Gut最新文献

{"title":"Butyrylcholinesterase alleviates hepatic stellate cell activation via paracrine muscarinic signalling","authors":"Le Tao,Nuoya Liu,Wei Zhang,Zongguo Yang,Wenya Xing,Liu Wu,Linqi Hou,Pingting Wei,Yuanyuan Xie,Wei Han,Yunqi Liu,Yesen Jin,Lianlian Xiang,Xuling Liu,Wenting Ma,Pingping Hu,Wei Li,Wenjun Zhou,Sai Wang,Hongzhuan Chen,Ping Liu,Dongmin Yin,Ying Li,Steven Dooley,Li Zhang,Jianrong Xu,Guang Ji,Cheng Liu","doi":"10.1136/gutjnl-2026-338932","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338932","url":null,"abstract":"Background Butyrylcholinesterase (BuChE) is a metabolic enzyme implicated in Alzheimer’s disease, detoxification and depression. Although reduced BuChE expression is recognised in cirrhosis, its functional role in fibrogenesis remains undefined. Objective We investigated whether BuChE regulates fibrosis by modulating acetylcholine (ACh) bioavailability and identified downstream cholinergic signalling. Design BuChE expression was assessed via qPCR and immunostaining in patient biopsies. Its contribution was studied using Buche ΔHep , Buche KI/KI-Hep mice, pharmacological inhibition, mutant BuChE conditioned medium and recombinant protein. ACh release and muscarinic ACh receptor (ChRM) function were measured using patch-clamp and calcium mobilisation assay; ChRM3 role was tested via Chrm3 ΔHSC mice and AAV6-mediated overexpression. Results BUCHE mRNA and serum activity are significantly downregulated in fibrotic patients and mice, correlating negatively with F stage and alpha-smooth muscle actin expression. BuChE is predominantly expressed in hepatocytes in the liver, which can be reduced by transforming growth factor beta or platelet-derived growth factor treatment, and its anti-fibrotic function requires enzymatic activity. Hepatocyte BuChE deletion or inhibition increases hepatic stellate cell (HSC) activation and fibrosis across multiple models, whereas overexpression is protective, establishing causality. Loss of BuChE leads to accumulation of unmetabolised ACh, which activates HSCs as a damage associated molecular pattern signal via ChRM3-NF-κB signalling. Chrm3 ΔHSC mice exhibit attenuated HSC activation and fibrosis, whereas Chrm3 overexpression promotes fibrogenesis. Conclusion Hepatocyte injury disrupts BuChE activity, causing local ACh accumulation and subsequent HSC activation via ChRM3 signalling. This newly identified cholinergic circuit drives fibrosis and represents a druggable target for therapeutic intervention.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"31 1","pages":"gutjnl-2026-338932"},"PeriodicalIF":24.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020417","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":"Incidental duodenal lesions found in a patient being investigated for reflux and abdominal pain","authors":"David Leonard,Joshua Lewis,Roxanna Zakeri,Rami Sweis,Kirit Ardeshna,Marnix Jansen,Vinay Sehgal","doi":"10.1136/gutjnl-2026-340539","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340539","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"1 1","pages":"gutjnl-2026-340539"},"PeriodicalIF":24.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020416","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":"Integrative multi-omics landscape and diagnostic-therapeutic modelling of steatohepatitic hepatocellular carcinoma","authors":"Laizhu Zhang,Chaobo Chen,Yanchao Xu,Yuchen Zhang,Huan Li,Jingyuan Wen,Yajing Yang,Yunzheng Li,Yican Zhu,Weiwei Zong,Yukun Zhang,Tianming Chen,Chu Qiao,Bo Ran,Jialin Gao,Bing Han,Yue Hu,Chun Xu,Jun Chen,Xiaoli Mai,Jun Chen,Donglin Liu,Leizhou Xia,Jianhua Rao,Wajahat Mehal,Binghua Li,Decai Yu","doi":"10.1136/gutjnl-2026-339304","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339304","url":null,"abstract":"Background Steatohepatitic hepatocellular carcinoma (SH-HCC) is a distinct subtype of hepatocellular carcinoma with poorly defined molecular features and limited diagnostic and therapeutic strategies. Objective This study aimed to delineate its multi-omics landscape, develop non-invasive diagnostic tools and identify actionable therapeutic targets. Design We integrated multimodal clinical and omics datasets from an overall cohort of 156 patients, including RNA-seq (n=69), spatial transcriptomics (n=36), spatial metabolomics (n=6), lipidomics (n=125) and serum proteomics (n=152), for comprehensive molecular profiling and diagnostic model construction. FABP4 was functionally validated in Sleeping Beauty-induced HCC mouse models. Results An SH-HCC index was established to reliably differentiate SH-HCC from conventional HCC. Drug response analysis suggested a potential reduction in responsiveness to sorafenib and immunotherapy-based regimens in SH-HCC, whereas transarterial chemoembolisation may remain an effective therapeutic option. Spatial transcriptomics revealed increased immune cell infiltration, a reinforced immune barrier and reduced tumour-immune cell communication. SH-HCC is characterised by a lipid-rich phenotype, and a diagnostic model based on 12 lipid species showed good performance in an independent cohort (area under the curve (AUC)=0.909). Serum proteomic model demonstrated good performance in the test cohort (AUC=0.828). Importantly, our preliminary findings suggest a potential therapeutic role for FABP4, as its genetic deletion suppressed tumour growth, reshaped the tumour immune microenvironment and enhanced the response to PD-1 blockade. Conclusion This study provides the first multi-omics characterisation of SH-HCC, highlighting the SH-HCC index and non-invasive diagnostic models, with FABP4 as a potential target.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"28 1","pages":"gutjnl-2026-339304"},"PeriodicalIF":24.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020420","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":"Persistent visual disturbance during rescue therapy for acute severe UC","authors":"Joel Thio,Hugh Eigeland,Andrew Groundwater,Thomas Smart,Aoife O’Sullivan,Xiaohua Chen,Gareth Walker","doi":"10.1136/gutjnl-2026-340266","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340266","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"1 1","pages":"gutjnl-2026-340266"},"PeriodicalIF":24.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020419","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-nucleus transcriptomics refine the hepatic cellular context of the MASLD proteosurvival signature","authors":"Jingxiang Zhang,Mingyuan Zhang,Dulguun Juramt,Wei Qi,Zhijie Feng,Lanlan Chen","doi":"10.1136/gutjnl-2026-340378","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340378","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"126 1","pages":"gutjnl-2026-340378"},"PeriodicalIF":24.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020418","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":"Cryptogenic steatotic liver disease: the peril of categorical thresholds in diverse populations","authors":"Harjot Singh,Jasvinder Nain,Naveen Bhagat,Arka De,Ajay Duseja","doi":"10.1136/gutjnl-2026-340611","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340611","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"23 1","pages":"gutjnl-2026-340611"},"PeriodicalIF":24.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022286","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":"Rapid skeletal muscle loss in cirrhosis: the 'silent killer' within CT imaging.","authors":"Matthew J Armstrong, Felicity R Williams","doi":"10.1136/gutjnl-2026-340144","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340144","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016786","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":"Prior endoscopic surveillance and diagnosis of Barrett-related dysplasia and cancer: evidence from a nationwide Dutch cohort.","authors":"Laura Sophie Boer, Matthijs Han, Alaa Alkhalaf, Lorenza Alvarez Herrero, Jacques J G H M Bergman, Lodewijk A A Brosens, Wouter Curvers, Richard van Hillegersberg, Martin H M G Houben, Pieter Jan Floris de Jonge, Arjun D Koch, Wouter B Nagengast, Roos E Pouw, Jelle Ruurda, Erik J Schoon, Jessie Westerhof, Bas L A M Weusten, Sanne van Munster","doi":"10.1136/gutjnl-2025-337477","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337477","url":null,"abstract":"<p><strong>Background: </strong>In patients with Barrett oesophagus (BE), surveillance aims to detect dysplasia or oesophageal adenocarcinoma (EAC) early. Whether most asymptomatic patients undergoing endoscopic treatment are identified through surveillance remains uncertain.</p><p><strong>Objective: </strong>To assess the contribution of surveillance to the diagnosis of dysplasia and cancer.</p><p><strong>Design: </strong>Patients in the Netherlands with curative treatment for BE-related dysplasia or EAC between 2008 and 2018 were identified from the Barrett Expert Center Registry for endoscopic therapy and the Cancer Registry for surgery or chemoradiotherapy. Endoscopy history was based on pathology reports, with at least one endoscopy with non-dysplastic BE 1-5 years before treatment. Primary endpoint was the proportion of patients with dysplasia or EAC with and without ('de novo patients') prior endoscopies.</p><p><strong>Results: </strong>In total, 8914 patients were included: 90% (95% CI 89% to 91%; 8025/8914) presented de novo, while 10% (95% CI 9% to 11%; 889/8914) had prior endoscopies (mean of 4/IQR 2-7). Overall, 65% had stage ≥II disease, mostly in the de novo group (stage ≥II: 70% de novo vs 11% with prior endoscopy; p<0.001). Two-thirds of endoscopically treated patients (65% (95% CI 62% to 67%); 1283/1989) presented de novo and 97% (95% CI 97% to 98%; 6742/6925) with non-endoscopic therapy. Among those with prior endoscopy, a low rate of missed advanced neoplasia was observed (11%; 96/889).</p><p><strong>Conclusion: </strong>In this nationwide cohort, 90% of patients with Barrett-related dysplasia and cancer and 65% undergoing organ-preserving endoscopic treatment had not undergone prior endoscopy. This underscores the need to evaluate whether targeted, evidence-based screening strategies can improve early detection and patient outcomes.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016763","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":"Persistent fever and refractory delayed gastric emptying after pancreaticoduodenectomy.","authors":"Yaozong Wang, Xiaoyuan Qiu, Kun He, Jiashu Han, Chen Lin, Weibin Wang","doi":"10.1136/gutjnl-2026-339308","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339308","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016825","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":"High rates of transition to immune active disease in a cohort of strictly defined immune tolerant patients with chronic hepatitis B: results from the RADICAL consortium.","authors":"Lisa M van Velsen, Won-Mook Choi, Mai Kilany, Norah A Terrault, Terry C F Yip, Karen Ho, Zillah Cargill, Gabriele Ricco, Sara Battistella, Marc G Ghany, Elena Vargas-Accarino, Stephanie Narguet, Özgür M Koc, Richard A J Post, Bettina E Hansen, Dirk Posthouwer, Tarik Asselah, Maria Buti, Sabela Lens, Maurizia R Brunetto, Kosh Agarwal, Wai-Kay Seto, Man-Fung Yuen, Grace L H Wong, Jordan J Feld, Yao-Chun Hsu, Young-Suk Lim, Milan J Sonneveld, Harry L A Janssen","doi":"10.1136/gutjnl-2026-338784","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338784","url":null,"abstract":"<p><strong>Background: </strong>Patients with immune tolerant (IT) chronic hepatitis B (CHB) have high viral loads, minimal inflammation and minimal fibrosis. Nevertheless, the benign nature of this phase and the need for antiviral therapy remain controversial.</p><p><strong>Objective: </strong>We explored the natural history of IT patients by assessing the risk of transition to immune active (IA) disease, fibrosis progression and hepatocellular carcinoma (HCC).</p><p><strong>Design: </strong>This international multicentre study from the RADICAL consortium includes mono-infected patients with CHB from sites around the world. The IT-phase was strictly defined as persistently (1) hepatitis B e-antigen (HBeAg)-positive, (2) alanine aminotransferase (ALT) ≤40 U/L, (3) HBV DNA >7 log₁₀ IU/mL and (4) F0-1 during the first year after baseline. We assessed the probabilities of transition to IA disease (ALT ≥50 U/L), the risk of significant fibrosis (≥F2) and HCC.</p><p><strong>Results: </strong>In total, 951 IT patients were included with a median age of 33, 40% were male with a median follow-up of 13 years. Median ALT and HBV DNA at baseline were 25.5 U/L and 8.4 log₁₀ IU/mL.The probability of transitioning to IA disease was 51%, 67% and 72% before 5 years, 10 years and 15 years. A high-normal ALT was associated with an increased risk of IA disease (subdistribution hazard ratio (sHR): 20-30 U/L: 1.744, p<0.001, sHR: >30U/L: 3.130, p<0.001). IT patients had a low risk of progression to significant fibrosis (15 years: 6.3%), and HCC (15 years: 1.1%).</p><p><strong>Conclusion: </strong>The majority of this large cohort of well-defined IT patients transition to IA disease within 5 years of follow-up, with the highest risk observed in those with a high-normal ALT, suggesting that these patients may benefit from either more frequent monitoring or pre-emptive therapy.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001734","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}