Gut最新文献

{"title":"MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.","authors":"Yang Chen, Gao-Wei Jin, Li-Hong He, Yu Dong, Yan-Na Zhang, Han-Xiang Guo, Yi-Ting Xu, Zi-Yang Wei, Bin-Fei Dang, Chun-Yang Mu, Wan-Yue Cao, Yi-Ze Zhang, Xiao-Bao Wei, Yu-Xiong Feng, Yun-Hua Liu, Qi Zhang, Ting-Bo Liang","doi":"10.1136/gutjnl-2025-336323","DOIUrl":"10.1136/gutjnl-2025-336323","url":null,"abstract":"<p><strong>Background: </strong>Liver metastasis is a common and fatal event for patients with pancreatic ductal adenocarcinoma (PDAC). Dysregulated mitochondrial dynamics reshape biological processes, including metabolism reprogramming, which disrupts immune cell function and promotes metastatic progression.</p><p><strong>Objective: </strong>To identify key drivers that reprogramme PDAC mitochondrial function and its role in remodelling the immunosuppressive tumour microenvironment (TME) during PDAC liver colonisation.</p><p><strong>Design: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"2182-2198"},"PeriodicalIF":24.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149520","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":"Two-year surveillance in Lynch syndrome: reconciling discordant cumulative-risk estimates","authors":"Jia Liu","doi":"10.1136/gutjnl-2026-340484","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340484","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"7 1","pages":"gutjnl-2026-340484"},"PeriodicalIF":24.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092426","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 'Rectal versus colonic submucosal cancer rates and procedural outcomes in large non-pedunculated polyps: French ESD registry data'.","authors":"Kareem Khalaf, Gary R May, Jeffrey D Mosko","doi":"10.1136/gutjnl-2025-337470","DOIUrl":"10.1136/gutjnl-2025-337470","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"2296-2297"},"PeriodicalIF":24.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742186","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":"Combined response to letters to the editors.","authors":"Veronique Van der Voort, Julien Magne, Jérémie Jacques","doi":"10.1136/gutjnl-2026-338206","DOIUrl":"10.1136/gutjnl-2026-338206","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"2297-2298"},"PeriodicalIF":24.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105325","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":"Catch me if you can! Is there protection from HCV (re)infection?","authors":"Birke Bartosch, Georg M Lauer","doi":"10.1136/gutjnl-2025-337209","DOIUrl":"10.1136/gutjnl-2025-337209","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"2084-2085"},"PeriodicalIF":24.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13069578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hospitalisation in cirrhosis is linked to distinct gut microbiome structural and functional profiles: a multinational metagenomic study.","authors":"Darja Nikitina, Ki Tae Suk, Aldo Torre, Ramazan Idilman, Mario R Alvares-da-Silva, Mette Munk Lauridsen, Andrew C Fagan, Edita Kreivenaite, Satya Priya Sharma, Elise Jonasson Nielsen, Dilara Turan, Vinay Jahagirdar, Matheus Truccolo Michalczuk, Alexander Khoruts, Sai Hruthik Bojja, Hye Won Lee, Jurgita Skieceviciene, Masoumeh Sikaroodi, Juozas Kupcinskas, Patrick M Gillevet, Jasmohan S Bajaj","doi":"10.1136/gutjnl-2026-339378","DOIUrl":"10.1136/gutjnl-2026-339378","url":null,"abstract":"<p><strong>Background: </strong>Hospitalisations represent major clinical events in cirrhosis, yet prediction based on clinical variables alone remains limited.</p><p><strong>Objective: </strong>Given the role of the gut microbiome in disease progression, we evaluated whether gut metagenomic profiles are associated with 90-day hospitalisation and provide additional prognostic information beyond clinical features in a multinational outpatient cirrhosis cohort.</p><p><strong>Design: </strong>We enrolled 679 outpatients with cirrhosis from seven countries and performed stool metagenomic profiling, including taxonomic, functional pathway and antibiotic resistance gene (ARG) analyses, with 90-day follow-up. Machine learning models were developed using clinical and microbiome features for predicting non-elective hospitalisations.</p><p><strong>Results: </strong>25% of patients required hospitalisation within 90 days. Hospitalised patients had more advanced cirrhosis, lower microbial diversity which was consistent across countries despite marked variation in microbial composition. Diet had a modest influence on microbiome structure. After adjustment for country, disease severity, cirrhosis aetiology and treatment, 19 bacterial species remained independently associated with hospitalisation, including enrichment of <i>Enterococcus faecium</i> and <i>Veillonella rogosae</i> and depletion of multiple commensal taxa. Functional profiling demonstrated coordinated taxonomic-functional alterations focusing on complex carbohydrate degradation pathways, glycan biosynthesis, lipid and nucleotide salvage pathways and association with antimicrobial resistance mechanisms. The combined clinical-microbiome model significantly outperformed both the clinical-only (area under the curve (AUC) 0.79) and microbiome-only (AUC 0.74) models, achieving an AUC of 0.84.</p><p><strong>Conclusion: </strong>Gut microbiome composition and function are associated with short-term hospitalisation risk and provide additional prognostic information beyond clinical variables in a multicountry cohort. Hospitalisation, regardless of country, is characterised by loss of short-chain fatty acid-producing taxa, functional shifts, ARG and pathway changes.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016760","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":"Short-term risk prediction model for pancreatic cancer in type 2 diabetes: development and validation across two independent Chinese cohorts.","authors":"Hong Zhu, Hanbing Fan, Wenzhe Yang, Shan Gao, Jingdan Chang, Guowei Zong, Yaxu Zhuang, Adilan Abudukeranmu, Xinyan Jia, Yun Zhu, Yaqi Zhang, Zhiwei Rong, Yanxu Yang, Zelong Wu, Mingzhen Li, Xiuchao Wang, Tao Zhang, Zhenqiang Song, Jihui Hao","doi":"10.1136/gutjnl-2026-339722","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339722","url":null,"abstract":"<p><strong>Background: </strong>Individuals with diabetes are prioritised for pancreatic cancer screening. Tailored risk prediction models can improve stratification and screening efficiency. However, most existing predictive tools focus on new-onset diabetes, overlooking individuals with long-standing type 2 diabetes.</p><p><strong>Objective: </strong>To develop and validate a short-term pancreatic cancer risk prediction model applicable to both new-onset and long-standing type 2 diabetes.</p><p><strong>Design: </strong>This retrospective longitudinal cohort study used two independent Chinese cohorts: the Tianjin Diabetes and Health Cohort (n=330 767, registration ID: NCT06913153) for derivation and internal validation, and the Xiamen Regional Electronic Health Record Database (n=105 537) for external validation. The Short-Term risk predictiOn of Pancreatic cancer in Diabetes Mellitus (STOP-DM) model was developed using a random forest algorithm and 11 routinely available clinical predictors to estimate pancreatic cancer risk at 6, 12, 24 and 36 months. Model performance was further evaluated in subgroups stratified by diabetes duration.</p><p><strong>Results: </strong>The STOP-DM model exhibited the highest predictive performance at a 6-month time window, with the area under the receiver operating characteristic curve of 0.88 (95% CI 0.84 to 0.92) in the derivation cohort, 0.89 (0.83 to 0.94) in internal validation and 0.86 (0.83 to 0.89) in external validation. The top 5% high-risk group identified 59.37% and 48.03% of incident cases in the two validation cohorts and had 11.00-fold and 14.37-fold higher risk than the lowest-risk group. The model performed well in both new-onset and long-standing diabetes, and outperformed existing models for new-onset diabetes in sensitivity and positive predictive value.</p><p><strong>Conclusion: </strong>The STOP-DM model provides a practical approach to stratify pancreatic cancer risk and deliver targeted screening for individuals with type 2 diabetes, particularly those living with long-standing diabetes. Prospective validation and real-world implementation studies are warranted.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108844","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":"Genetically predicted BMI and long-term outcomes in MASLD: revisiting the obesity paradox using genetic evidence","authors":"Di Liu,Youxin Wang,Jianguang Ji","doi":"10.1136/gutjnl-2026-339631","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339631","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"294 1","pages":"gutjnl-2026-339631"},"PeriodicalIF":24.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088900","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":"Microbiota-host genetic interactions modulate MASLD risk in\u0000 \u0000 PNPLA3\u0000 I148M\u0000 \u0000 carriers via ceramides and are reversible by targeted microbial interventions","authors":"Madhuri Haque,Till Robin Lesker,Ulrike Rolle-Kampczyk,Anneleen Segers,Willem M De Vos,Antonio Molinaro,Thriveni Basavanapura,Yazhou Chen,Maria Backhaus,Mohamed Ramadan Mohamed,Lu Jiang,Qusay Salih,Lena Candels,Marcus Henricsson,Agata Bielecka,Sonja Lang,Frank Tacke,Jan G Hengstler,Carolin Victoria Schneider,Münevver Demir,Till Strowig,Martin von Bergen,Kai Markus Schneider,Christian Trautwein","doi":"10.1136/gutjnl-2026-338178","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338178","url":null,"abstract":"Background The factors that determine when genetic susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD) progresses to clinically significant liver injury remain incompletely understood. Objective We investigated whether disruption of the intestinal host-microbiota interface acts as a contextual modifier that amplifies PNPLA3 I148M -associated hepatic injury. Design We used a dual-hit mouse model combining hepatic Pnpla3 I148M -expression with Nlrp6 -deficiency, a model of impaired intestinal mucosal homeostasis, under western-diet conditions. Multi-omics profiling, including metagenomics, metabolomics and transcriptomics, was integrated with analyses in human cohorts (Lifelines, Charité MASLD, Human Phenotype Project). Microbiota-dependent effects were examined using faecal microbiota transplantation (FMT), antibiotic-mediated depletion and targeted intervention with Akkermansia muciniphila or its membrane protein Amuc_1100. Results In mice, the combination of Pnpla3 I148M expression and impaired intestinal sensing synergistically exacerbated gut-barrier dysfunction and bacterial encroachment, accompanied by increased portal levels of microbiota-associated metabolites, including long-chain ceramides (Cer(d18:1/16:0), Cer(d18:1/18:0)) and bile acids. These changes were associated with hepatic mitochondrial stress and inflammatory responses. Human carriers with advanced MASLD displayed microbial and metabolic signatures consistent with increased gut-derived metabolic signalling. Restoration of eubiotic microbiota via FMT or Amuc_1100 treatment improved intestinal barrier integrity and attenuated hepatic lipid accumulation in experimental models. Conclusion These findings suggest that gut-derived signals resulting from a disrupted intestinal barrier may act as modifiers of PNPLA3 I148M -clinical penetrance by amplifying downstream metabolic and inflammatory responses. By identifying these pathways linking environmental context to genetic susceptibility, this study highlights the host-microbiota interface as a potential target for strategies aimed at limiting MASLD progression in genetically at-risk individuals.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"20 1","pages":"gutjnl-2026-338178"},"PeriodicalIF":24.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088899","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":"Clinical impact of prospective circulating tumour DNA testing for minimal residual disease in colorectal cancer: the INTERCEPT programme experience","authors":"Giulia Maddalena,Kathryn Aziz,Ryan Sun,Timothy E Newhook,Kristin Alfaro,Andrew Bowling,Dylan N Gil,Ramy S Behman,Mahmoud Yousef,Y Nancy You,Tsuyoshi Konishi,Alisha Bent,Ryan Huey,Bryan Kee,Guglielmo Vetere,Emerik Osterlund,Kaysia Ludford,Victoria Serpas,Madhulika Eluri,Jason Willis,John Paul Shen,Maria P Morelli,Emily Kopetz,Sara Lonardi,Christine Parseghian,Kanwal Raghav,Michael Overman,Gayathri Anandappa,Robert A Wolff,James Yao,George J Chang,Van K Morris,Jean-Necolas Vauthey,Arvind Dasari,Scott Kopetz","doi":"10.1136/gutjnl-2026-339167","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339167","url":null,"abstract":"Background The impact of circulating tumour DNA (ctDNA) detection, which informs minimal residual disease (MRD) after curative treatment, remains debated especially for stage IV patients. Objective The study objectives were to evaluate the prognostic role of MRD and to estimate lead time (LT) at different timepoints when adopting longitudinal MRD testing. Design INTERCEPT, is a prospective, observational cohort study of stage II–IV patients with colorectal cancer receiving curative-intent treatment who are longitudinally monitored using tissue-informed MRD assays as part of routine clinical care. Results Study results confirm the prognostic value of MRD, also beyond 12 months from surgery, with higher recurrence incidence in MRD-positive stage II–III patients than in MRD-negative stage IV patients (p&lt;0.0001). Adjuvant therapy in stage IV disease showed limited durable benefit in both MRD-positive and negative patients. Clinical management was associated with increased use of more intensive second-line imaging (MRI, positron emission tomography; p&lt;0.0001) when ctDNA was detected. Concurrent macroscopic disease detection was observed in 26% of cases and when excluded, LT from MRD detection to radiographic recurrence varies during surveillance (p=0.007). Multitimepoint testing improves sensitivity for recurrence (79.9% vs 48.5%) and may enable earlier, potentially curative interventions. Conclusion ctDNA testing provides a framework for risk stratification and defines temporal windows that may inform future interventional strategies. Prospective interventional studies are required to define clinical utility and optimal implementation.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"1 1","pages":"gutjnl-2026-339167"},"PeriodicalIF":24.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088909","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}