eGastroenterology最新文献

{"title":"Intestinal neutral ceramidase exacerbates MASH pathogenesis.","authors":"Ting Wang, Liang Chen, Chao Lei, Xiaotong Song, Amanguli Tuohongerbieke, Jing Feng, Regina Gasparetto, Xiang Zhang, Craig J McClain, Yi Tan, Zhongbin Deng","doi":"10.1136/egastro-2026-100417","DOIUrl":"10.1136/egastro-2026-100417","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease and its more severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH), are intimately linked to genetic factors, gut microbiota and barrier alteration. Ceramidases and ceramides are associated with MASH, yet the role of intestinal neutral ceramidase in MASH development remains unclear.</p><p><strong>Methods: </strong>Murine models with intestinal epithelial cell (IEC)-specific depletion of neutral ceramidase (<i>Asah2^ΔIEC</i> ) or aryl hydrocarbon receptor (<i>AhR</i> ^ΔIEC) were subjected to either a Western diet (WD) at 6 weeks old for 10-12 months to induce MASH, or a hydrogenated vegetable oil, sucrose, palmitate and cholesterol (HSPC) diet to accelerate MASH progression. Fecal microbiota transplantation was performed in germ-free mice.</p><p><strong>Results: </strong>MASH is associated with the induction of neutral ceramidase, which reshapes the intestinal microbiota and metabolite profiles, leading to increased production of 2-hydroxyhippuric acid (2-HHA). We identified 2-HHA as an inhibitor of AhR signalling, a pathway that normally promotes intestinal fucosylation. Elevated 2-HHA suppresses AhR activity, reduces fucosylation and contributes to MASH and associated airway inflammation in mice fed WD or HSPC diet. Notably, IEC-specific deletion of neutral ceramidase decreases 2-HHA levels, restores AhR signalling, enhances fucosylation and protects against MASH. Consistently, intestinal AhR deficiency exacerbates MASH by reducing intestinal fucosylation, whereas supplementation with fucoidan increases fucosylation, improves barrier function and attenuates MASH.</p><p><strong>Conclusions: </strong>These findings identify intestinal neutral ceramidase as a key driver of MASH through a microbiota-2-HHA-AhR axis that impairs intestinal fucosylation and barrier function, highlighting a potential therapeutic target.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100417"},"PeriodicalIF":10.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148392708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal neutral ceramidase, microbial metabolites and epithelial fucosylation in MASH.","authors":"Cristina Llorente","doi":"10.1136/egastro-2026-100458","DOIUrl":"10.1136/egastro-2026-100458","url":null,"abstract":"","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100458"},"PeriodicalIF":10.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148392650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy in HCC: aetiology matters.","authors":"Irene Oi-Lin Ng, Guoyue Lyu","doi":"10.1136/egastro-2026-100465","DOIUrl":"10.1136/egastro-2026-100465","url":null,"abstract":"","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100465"},"PeriodicalIF":10.5,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13223639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148152069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TERT rs10069690 variant is linked to reduced cholangiocarcinoma incidence but adverse prognosis in patients undergoing resection.","authors":"Isabella Lurje, Justus Pein, Paul Horn, Deniz Uluk, Marlene Kohlhepp, Minh Duc Phan, Saskia Niklisch, Frederik Schliephake, Niharika Jakhar, Kai Markus Schneider, Florian Roßner, David Horst, Johann Pratschke, Frank Tacke, Carolin Victoria Schneider, Georg Lurje","doi":"10.1136/egastro-2025-100320","DOIUrl":"10.1136/egastro-2025-100320","url":null,"abstract":"<p><strong>Background: </strong>Cholangiocarcinoma (CCA) is a rare cancer, with limited understanding of genetic and prognostic determinants. We aimed to explore genetic risk factors, assess their prognostic implications and evaluate associated systemic and intratumoral features.</p><p><strong>Methods: </strong>We screened the UK Biobank to identify single-nucleotide polymorphisms (SNPs) potentially associated with intrahepatic CCA (International Classification of Diseases, 10th Revision (ICD-10) code: C22.1). Candidate SNPs were genotyped in a real-life cohort of 221 patients undergoing liver resection for intrahepatic or perihilar CCA at Charité - Universitätsmedizin Berlin. Intratumoral gene expression and pathway co-expression were examined. Serum proteomic profiles were evaluated in patients with intrahepatic CCA and the overall population.</p><p><strong>Results: </strong>In exploratory analyses, the telomerase reverse transcriptase <i>(TERT)</i> rs10069690 T allele was associated with a reduced risk of intrahepatic CCA (T allele vs C/C homozygotes: adjusted OR 0.824 (95% CI 0.713 to 0.951), p=0.008). However, T allele carriers undergoing liver resection for CCA had independently shorter overall survival (OS) compared with C/C homozygotes (median OS 21 (17-25) months vs 31 (24-38) months, p=0.034, HR 1.427 (1.023-1.991)). In serum proteomic analyses of the general population, presence of the T allele was associated with differences in immune-related pathways, including signatures consistent with increased lymphocyte differentiation and reduced NK-cell-mediated cytotoxicity. In intrahepatic CCA tumours, higher <i>TERT</i> mRNA expression was positively correlated with gene expression patterns consistent with increased cell cycle activity and regulatory T cell signatures, and negatively associated with pathways of cell differentiation, adhesion and immune effector function.</p><p><strong>Conclusions: </strong>These exploratory, hypothesis-generating findings suggest that the <i>TERT</i> rs10069690 variant may be associated with intrahepatic CCA risk and clinical outcomes, as well as with immune-related and proliferative pathways. The observed context-dependent associations warrant independent validation and further functional investigation.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100320"},"PeriodicalIF":10.5,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13223632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148152138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From static labels to dynamic trajectories: MASLD-MetALD-ALD as a dynamic continuum within the framework of steatotic liver disease.","authors":"Lanlan Chen, Paul Horn, Frank Tacke","doi":"10.1136/egastro-2026-100430","DOIUrl":"10.1136/egastro-2026-100430","url":null,"abstract":"","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100430"},"PeriodicalIF":10.5,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Megamitochondria in alcohol-associated liver disease and cancer: a friend or foe?","authors":"Mengwei Niu, Xiaoli Wei, Xiaowen Ma, Wen-Xing Ding","doi":"10.1136/egastro-2026-100408","DOIUrl":"10.1136/egastro-2026-100408","url":null,"abstract":"","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100408"},"PeriodicalIF":10.5,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unified platform for multiplex immunofluorescence across liver tissues and engineered models.","authors":"Bianca Franco Leonardi, Guo Yin, Natalja Amiridze, Tian Lan, Yeni Ait Ahmed, Hilmar Berger, Frank Tacke, Marlene S Kohlhepp, Adrien Guillot","doi":"10.1136/egastro-2026-100379","DOIUrl":"10.1136/egastro-2026-100379","url":null,"abstract":"<p><strong>Background: </strong>Multiplex immunostaining combined with digital image analysis has become a central tool in hepatology research because it allows for the simultaneous visualisation and spatial mapping of multiple cellular markers within a single tissue section, providing critical insights into the complex, heterogeneous microenvironments of liver diseases like cholangiopathies, hepatocellular carcinoma, metabolic dysfunction-associated steatohepatitis or hepatic fibrosis. Nevertheless, significant barriers prevent the widespread adoption of most multiplexing platforms, including the technological complexity that necessitates specialised equipment and personnel. Additionally, several technologies remain incompatible with standard laboratory workflows and archival formalin-fixed paraffin-embedded (FFPE) tissue or in vitro culture samples.</p><p><strong>Methods: </strong>We developed a customised immunofluorescence workflow based on sequential cycles of antibody stripping to generate multiplexed digital images from FFPE liver sections, intrahepatic cholangiocyte organoids and primary mouse liver cells cultured either in conventional two-dimensional systems or within a biliary niche-on-a-chip platform. Subsequent image processing and channel alignment were performed using an in-house and open-source, Python-based software tool.</p><p><strong>Results: </strong>We demonstrate the functionality of a multiplex immunofluorescence protocol that can be readily adapted to a broad range of archival tissues and primary cell-based samples. This workflow allows the visualisation of antigen-expressing cells and protein-protein interactions using proximity ligation assays. This study also details the technical considerations necessary for its rapid integration into routine workflows in virtually any laboratory equipped for conventional immunohistochemistry.</p><p><strong>Conclusions: </strong>This methodology integrates multiplex immunofluorescence into standard laboratory workflows, thereby enabling researchers to overcome challenges such as technological complexity and cost for transitioning from conventional to multiplexed microscopy.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100379"},"PeriodicalIF":10.5,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13141115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extended precision cut liver slice culture models liver regeneration and ductular reaction.","authors":"Sofia Izunza Barba, Denisse Rubio-Cruz, Sehrish Naz, Shanshan Su, Susmita Bhattarai, Hua Xu, Imad Nasser, David Lee, Martin Dib, Amy Evenson, Vanessa Cowan, Vincenzo Villani, Devin Eckhoff, Alan Bonder, Abby Chu, Gyongyi Szabo, Z Gordon Jiang","doi":"10.1136/egastro-2026-100389","DOIUrl":"10.1136/egastro-2026-100389","url":null,"abstract":"","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100389"},"PeriodicalIF":10.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting gut immunity as a therapy for steatotic liver disease.","authors":"Rachel Yue Gao","doi":"10.1136/egastro-2026-100404","DOIUrl":"10.1136/egastro-2026-100404","url":null,"abstract":"","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 2","pages":"e100404"},"PeriodicalIF":10.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147790793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphoinositide kinase PIKfyve inhibitor apilimod blocks hepatitis E virus infection.","authors":"Julian J Ring, Sarah Schlienkamp, Maria L Goussain Darido, Xin Zhang, Olinda Pinto Veiga, Jil Alexandra Haase, Emely Richter, André Gömer, Rebecca Menhua Fu, Viet Loan Dao Thi, Rainer G Ulrich, Mara Klöhn, Daniel Todt, Verian Bader, Konstanze F Winklhofer, Volker Kinast, Johan Neyts, Suzanne J F Kaptein, Eike Steinmann, Yannick Brüggemann","doi":"10.1136/egastro-2025-100348","DOIUrl":"10.1136/egastro-2025-100348","url":null,"abstract":"<p><strong>Background: </strong>Hepatitis E virus (HEV) is a leading cause of viral hepatitis, yet treatment remains limited to the off-label use of ribavirin, which can have significant side effects and is not suitable for all patients, highlighting the need for new antiviral strategies. HEV infection depends on endolysosomal trafficking of virions to lysosomal compartments to initiate host cell entry. To deepen our understanding of the HEV infection cycle and support the development of novel antiviral strategies, we assessed the antiviral efficacy of compounds targeting components of the endocytic machinery.</p><p><strong>Methods: </strong>Using an established HEV cell culture model, we screened a panel of experimental and Food and Drug Administration-approved compounds targeting the endocytic pathway. Following the initial screen, the antiviral activity of apilimod was further characterised using infectivity assays, siRNA-mediated knockdown, time-of-addition experiments and mechanistic analyses of endolysosomal organisation and lysosomal protease activity. Efficacy was additionally evaluated in primary human hepatocytes and in a ratHEV infection model in vivo.</p><p><strong>Results: </strong>Five compounds (apilimod, raloxifen, verapamil, chloroquine and tamoxifen) inhibited HEV infection in a dose-dependent manner. The FYVE-type zinc finger containing phosphoinositide kinase (PIKfyve) inhibitor apilimod exhibited the highest antiviral potency. Requirement of PIKfyve for HEV infection was confirmed by siRNA knockdown, and time-of-addition assays demonstrated that apilimod acts during viral entry without affecting replication. Mechanistically, PIKfyve inhibition disrupted lysosomal organisation, impaired HEV trafficking to late endosomal/lysosomal compartments and reduced lysosomal cathepsin activity. Apilimod significantly reduced HEV infectivity in primary human hepatocytes and decreased viral RNA levels in faeces and tissues in a ratHEV infection model.</p><p><strong>Conclusion: </strong>Overall, our data suggest that the endolysosomal protein PIKfyve plays a crucial role during the entry of HEV. Considering the reported safety profile of apilimod in previous human clinical trials, the pharmacological targeting of PIKfyve kinase activity might guide novel antiviral strategies against HEV.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"4 1","pages":"e100348"},"PeriodicalIF":10.5,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13052532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147635336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}