA/HIF-1α and CXCL6 axis plays a pivotal role in ATZ/BVZ therapy resistance. Galectin-4 serves as a promising therapeutic target to improve immunotherapy efficacy and an effective predictive biomarker for immunotherapy response in HCC.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"31 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asian Pacific Association of Gastroenterology task force recommendations on surveillance for Helicobacter pylori associated gastric premalignant conditions.","authors":"Wai Keung Leung,Tiing Leong Ang,Shailja Shah,Ka Shing Cheung,Yunhao Li,Noriya Uedo,Wen-Qing Li,Khay-Guan Yeoh,Ratha-Korn Vilaichone,Thomas Kl Lui,Duc Trong Quach,Lai Mun Wang,Il Ju Choi,Hidekazu Suzuki,Hwoon-Yong Jung,Hang Viet Dao,Kaichun Wu,Alex Boussioutas,Mario Dinis-Ribeiro,Yi-Chia Lee","doi":"10.1136/gutjnl-2025-335823","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335823","url":null,"abstract":"BACKGROUNDThe burden of gastric cancer remains substantial in Asia. Gastric premalignant conditions, including chronic atrophic gastritis, intestinal metaplasia and dysplasia, are important intermediate stages in the gastric carcinogenesis cascade. The sojourn time allows endoscopic surveillance to have a pivotal role in early detection and timely intervention.OBJECTIVEThis task force was commissioned by the Asian Pacific Association of Gastroenterology to formulate recommendations for the surveillance and management of Helicobacter pylori associated gastric premalignant conditions in the region.DESIGNA systematic literature review was conducted across multiple databases, including PubMed, Cochrane Library and Embase, focusing on studies related to gastric premalignant conditions and their surveillance, particularly from Asia. The evidence quality and strength of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.RESULTSThese recommendations address four key aspects of gastric premalignant condition surveillance: (1) epidemiology and risk factors; (2) endoscopic and histopathological diagnosis; (3) risk stratification and endoscopic surveillance strategies; and (4) management strategies. 28 statements were made after multiple rounds of voting by experts. The statements offer a comprehensive, evidence based framework designed to assist clinicians in the Asia Pacific region on the early detection and management of gastric premalignant conditions.CONCLUSIONThese statements aim to provide a structured, evidence based surveillance framework for clinical practice in the Asia Pacific region, while also identifying priority areas for future research.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"20 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis identifies RETN+ monocyte-derived Resistin as a therapeutic target in hepatitis B virus-related acute-on-chronic liver failure","authors":"Xianbin Xu, Jiyang Chen, Xia Yu, Zhiwei Li, Jianing Chen, Danfeng Fang, Xingchen Lin, Huilan Tu, Xinyi Xu, Sisi Yang, Jinlin Cheng, Kai Gong, Haoda Weng, Yue Yu, Xiuding Zhang, Yan Lan, Biao Li, Guoqiang Cao, Hai Chen, Leiming Chen, Xiaohan Qian, Wenzheng Han, Meng Jiang, Weibo Du, Yida Yang, Jifang Sheng, Xiaopeng Wu, Yu Shi","doi":"10.1136/gutjnl-2025-335998","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335998","url":null,"abstract":"Background Acute-on-chronic liver failure (ACLF) is characterised by intense systemic inflammation and high short-term mortality, yet effective targeted therapies are lacking. Objective To explore monocyte heterogeneity in HBV-related ACLF (HBV-ACLF) to identify specific subsets and associated therapeutic targets. Design Peripheral blood mononuclear cells from healthy controls (n=4), patients with acute decompensation (n=5), and patients with ACLF (n=9) underwent single-cell RNA sequencing (scRNA-seq). Findings were integrated with hepatic scRNA-seq, bulk transcriptomics, multiplex immunohistochemistry and in vitro functional assays. The in vivo roles of candidate targets were validated in two murine ACLF models. Results We identified a distinct RETN+ monocyte subset that was expanded in the circulation and liver of patients with HBV-ACLF. These RETN+ monocytes displayed a transcriptional programme enriched for anti-inflammatory and pro-resolving signatures, including MS1-B-like features. Interleukin-6 promoted the expansion of RETN+ monocyte via the JAK/STAT3/RUNX1 signalling axis. In murine ACLF models, neutralisation of Resistin exacerbated liver injury, increased systemic cytokine levels and augmented hepatocyte apoptosis. Conversely, administration of recombinant Resistin mitigated liver damage, diminished levels of inflammatory cytokines and improved survival. Mechanistically, Resistin activated PI3K/AKT signalling in hepatocytes, preserved the Bcl-2/Bax balance and suppressed intrinsic apoptosis. Clinically, plasma Resistin levels in HBV-ACLF patients inversely correlated with systemic inflammatory markers, liver injury, ACLF severity scores (Model for End-Stage Liver Disease, Chronic Liver Failure Consortium ACLF score) and short-term mortality. Conclusions RETN+ monocytes constitute a distinct immunoregulatory subset enriched in HBV-ACLF, and their product, Resistin, exerts significant hepatoprotective and anti-inflammatory effects. These findings highlight RETN+ monocytes and Resistin as promising immunotherapeutic targets for HBV-ACLF. Data are available in a public, open access repository. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Data are available in a public, open access repository. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The raw sequence data for scRNA-seq and bulk RNA-seq used in this study have been deposited into Genome Sequence Archive for Human (GSA-Human) under accession number HRA004600, HRA011131 and HRA011356 (<https://ngdc.cncb.ac.cn/gsa-human>).","PeriodicalId":12825,"journal":{"name":"Gut","volume":"30 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rise of precision medicine: can it deliver on its promise in IBD?","authors":"Stefan Schreiber, Konrad Aden, Florian Tran, Philip Rosenstiel","doi":"10.1136/gutjnl-2023-330000","DOIUrl":"https://doi.org/10.1136/gutjnl-2023-330000","url":null,"abstract":"The clinical and molecular heterogeneity of IBD—both between patients and within the same individual over time—continues to pose a significant challenge to the implementation of truly personalised treatment strategies. Unlike oncology, where somatic mutation patterns define an actionable information layer, IBD lacks detectable dominant molecular drivers that can guide therapeutic choices. Although the therapeutic landscape has broadened with the advent of numerous biologics and small molecule drugs, predictive ( ex ante ) biomarkers for treatment response remain elusive. In this review, we assess the current progress and limitations of biomarker-guided precision therapy in IBD. We argue that traditional binary response definitions at single landmark endpoints fail to reflect the multidimensional and dynamic nature of therapeutic outcomes. We hence propose combined, and thus individualised, endpoints such as comprehensive disease control as a more holistic and responsive therapy goal in IBD. We propose to integrate the individual longitudinal dynamics of treatment response, and also continuous, objective monitoring of subclinical residual inflammation, analogous to the concept of minimal residual disease in oncology. In this concept, longitudinal assessment of patient-reported outcomes and molecular profiling in response to therapy may serve as early predictors of long-term outcomes, guide early therapeutic adjustments and reveal mechanisms that open new therapeutic avenues, such as adjunct or combination treatments. Adopting this dynamic, data-driven approach to treatment adaptation could shift management of IBD from reactive to proactive and substantially improve long-term outcomes with the vision to fully control a life-long disease.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"54 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}