Gut最新文献

{"title":"Targeting Treg-fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma.","authors":"Aldo Prawira,Hang Xu,Yu Mei,Nurul Jannah Mohamed Nasir,Marie J Y Reolo,Masayuki Otsuka,Wei Qiang Leow,Mohammad Rahbari,Ziyao Chen,Madhushanee Weerasooriya,Liyana Bte Abdullah,Jiawei Wu,Sharifah N Hazirah,Martin Wasser,Alexander Chung,Brian Kp Goh,Pierce Kh Chow,Salvatore Albani,Joycelyn Lee,Tony Kiat Hon Lim,Weiwei Zhai,Yock Young Dan,George Bb Goh,Mathias F Heikenwälder,Yongliang Zhang,Ramanuj Dasgupta,Wai Meng David Tai,Haiyan Liu,Jinmiao Chen,Valerie Chew","doi":"10.1136/gutjnl-2025-335084","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335084","url":null,"abstract":"BACKGROUNDSteatotic liver disease-related hepatocellular carcinoma (SLD-HCC), a rising global challenge, is characterised by unique tumour microenvironment (TME) adaptations.OBJECTIVEThis study investigates the immune microenvironment and interactions driving immunosuppression and potential resistance to immunotherapy in SLD-HCC.DESIGNWe employed single-cell transcriptomics, cytometry by time-of-flight (CyTOF) and two independent spatial transcriptomics platforms to study the TME of 22 SLD-HCC and 31 non-SLD-HCC cases. Findings were further validated using multiplex immunohistochemistry in an independent cohort of 103 patients, an HCC model and an immunotherapy-treated patient cohort to evaluate clinical relevance.RESULTSOur findings revealed significant alterations in immune and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs), suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. CyTOF revealed a cold, immunosuppressive TME with reduced CD8+ T cells and increased Tregs. Spatial transcriptomics further highlighted distinct Treg-CAF clusters localised at tumour margins, suggesting a spatially organised immunosuppressive niche. Mechanistically, tumour necrosis factor superfamily member 14 (TNFSF14)-tumour necrosis factor receptor superfamily member 14 (TNFRSF14)-mediated Treg-CAF interaction was identified as a critical driver of immunotherapy resistance in SLD-HCC. Blocking TNFRSF14 in an HCC model fed with a high-fat diet resulted in reduced Tregs, increased active CD8+ and memory CD4+ T cells, and a synergistic effect with anti-programmed cell death protein 1 therapy to enhance antitumour immunity and overcome immunotherapy resistance in SLD-HCC.CONCLUSIONThis study uncovers critical immune and metabolic adaptations in SLD-HCC, identifying TNFSF14-TNFRSF14 signalling as a key driver of immunotherapy resistance. Targeting this signalling axis enhances antitumour immunity and improves immunotherapy efficacy, offering a promising therapeutic strategy for SLD-HCC.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"111 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684111","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":"Hybrid identity and distinct methylation profiles of incomplete intestinal metaplasia in the stomach","authors":"Hyesung Kim, Junseong Kim, In Ho Jeong, Eunsun Park, Mira Yoo, Seokho Yoon, Donghyun Lee, Jaekyung Myung, Eunyoung Choi, Jim Goldenring, Bogun Jang","doi":"10.1136/gutjnl-2025-335793","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335793","url":null,"abstract":"Background Gastric intestinal metaplasia (GIM), particularly the incomplete subtype (Inc IM), is strongly associated with increased gastric cancer (GC) risk. However, its role as a true precursor lesion remains uncertain. Objective We aimed to delineate the molecular identity, differentiation potential and oncogenic relevance of Inc IM. Methods Spatial transcriptomics using a custom lineage-enriched panel was applied to profile GIM and GC tissues. Subtype-specific GIM organoid models were developed for DNA methylation and chromatin accessibility profiling. Single-cell RNA sequencing was performed to evaluate differentiation capacity. Results Spatial transcriptomics revealed that Inc IM potentially originates from the deep antral gland cells and harbours a hybrid transcriptomic signature incorporating gastric, small intestinal and large intestinal lineages across both differentiated and stem/progenitor compartments. DNA methylation profiling of subtype-specific organoids showed that Inc IM exhibits extensive intergenic hypermethylation, resembling native antral mucosa. In contrast, complete subtype was marked by promoter hypermethylation of tumour suppressor genes and displayed a more fully intestinalised epigenetic profile. Organoid models recapitulated subtype-specific traits and demonstrated lineage plasticity. Spatial mapping of GC samples revealed an enrichment of Inc IM-like cells, particularly within microsatellite stable tumours. Approximately 76% of the GCs analysed were linked to GIM, while the remaining (24%) appeared to be associated with deep antral differentiation. Conclusions Inc IM represents a phenotypically unstable and epigenetically deregulated metaplastic state with dual-lineage potential and molecular resemblance to GC. These findings establish Inc IM as a true precursor to GC and underscore the importance of active surveillance and early intervention strategies. Data are available on reasonable request. The raw and processed sequencing data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession numbers GSE294729, GSE295640 and GSE295401. This includes scRNA-seq, Xenium, bulk ATAC-seq and DNA methylation microarray data.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"184 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678028","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":"New look on oats in coeliac disease","authors":"Knut E A Lundin, Katri Lindfors, Louise Fremgaard Risnes","doi":"10.1136/gutjnl-2025-334965","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-334965","url":null,"abstract":"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 undertook a large effort to isolate oat avenin—the counterpart of wheat gluten. From 400 kg of contamination-free oats, they had 2.1 kg to use. This powder was used for clinical oat re-challenge in a total of 33 well-treated patients with CD allowing ingestion of oat avenin corresponding to as much as 12 servings of porridge. They recorded symptoms and collected serum in the first hours during challenge, in consideration of the knowledge that gluten challenge in patients with CD induces nausea and interleukin 2 (IL-2) release.2 3 The investigators performed challenges with either single bolus, 6-week oat avenin or 3 months whole oats in patients with …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"110 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678025","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":"Balancing safety and recurrence: pooled analysis of cold snare EMR for large colorectal polyps.","authors":"Baobao Wang,Qingzhou Kong,Yue-Yue Li,Yanqing Li","doi":"10.1136/gutjnl-2025-336150","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336150","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"5 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664229","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":"Endoscopic intermuscular dissection for rectal cancer: are we ready to skip surgery?","authors":"Katsuro Ichimasa,Shin-Ei Kudo,Masashi Misawa","doi":"10.1136/gutjnl-2025-336308","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336308","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"153 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664231","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":"Non-invasive tests of fibrosis in the management of MASLD: revolutionising diagnosis, progression and regression monitoring","authors":"Gong Feng, Vincent Wai-Sun Wong, Giovanni Targher, Christopher D Byrne, Ming-Hua Zheng","doi":"10.1136/gutjnl-2025-335542","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335542","url":null,"abstract":"With the recent conditional approval of resmetirom by the US Food and Drug Administration, the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) has potentially entered a new era, requiring a comprehensive understanding of the strengths and weaknesses of non-invasive tests (NITs) for diagnosing and monitoring MASLD-related fibrosis. This article focuses on F2/F3 liver fibrosis and summarises the current application status of NITs, including serum biomarkers, imaging methods and their combined use in the management of MASLD. The article highlights the application of NITs in several areas, including diagnosis and baseline stratification, monitoring progression of fibrosis, prediction of liver-related clinical events, as well as assessment of disease regression, remission and long-term liver-related outcomes. Furthermore, we compare the advantages and limitations of NITs and propose practical strategies for integrating them into clinical practice. Additionally, we highlight the main challenges currently faced in the application of these NITs and potential future research avenues. We suggest that future studies prioritise the validation of NITs across diverse ethnic populations. We believe it essential to explore the role of NITs in dynamic monitoring and integration of multiomics technologies, artificial intelligence and personalised risk models to improve diagnostic accuracy and treatment planning.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"16 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652224","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":"Hepatocyte senescence in alcohol-associated hepatitis: epiphenomenon or disease-driving mechanism?","authors":"Adrien Guillot, Elisa Pose","doi":"10.1136/gutjnl-2025-335271","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335271","url":null,"abstract":"Alcohol-associated hepatitis (AH) is a severe clinical syndrome within the spectrum of alcohol-related liver disease (ALD), characterised by acute-onset jaundice, systemic inflammation and liver dysfunction in individuals with chronic excessive alcohol use and underlying chronic liver disease in most of the cases. The prognosis of AH is poor, and effective therapeutic options besides corticosteroid therapy are scarce.1 There are few studies evaluating the histological changes that occur in the liver following an episode of AH. While it is known that some patients experience improvement with abstinence and medical management, the specific histopathological and molecular evolution remains poorly explored.2 The assessment of post-AH liver biopsies could provide valuable insights into mechanisms of fibrosis regression, resolution of inflammation and persistence of liver injury, and provide the needed information to identify potential therapeutic strategies to promote liver recovery. In Gut , Rodrigo-Torres et al performed bulk RNA sequencing on a cohort …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"42 8 Pt 1 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652222","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":"To be or not to be (a biliary cancer): RAS (signalling) is the question","authors":"Konstantina Morali, Silvestre Vicent","doi":"10.1136/gutjnl-2025-335690","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335690","url":null,"abstract":"Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent type of primary liver cancer, presents with a highly dismal prognosis, and its incidence is on the rise compared with most cancers.1 iCCA features histological traits of the biliary tract including expression of biliary epithelial cell markers such as SRY-box transcription factor 9 and cytokeratin 19. Based on the histological appearance, iCCA has been considered to arise from mature cholangiocytes. Indeed, epidemiological studies associate iCCA with pathological conditions involving the biliary compartment such as primary sclerosing cholangitis and liver fluke infection.1 Nonetheless, the presence of mixed hepatocellular carcinoma (HCC)/iCCA tumours, along with the association of iCCA with conditions affecting the hepatocellular compartment such as hepatitis B and C, and cirrhosis, points to the potential involvement of additional cell types, such as hepatocytes, in the origin of iCCA.1 Pioneering lineage tracing studies reported the development of murine iCCA derived from hepatocytes on treatment with the carcinogenic agent thioacetamide or by hydrodynamic tail vein injection (HTVI) delivery of iCCA-related oncogene Notch (ie, Notch intracellular domain), into hepatocytes of adult mice using the Sleeping Beauty transposon-transposase system.2 3 Hepatocyte to biliary cell (H-BC) transdifferentiation was further supported by subsequent studies using HTVI to overexpress oncogenes and/or deplete tumour suppressor genes (TSGs) and, more recently, by the use of adeno-associated virus with preferential tropism to hepatocytes.4–8 While these studies started to highlight that different liver injuries and pro-oncogenic insults foster H-BC transdifferentiation, the molecular understanding of how this process is regulated is far from being complete. This issue of Gut features a study …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"52 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639774","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":"Gut microbiota and atherosclerosis","authors":"William Fusco, Timon Adolph, Giovanni Cammarota, Antonio Gasbarrini, Gianluca Ianiro, Herbert Tilg","doi":"10.1136/gutjnl-2025-335610","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335610","url":null,"abstract":"Atherosclerosis reflects a chronic inflammatory process of arteries. The origin of chronic vascular inflammation has been associated over a long time primarily with lipid disorders, but evidence from the past years has suggested that lipid-independent pathways are also involved. Recent research has demonstrated that the gastrointestinal microbiota has an impact on the development of atherosclerosis. Many clinical studies have revealed that there exist altered gut microbiota and increased intestinal abundance of bacteria from the oral cavity in atherosclerosis-related disorders such as cardiovascular disease or stroke, while several studies have demonstrated insights into underlying mechanisms. Various microbial-derived metabolites, such as the pathogen-associated molecular pattern endotoxin, trimethylamine N-oxide or imidazole propionate, contribute to atherosclerosis, while other bacterial metabolites, such as some tryptophan derivatives, might be protective. Furthermore, gut microbiota and lipid pathways are highly interactive, and the gut microbiota affects lipid absorption and storage, and the gut microbiota also contributes to vascular ageing. Interference with the gut microbiota by prebiotics, probiotics and antibiotics has demonstrated beneficial effects on atherosclerosis mainly in preclinical models. Overall, the gut microbiota has appeared as an important rheostat for vascular inflammation in atherosclerosis, which is controlled by host-microbe interactions that may be therapeutically exploited in the future.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"44 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611133","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":"Helicobacter pylori antibiotic resistance: a global challenge in search of solutions","authors":"Christian Schulz, Jyh-Ming Liou, Mohamed Alboraie, Jan Bornschein, Christian Campos Nunez, Luiz Gonzaga Coelho, Duc Trong Quach, Carlo A Fallone, Yi-Chu Chen, Markus Gerhard, Javier P Gisbert, Hwoon-Yong Jung, Peter H Katelaris, Jae Gyu Kim, Hong Lu, Lukas Macke, Varocha Mahachai, Steven F Moss, Jose Maria Remes Troche, Arnoldo Riquelme, Marco Romano, Mashiko Setshedi, Stella Smith, Sebastian Suerbaum, Evariste Tshibangu-Kabamba, Ratha-Korn Vilaichone, Abbas Yadegar, Yoshio Yamaoka, Francis Mégraud, Emad M El-Omar, Kentaro Sugano, Peter Malfertheiner","doi":"10.1136/gutjnl-2025-335523","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335523","url":null,"abstract":"Background Helicobacter pylori resistance to antibiotics commonly used in eradication regimens is increasing dramatically in many locations; new strategies are needed to manage this infectious disease. Objective This study’s aim was to collect and update information on antibiotic resistance (AR) rates in H. pylori as well as current strategies for H. pylori management, including public health issues, from a global perspective. Design An international survey was conducted in 31 countries on 6 continents to address key issues concerning the management of H. pylori -related AR. Individual aspects included the prevalence of AR for specific antibiotics, antibiotic susceptibility testing (AST) in different healthcare systems, availability of drugs, reimbursement issues and strategies for H. pylori AR surveillance. Results Resistance to the most effective antibiotics used in H. pylori eradication regimens is increasing globally, with clarithromycin and levofloxacin resistance exceeding 15% in 24/31 and 18/31 countries, respectively. Amoxicillin remains an exception, with resistance rates under 2% in 14/31 countries; though African countries have reported amoxicillin resistance rates of over 90%. Bismuth-based treatment regimens are the most effective and are recommended as first-line treatment in several countries. However, more than 1 billion inhabitants worldwide have no access to bismuth-based regimens. PCR-based tests for AR are used in 16/26 countries but are reimbursed in only 4, while next generation sequencing-based tests are available, but not reimbursed, in 3 countries. In 22/26 countries only culture-based methods are available (reimbursed in 9/26 countries). AR surveillance programmes have only been established in 4/26 countries. Therefore, in most countries, empirical therapy with the most effective local regimen available locally is practiced. Conclusion The dramatic global rise in H. pylori antibiotic resistance requires an urgent revision of current management strategies. Possible solutions include AST-based selection of effective treatment regimens, identification of novel combinations of existing drugs and exploration of novel drugs. Data are available in a public, open access repository.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"22 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611125","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}