Gut最新文献

{"title":"Rewinding the gut clock: from chronodisruption to targeted therapies","authors":"Hui Leng,Inge Depoortere","doi":"10.1136/gutjnl-2026-338750","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338750","url":null,"abstract":"Circadian rhythms orchestrate daily oscillations in physiology and behaviour, enabling optimal alignment between internal biological processes and environmental cycles. A hierarchical system centred in the suprachiasmatic nucleus and supported by peripheral clocks across tissues ensures temporal alignment of metabolic, immune and GI functions. Within the GI tract, local clocks drive rhythmic programmes that regulate digestion, absorption, motility, hormone secretion, immune responses and interactions with the gut microbiota. Feeding-fasting cycles and microbial metabolites act as powerful zeitgebers for intestinal clocks, shaping rhythmic gene expression and intestinal metabolic oscillations. Chronodisruption—arising from misaligned light exposure, sleep disturbances or mistimed eating schedules—uncouples central and peripheral clocks. These disturbances, increasingly prevalent in shift workers, disrupt microbial rhythmicity and intestinal homeostasis. Chronodisruption contributes to metabolic disorders, including obesity, dyslipidaemia and type 2 diabetes, and increases the susceptibility to GI disorders such as IBD, IBS, GORD and colorectal cancer. Emerging therapeutic strategies aim to restore circadian alignment. Time-restricted feeding reinforces endogenous rhythmicity, improves metabolic health and restores GI rhythmic processes through entrainment of clock genes, nutrient-sensing pathways and microbial oscillations. Chronobiotics, including melatonin and phytochemicals, further offer non-invasive approaches to resynchronise disrupted clocks. Finally, chronotherapy and chronotype-tailored interventions further underscore the potential of personalised medicine based on circadian biology. Advances in research on rhythmic metabolites and interorgan metabolic coupling offer promising opportunities for understanding systemic circadian coordination. Overall, reinforcing circadian alignment holds potential for preventing and treating metabolic and GI diseases associated with modern lifestyle-induced chronodisruption.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"21 1","pages":"gutjnl-2026-338750"},"PeriodicalIF":24.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092688","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":"Hypothermic oxygenated and normothermic machine perfusion mitigate innate systemic and hepatic inflammation after liver transplantation.","authors":"Isabella Lurje, Paul Horn, Adrien Guillot, Deniz Uluk, Frederik Schliephake, Luna Rohm, Dina Katharina Liefke-Biegel, Malte Lehnert, Katharina Remih, Rabea Hokamp, Wiebke Werner, Alix Bruneau, Justus Pein, Yaroslava Shevchenko, Ingrid Wei Zhang, Pavitra Kumar, Cornelius Engelmann, Moritz Peiseler, Janina Eden, Philipp Dutkowski, David Meierhofer, Nadine Gaisa, Pavel Strnad, Johann Pratschke, Linda Hammerich, Frank Tacke, Georg Lurje","doi":"10.1136/gutjnl-2026-338907","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338907","url":null,"abstract":"<p><strong>Background: </strong>Immune-mediated injury drives ischaemia-reperfusion injury (IRI) following liver transplantation. While hypothermic oxygenated (HOPE) and normothermic machine perfusion (NMP) improve clinical outcomes, their immunological effects in humans remain unclear.</p><p><strong>Objective: </strong>To examine hepatic and systemic immune responses across preservation strategies in a randomised controlled clinical setting.</p><p><strong>Design: </strong>In this mechanistic substudy of the HOPE-NMP randomised controlled trial (NCT04644744), we analysed immune responses in n=47 recipients of extended criteria donor livers from brain-dead donors randomised to static cold storage (SCS), end-ischaemic HOPE or end-ischaemic NMP. Liver biopsies were obtained at organ arrival and early IRI. Blood samples were collected preoperatively, during reperfusion and on postoperative days 1, 2, 3 and 7.</p><p><strong>Methods: </strong>Analyses included spectral flow cytometry, multiplex immunofluorescence with spatial analyses, cytokine profiling, cellular bioenergetics and mass spectrometry.</p><p><strong>Results: </strong>In human liver allografts, both HOPE and NMP reduced neutrophil infiltration during early IRI, without altering intrahepatic spatial distribution. Machine perfusion induced phenotypic modulation of graft-infiltrating myeloid cells, characterised by downregulation of pro-inflammatory and adhesion markers. Peripheral lymphocyte numbers, particularly of NK cells and T cells, normalised faster after HOPE, compared with SCS and NMP groups, correlating with reduced liver injury. Absolute and relative systemic neutrophil numbers were lower in HOPE-recipients. Machine perfusion decreased the inflammatory activation of circulating myeloid and innate lymphoid cells, while inhibitory immune checkpoints were upregulated postoperatively.</p><p><strong>Conclusions: </strong>In a randomised controlled trial using human samples, HOPE and NMP differentially modulate hepatic and systemic immune responses, attenuating neutrophil-driven inflammation and promoting immune regulation after liver transplantation.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080452","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":"GLP-1 receptor agonists versus DPP-4 inhibitors after curative resection of hepatocellular carcinoma in patients with type 2 diabetes.","authors":"Chi-Ling Chen, Wei-Shiung Yang","doi":"10.1136/gutjnl-2026-339889","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339889","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080461","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":"Beyond liver fibrosis: uncovering systemic risk in MASLD.","authors":"Umberto Vespasiani-Gentilucci, Stefano Romeo","doi":"10.1136/gutjnl-2026-340069","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340069","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080450","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":"Reply to 'DR1-DR2 enrichment in HBeAg-negative chronic hepatitis B: integration hotspot or survivor signature?'","authors":"Daryl T-Y Lau, Ying-Hsiu Su, Haitao Guo","doi":"10.1136/gutjnl-2026-340701","DOIUrl":"10.1136/gutjnl-2026-340701","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080459","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":"EUropean consensus on the Resolution Of SympToms After oesophago-gastric Resection (EUROSTAR): Peri-Operative Quality Initiative (POQI) consensus statement","authors":"Sowrav Barman,Mickael Chevallay,Suzanne S Gisbertz,Mieke Van Hemelrijck,Ben E Byrne,Bas Wijnhoven,Sheraz Markar,Jessie A Elliott,Jan Bornschein,Mark Pritchard,Magnus Nilsson,Donald Low,Christian Alexander Gutschow,Jason M Dunn,Sebastian Zeki,Sam H Ahmedzai,Barry Laird,Jafar Jafari,Orla Evans,Christopher J Peters,Pernilla Lagergren,Jesper Lagergren,Manuel Pera Roman,Maria Dolors Muns Cornellas,Fiona Huddy,Anthony Hobson,Zainab Noor,Andrew J Cockbain,Fredrik Klevebro,Louis Fox,Charlotte Moss,Kellie Owen,Anne-Margrethe Phillips,Chantal T Hoen,Elizabeth Ward,Cathy White,Mark I van Berge Henegouwen,Stefan Mönig,Loes Noteboom,Kiran Purushothaman,Thibaud Koessler,Marcel André Schneider,Gwen Masclee,Christian Geroin,Jacopo Weindelmayer,Silvia Lazzaris,Misha Luyer,Jakob Hedberg,Visvakanth Sivanathan,John Reynolds,Arnulf H Hölscher,Guillaume Piessen,Timothy E Miller,Mike Grocott,Jervoise Andreyev,Andrew Davies","doi":"10.1136/gutjnl-2025-337109","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337109","url":null,"abstract":"Background Symptoms after upper gastrointestinal (UGI) cancer surgery are common, frequently overlap, and can substantially affect quality of life. Despite increasing recognition of this problem, there is limited standardisation in the definition, investigation and management of the postoperative conditions responsible for these symptoms. Methods A society-endorsed, European-wide series of consensus meetings was conducted using a modified Delphi process developed by the PeriOperative Quality Initiative (POQI). A multidisciplinary panel of experts from 10 European countries, selected for their expertise in UGI cancer survivorship, participated in the development of consensus-based recommendations for symptoms following major UGI cancer surgery. Independent oversight was provided by POQI, and statements and recommendations were graded using a modified GRADE methodology informed by a comprehensive literature review. Results A total of 8 statements and 13 recommendations relating to symptom monitoring and service provision after major UGI cancer surgery were developed, refined and agreed upon through a preliminary meeting and two semistructured POQI consensus meetings. Diagnostic criteria, investigation pathways and management recommendations for the common postoperative conditions encountered after UGI cancer surgery were also developed and refined through multidisciplinary discussion before achieving consensus. 16 future research priorities were identified. Conclusions The EUROSTAR consensus provides guidance on symptom monitoring, service provision and the investigation and management of common postoperative conditions following UGI cancer surgery. These recommendations represent an important step towards standardising survivorship care and supporting future research in this patient population.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"9 1","pages":"gutjnl-2025-337109"},"PeriodicalIF":24.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049103","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":"Metastatic pancreatic cancer: from human disease to preclinical modelling.","authors":"Jimin Min, Vasiliki Liaki, Peter Y Yu, Carmen Guerra, Anirban Maitra","doi":"10.1136/gutjnl-2025-336334","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336334","url":null,"abstract":"<p><p>Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid cancers, portending poor patient outcomes due to challenges in precise diagnosis and therapeutic resistance. Extensive molecular heterogeneity of metastatic tumours and their frequent evasion from clinical detection represent critical bottlenecks in disease management. Despite substantial research efforts, optimal clinical management remains an ongoing challenge. In this review, we outline the current understanding of metastatic pancreatic cancer, including its clinical features in patients. Emerging evidence highlights the pivotal roles of dynamic interactions between cancer cells and organ-specific and niche-specific microenvironments during metastatic spread. We further summarise the known molecular characteristics of metastatic PDAC and the preclinical models developed in pancreatic cancer research for functional interrogation. Finally, based on the current knowledge of this disease, we discuss existing limitations and future opportunities for advancing precision oncology approaches. These efforts may open promising avenues for the development of more effective clinical strategies aimed at mitigating metastasis in PDAC.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038096","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":"Clarifying the clinical utility of extracellular-vesicle immune checkpoints in HCC.","authors":"Man Sun, Dan Zang, Jun Chen","doi":"10.1136/gutjnl-2026-340345","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340345","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038093","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":"Checkpoints in circulation: extracellular vesicles can predict immunotherapy response and resistance in hepatocellular carcinoma.","authors":"Moritz Peiseler, Bertram Bengsch","doi":"10.1136/gutjnl-2026-340093","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340093","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038044","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":"Expert consensus on clinical trials for use of systemic therapy in patients with hepatocellular carcinoma undergoing surgical and locoregional therapies.","authors":"Mark Yarchoan, Josep M Llovet, Robin Kate Kelley, Richard Finn, Neehar D Parikh, Parissa Tabrizian, Adam M Burgoyne, Vatche G Agopian, Nina N Sanford, Hop S Tran Cao, Siddharth A Padia, Arndt Vogel, Robert J Lewandowski, Garcia-Reyes Kirema, Ruitao Lin, Neil Mehta, Gonzalo Sapisochin, Adam Yopp, Augusto Villanueva, Karim Halazun, David J Pinato, Edward Kim, Julie K Heimbach, Anjana Pillai, Riad Salem, Anthony El-Khoueiry, Amit G Singal","doi":"10.1136/gutjnl-2026-339505","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339505","url":null,"abstract":"<p><strong>Background: </strong>Advances in systemic therapy for advanced hepatocellular carcinoma (HCC) have fuelled a growing interest in evaluating these therapies in earlier stages of disease. However, trial design remains challenging due to the marked clinical and biological heterogeneity of early-stage and intermediate-stage HCC.</p><p><strong>Objective: </strong>A multidisciplinary group of cancer experts was convened by the HCC-Live Consortium to discuss inclusion criteria, risk stratification, treatment arms and appropriate endpoints of trials evaluating perioperative and combination therapies in patients with HCC.</p><p><strong>Design: </strong>Consensus statements were defined as those obtaining >70% approval by panellists.</p><p><strong>Results: </strong>The panel achieved consensus regarding nine consensus statements for neoadjuvant or perioperative systemic therapy and nine statements for combination locoregional plus systemic therapy. Statements emphasised recruiting carefully selected patient populations, employing treatment strategies and duration that balance efficacy with safety and using clinically relevant endpoints. Trials evaluating neoadjuvant/perioperative approaches should include patients at the highest risk of recurrence, with a recommended primary outcome of 2-year event-free survival using restricted mean survival time. Trials evaluating combination therapies should include a homogeneous patient population and use an appropriate comparator arm that aligns with clinical practice. Specifically, systemic therapy was the recommended comparator arm for patients with larger tumour burden and locally advanced disease. The recommended primary outcome for combination trials was progression-free survival and overall survival, with an alpha-recycling strategy. Secondary endpoints are essential to inform clinical applicability.</p><p><strong>Conclusion: </strong>Optimal design of HCC trials is important to rigorously evaluate the role of systemic therapy in patients undergoing surgical resection or in combination with locoregional therapy.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038136","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}