Pub Date : 2026-03-23DOI: 10.1136/gutjnl-2026-338664
Tien Manh Huynh,Thinh Ong,Naveen Gautam,Hung Song Nguyen
{"title":"Refining intergenerational MASLD risk: are measurement and mediation shaping the signal?","authors":"Tien Manh Huynh,Thinh Ong,Naveen Gautam,Hung Song Nguyen","doi":"10.1136/gutjnl-2026-338664","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338664","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"146 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502502","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}
BACKGROUNDPrimary sclerosing cholangitis-associated UC (PSC-UC) carries excess colorectal neoplasia despite often mild-appearing endoscopy, implicating persistent microscopic inflammation and microbiota-bile acid (BA) dysfunction.OBJECTIVETo test whether PSC-UC neoplasia is driven by transferable microbiota-mediated inflammation linked to secondary BA loss.DESIGNSurveillance colonoscopies (2012-2022) from PSC-UC (n=251) and UC-only (n=8839) were compared for segmental endoscopic/histological activity and dysplasia. We generated multidrug resistance protein 2 (MDR2)-/- × interleukin (IL)-10-/- double-knockout (DKO) mice and used germ-free (GF) derivation, faecal microbiota transplantation (FMT), antibiotic conditioning and cohousing with shotgun metagenomics and liquid chromatography-tandem mass spectrometry BA profiling.RESULTSPSC-UC showed greater inflammatory activity and a right-shifted dysplasia burden versus UC-only. Under specific-pathogen-free conditions, DKO mice developed early right-predominant colitis and multifocal dysplasia progressing with age. DKO communities were depleted of 7α-dehydroxylation capacity with near absence of deoxycholic and lithocholic acids and no enrichment of canonical bacterial genotoxins. GF DKO mice were protected, whereas live DKO donor FMT reinstated severe colitis and dysplasia; sterile-filtered stool supernatant was inactive. IL-10-/- donor FMT or cohousing attenuated colitis and increased recipient secondary BA, whereas wild-type/MDR2-/- donor transfers were non-colitogenic. In GF DKO mice, direct deoxycholic acid repletion caused hepatotoxicity.CONCLUSIONPSC-UC neoplasia associates with transmissible microbiota-dependent inflammation and secondary BA deficiency. Controlled restoration of BA-transforming microbial functions, rather than indiscriminate secondary BA replacement, is a rational translational direction.
{"title":"Dysbiotic microbiota trigger colitis-associated colorectal cancer and imprint a distinctive bile acid profile in a PSC-IBD model.","authors":"Muyiwa Awoniyi,Mohamed El Hag,Josue Hernandez,Qijun Yang,Nicholas Evans,Ina Nemet,Billy Ngo,Deniz Coskuner,Julie Zhou,Morgan Farmer,Lianyong Su,Huiping Zhou,Jeffery Roach,Thaddeus Stappenbeck,R Balfour Sartor","doi":"10.1136/gutjnl-2025-336675","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336675","url":null,"abstract":"BACKGROUNDPrimary sclerosing cholangitis-associated UC (PSC-UC) carries excess colorectal neoplasia despite often mild-appearing endoscopy, implicating persistent microscopic inflammation and microbiota-bile acid (BA) dysfunction.OBJECTIVETo test whether PSC-UC neoplasia is driven by transferable microbiota-mediated inflammation linked to secondary BA loss.DESIGNSurveillance colonoscopies (2012-2022) from PSC-UC (n=251) and UC-only (n=8839) were compared for segmental endoscopic/histological activity and dysplasia. We generated multidrug resistance protein 2 (MDR2)-/- × interleukin (IL)-10-/- double-knockout (DKO) mice and used germ-free (GF) derivation, faecal microbiota transplantation (FMT), antibiotic conditioning and cohousing with shotgun metagenomics and liquid chromatography-tandem mass spectrometry BA profiling.RESULTSPSC-UC showed greater inflammatory activity and a right-shifted dysplasia burden versus UC-only. Under specific-pathogen-free conditions, DKO mice developed early right-predominant colitis and multifocal dysplasia progressing with age. DKO communities were depleted of 7α-dehydroxylation capacity with near absence of deoxycholic and lithocholic acids and no enrichment of canonical bacterial genotoxins. GF DKO mice were protected, whereas live DKO donor FMT reinstated severe colitis and dysplasia; sterile-filtered stool supernatant was inactive. IL-10-/- donor FMT or cohousing attenuated colitis and increased recipient secondary BA, whereas wild-type/MDR2-/- donor transfers were non-colitogenic. In GF DKO mice, direct deoxycholic acid repletion caused hepatotoxicity.CONCLUSIONPSC-UC neoplasia associates with transmissible microbiota-dependent inflammation and secondary BA deficiency. Controlled restoration of BA-transforming microbial functions, rather than indiscriminate secondary BA replacement, is a rational translational direction.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"27 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502505","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":"Rectal lesion with a submucosal tumour-like appearance in a middle-aged woman.","authors":"Shigeki Otani,Shin-Ei Kudo,Yasuharu Maeda,Katsuro Ichimasa,Masashi Misawa,Taishi Okumura","doi":"10.1136/gutjnl-2026-338551","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338551","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"19 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502503","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}
Pub Date : 2026-03-23DOI: 10.1136/gutjnl-2025-337436
Jorge F Vázquez-Castellanos,Sang Jun Yoon,Sung-Min Won,Jeroen Raes,Hak Cheol Kwon,Jiyeon Si,Ki Tae Suk
BACKGROUNDThe gut-liver axis plays a critical role in liver disease progression; however, how gut microbial ecology and function vary across disease stages remains unclear.OBJECTIVETo define stage-specific microbial and functional signatures and evaluate their diagnostic potential.DESIGNWe analysed faecal samples from 1168 individuals spanning healthy controls, fatty liver, hepatitis, cirrhosis and hepatocellular carcinoma by 16S rRNA sequencing, with a subset (n=141) profiled by shotgun metagenomics. To increase statistical power and enable external validation, 2376 publicly available metagenomic datasets, including 734 liver-related, were integrated. Machine learning-based multicohort analysis was used to identify microbial biomarkers, assess risk factors and classify disease stages.RESULTSMicrobial diversity declined and a low-richness enterotype expanded with disease severity. Machine learning revealed a discordance in hepatitis, which lacked taxonomic markers but was defined by a conserved functional signature of biosynthetic upregulation. In contrast, advanced stages featured consistent markers like Ligilactobacillus and Veillonella, with strain-level evidence confirming oral-gut transmission. Functional profiling delineated a metabolic continuum from anabolic precursor synthesis in hepatitis to virulence factor production in cirrhosis and putrefactive metabolism in carcinoma. Comparative analysis confirmed that these signatures were distinct from those in non-liver metabolic and oncologic disorders. Importantly, the expansion of oral-derived Veillonella spp and the low-richness enterotype were significantly associated with increased mortality.CONCLUSIONThis large-scale study delineates stage-dependent ecological and functional remodelling of the gut microbiome across liver diseases. These findings highlight the potential of microbiome-based markers for non-invasive diagnosis and prognostic risk stratification in liver diseases.
{"title":"Stage-dependent gut microbiome and functional signatures across the liver disease spectrum: an integrative multicohort study.","authors":"Jorge F Vázquez-Castellanos,Sang Jun Yoon,Sung-Min Won,Jeroen Raes,Hak Cheol Kwon,Jiyeon Si,Ki Tae Suk","doi":"10.1136/gutjnl-2025-337436","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337436","url":null,"abstract":"BACKGROUNDThe gut-liver axis plays a critical role in liver disease progression; however, how gut microbial ecology and function vary across disease stages remains unclear.OBJECTIVETo define stage-specific microbial and functional signatures and evaluate their diagnostic potential.DESIGNWe analysed faecal samples from 1168 individuals spanning healthy controls, fatty liver, hepatitis, cirrhosis and hepatocellular carcinoma by 16S rRNA sequencing, with a subset (n=141) profiled by shotgun metagenomics. To increase statistical power and enable external validation, 2376 publicly available metagenomic datasets, including 734 liver-related, were integrated. Machine learning-based multicohort analysis was used to identify microbial biomarkers, assess risk factors and classify disease stages.RESULTSMicrobial diversity declined and a low-richness enterotype expanded with disease severity. Machine learning revealed a discordance in hepatitis, which lacked taxonomic markers but was defined by a conserved functional signature of biosynthetic upregulation. In contrast, advanced stages featured consistent markers like Ligilactobacillus and Veillonella, with strain-level evidence confirming oral-gut transmission. Functional profiling delineated a metabolic continuum from anabolic precursor synthesis in hepatitis to virulence factor production in cirrhosis and putrefactive metabolism in carcinoma. Comparative analysis confirmed that these signatures were distinct from those in non-liver metabolic and oncologic disorders. Importantly, the expansion of oral-derived Veillonella spp and the low-richness enterotype were significantly associated with increased mortality.CONCLUSIONThis large-scale study delineates stage-dependent ecological and functional remodelling of the gut microbiome across liver diseases. These findings highlight the potential of microbiome-based markers for non-invasive diagnosis and prognostic risk stratification in liver diseases.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"17 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502501","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}
Pub Date : 2026-03-19DOI: 10.1136/gutjnl-2025-337579
Virag Gehl,Colm J O'Rourke,Martin Cornillet,Orestis Nousias,Achilleas Fardellas,Supaporn Yangngam,Magdalena Rogalska-Taranta,Blanca I Aldana,Dan Hogdall,Jens U Marquardt,Niklas K Björkström,Jesper B Andersen
BACKGROUNDHigh serum levels of interleukin 6 (IL-6) predict poor prognosis in intrahepatic cholangiocarcinoma (iCCA), a malignancy that often develops in a chronically inflamed milieu. Here, tumour cells are capable of autonomously producing and engaging autocrine IL-6 signalling, yet the consequences of this remain unknown.OBJECTIVEThis study aims to explore the intracellular and intercellular consequences of sustained, tumour-derived IL-6 signalling.DESIGNWe generated CRISPR-activated IL-6high patient-derived iCCA cell models and characterised them using RNA-sequencing and secretome analysis. Therapeutic vulnerabilities were determined with high-throughput drug screening, while the impact of tumour-conditioned media on the phenotype and function of circulating immune cells was assessed with high-dimensional flow cytometry. Spatial transcriptomic analysis (Visium HD) was performed on 14 resected tumours to quantify tumour-derived IL6 expression, cell type composition and ligand-receptor interactions in the tumour microenvironment.RESULTSChronic IL-6 signalling drives distinct transcriptional programmes, metabolic vulnerabilities and immunomodulatory effects. IL-6high tumour cells confer sensitivity to nicotinamide phosphoribosyltransferase inhibition, leading to disrupted mitochondrial fitness and selective IL-6 downregulation. Chronic IL-6 signalling also alters the tumour secretome, which modulates immune cell composition and impairs cellular function, including the suppression of MER proto-oncogene tyrosine kinase-mediated macrophage efferocytosis. Spatial transcriptomic analysis confirms that tumour IL6 expression correlates with myeloid cell depletion, cancer-associated fibroblast (CAF) enrichment and enhanced tumour-CAF communication.CONCLUSIONSThese findings uncover a multifaceted role for IL-6 in shaping tumour-intrinsic, microenvironmental and macroenvironmental features, revealing novel molecular mechanisms and potential therapeutic vulnerabilities in iCCA.
{"title":"Molecular and cellular consequences of tumour-autonomous IL-6 signalling in intrahepatic cholangiocarcinoma.","authors":"Virag Gehl,Colm J O'Rourke,Martin Cornillet,Orestis Nousias,Achilleas Fardellas,Supaporn Yangngam,Magdalena Rogalska-Taranta,Blanca I Aldana,Dan Hogdall,Jens U Marquardt,Niklas K Björkström,Jesper B Andersen","doi":"10.1136/gutjnl-2025-337579","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337579","url":null,"abstract":"BACKGROUNDHigh serum levels of interleukin 6 (IL-6) predict poor prognosis in intrahepatic cholangiocarcinoma (iCCA), a malignancy that often develops in a chronically inflamed milieu. Here, tumour cells are capable of autonomously producing and engaging autocrine IL-6 signalling, yet the consequences of this remain unknown.OBJECTIVEThis study aims to explore the intracellular and intercellular consequences of sustained, tumour-derived IL-6 signalling.DESIGNWe generated CRISPR-activated IL-6high patient-derived iCCA cell models and characterised them using RNA-sequencing and secretome analysis. Therapeutic vulnerabilities were determined with high-throughput drug screening, while the impact of tumour-conditioned media on the phenotype and function of circulating immune cells was assessed with high-dimensional flow cytometry. Spatial transcriptomic analysis (Visium HD) was performed on 14 resected tumours to quantify tumour-derived IL6 expression, cell type composition and ligand-receptor interactions in the tumour microenvironment.RESULTSChronic IL-6 signalling drives distinct transcriptional programmes, metabolic vulnerabilities and immunomodulatory effects. IL-6high tumour cells confer sensitivity to nicotinamide phosphoribosyltransferase inhibition, leading to disrupted mitochondrial fitness and selective IL-6 downregulation. Chronic IL-6 signalling also alters the tumour secretome, which modulates immune cell composition and impairs cellular function, including the suppression of MER proto-oncogene tyrosine kinase-mediated macrophage efferocytosis. Spatial transcriptomic analysis confirms that tumour IL6 expression correlates with myeloid cell depletion, cancer-associated fibroblast (CAF) enrichment and enhanced tumour-CAF communication.CONCLUSIONSThese findings uncover a multifaceted role for IL-6 in shaping tumour-intrinsic, microenvironmental and macroenvironmental features, revealing novel molecular mechanisms and potential therapeutic vulnerabilities in iCCA.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"13 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483640","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}
BACKGROUNDSurvival outcomes after transarterial chemoembolisation (TACE) vary in hepatocellular carcinoma (HCC) patients, and existing prognostic scores and imaging models often lack generalisability and biological interpretability.OBJECTIVETo develop and validate a multimodal prognostication model for HCC that allows for a precise assessment of survival outcomes of HCC patients receiving TACE therapy.DESIGNThis study enrolled 1448 HCC patients, including a TACE cohort (n=1349), a biomarker subset from a randomised trial (n=41), a single-cell RNA sequencing cohort and The Cancer Genome Atlas (TCGA) HCC cohort (n=50). Pre-treatment contrast-enhanced CT images were used to construct deep learning and conventional radiomic models. The early-fusion and late-fusion models (LFMs) were compared, and a clinical-radiologic model (CRM) was formed by integrating the better-performing LFM with clinical variables. Using TCGA data and single-cell transcriptomic profiles, the differences between high-score and low-score groups in tumour immune microenvironment, cellular functional states and key signalling pathways were investigated.RESULTSThe CRM effectively stratified patients' survival across multiple independent cohorts and achieved more granular risk stratification than the existing clinical models. Multi-omic analyses revealed that in the LFM high-score group, myelocytomatosis oncogene was activated, epithelial-mesenchymal transition enhanced, glycolysis upregulated and hypoxia pathway activated. Single-cell transcriptomic data confirmed that virtually all cell types in high-risk patients scored high in hypoxia, and cytotoxic T cells had a reduced cytotoxic activity.CONCLUSIONThe CRM model can non-invasively predict the prognosis of HCC patients treated by TACE therapy.
{"title":"Hypoxia-related and immune phenotype-related fusion model for non-invasive prognostication of hepatocellular carcinoma treated by TACE: a multicentre study.","authors":"Yusheng Guo,Guilin Zhang,Xiaona Fu,Shanshan Jiang,Yi Li,Shanmei Li,Xiaofang Guo,Xiaolin Zhang,Chang Zhao,Rong Ding,Lei Yu,Xuegang Yang,Kai Zhao,Yuxin Sun,QiuPing Liu,YuDong Zhang,Xuhua Duan,Hui Zhao,Jiahua Zou,Bin Liang,Lian Yang,Chuansheng Zheng,Xuefeng Kan","doi":"10.1136/gutjnl-2025-337938","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337938","url":null,"abstract":"BACKGROUNDSurvival outcomes after transarterial chemoembolisation (TACE) vary in hepatocellular carcinoma (HCC) patients, and existing prognostic scores and imaging models often lack generalisability and biological interpretability.OBJECTIVETo develop and validate a multimodal prognostication model for HCC that allows for a precise assessment of survival outcomes of HCC patients receiving TACE therapy.DESIGNThis study enrolled 1448 HCC patients, including a TACE cohort (n=1349), a biomarker subset from a randomised trial (n=41), a single-cell RNA sequencing cohort and The Cancer Genome Atlas (TCGA) HCC cohort (n=50). Pre-treatment contrast-enhanced CT images were used to construct deep learning and conventional radiomic models. The early-fusion and late-fusion models (LFMs) were compared, and a clinical-radiologic model (CRM) was formed by integrating the better-performing LFM with clinical variables. Using TCGA data and single-cell transcriptomic profiles, the differences between high-score and low-score groups in tumour immune microenvironment, cellular functional states and key signalling pathways were investigated.RESULTSThe CRM effectively stratified patients' survival across multiple independent cohorts and achieved more granular risk stratification than the existing clinical models. Multi-omic analyses revealed that in the LFM high-score group, myelocytomatosis oncogene was activated, epithelial-mesenchymal transition enhanced, glycolysis upregulated and hypoxia pathway activated. Single-cell transcriptomic data confirmed that virtually all cell types in high-risk patients scored high in hypoxia, and cytotoxic T cells had a reduced cytotoxic activity.CONCLUSIONThe CRM model can non-invasively predict the prognosis of HCC patients treated by TACE therapy.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"57 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483638","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}
Pub Date : 2026-03-19DOI: 10.1136/gutjnl-2025-336377
Klaus Peter Janssen,Marijana Basic,Silvia Bolsega,Amira Metwaly,Florian Jokisch,Sophia von Gamm,Josef Scheiber,Ralph Burkhardt,Gerhard Liebisch,Klaus Neuhaus,Sarah Brunner,Thomas Clavel,Esther Wortmann,Olivia I Coleman,Dirk Haller,Andre Bleich,Sabrina Krautbauer,Josef Ecker
BACKGROUNDColorectal cancer (CRC) exhibits increased levels of arachidonic acid-derived pro-inflammatory derivatives indicating an uptake of dietary polyunsaturated fatty acids (PUFAs).OBJECTIVEWe aimed to investigate uptake of extrinsic fatty acids (FAs) in tumours and their relevance for CRC lipid metabolism and progression.DESIGNTotal FAs were quantified using gas chromatography-mass spectrometry in non-diseased mucosa and tumour tissue from patients with CRC of a discovery cohort (n=152), validated in an independent cohort (n=28) and associated with clinical, genomic and microbiome data. The genetic mouse tumour model Apc1638N was used to track the flux of stable isotope-labelled FAs in tumours from the intestinal lumen. The relationship between FA uptake and tumour progression was investigated in 2D and 3D cell models.RESULTSExtrinsic long chain PUFAs, including arachidonic acid, accumulate in CRC, particularly in right-sided tumours, and in tumours of Apc1638N mice. The CRC-specific FA profiles were independent of sex, molecular subtypes, early-disease or late-disease onset. The absorption of FAs from the intestinal lumen in tumours was confirmed in specific pathogen-free Apc1638N mice. In the absence of the microbiome, in germ-free Apc1638N mice, fewer tumours were developed, and survival was increased. Inhibition of FA import or β-oxidation reduces cancer cell proliferation.CONCLUSIONExtrinsic FAs accumulate in CRC, verifying a central role of arachidonic acid-derived inflammatory mediators, but also suggesting a relevance of dietary FAs for cancer cell proliferation. It will be intriguing to explore to what extent targeting this flux pathway together with the interrelated microbiome opens new therapeutic avenues for CRC in humans.
{"title":"Extrinsic lipids are absorbed and accumulate in colorectal cancer.","authors":"Klaus Peter Janssen,Marijana Basic,Silvia Bolsega,Amira Metwaly,Florian Jokisch,Sophia von Gamm,Josef Scheiber,Ralph Burkhardt,Gerhard Liebisch,Klaus Neuhaus,Sarah Brunner,Thomas Clavel,Esther Wortmann,Olivia I Coleman,Dirk Haller,Andre Bleich,Sabrina Krautbauer,Josef Ecker","doi":"10.1136/gutjnl-2025-336377","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336377","url":null,"abstract":"BACKGROUNDColorectal cancer (CRC) exhibits increased levels of arachidonic acid-derived pro-inflammatory derivatives indicating an uptake of dietary polyunsaturated fatty acids (PUFAs).OBJECTIVEWe aimed to investigate uptake of extrinsic fatty acids (FAs) in tumours and their relevance for CRC lipid metabolism and progression.DESIGNTotal FAs were quantified using gas chromatography-mass spectrometry in non-diseased mucosa and tumour tissue from patients with CRC of a discovery cohort (n=152), validated in an independent cohort (n=28) and associated with clinical, genomic and microbiome data. The genetic mouse tumour model Apc1638N was used to track the flux of stable isotope-labelled FAs in tumours from the intestinal lumen. The relationship between FA uptake and tumour progression was investigated in 2D and 3D cell models.RESULTSExtrinsic long chain PUFAs, including arachidonic acid, accumulate in CRC, particularly in right-sided tumours, and in tumours of Apc1638N mice. The CRC-specific FA profiles were independent of sex, molecular subtypes, early-disease or late-disease onset. The absorption of FAs from the intestinal lumen in tumours was confirmed in specific pathogen-free Apc1638N mice. In the absence of the microbiome, in germ-free Apc1638N mice, fewer tumours were developed, and survival was increased. Inhibition of FA import or β-oxidation reduces cancer cell proliferation.CONCLUSIONExtrinsic FAs accumulate in CRC, verifying a central role of arachidonic acid-derived inflammatory mediators, but also suggesting a relevance of dietary FAs for cancer cell proliferation. It will be intriguing to explore to what extent targeting this flux pathway together with the interrelated microbiome opens new therapeutic avenues for CRC in humans.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"12 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483785","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}
BACKGROUNDThe tumour-stroma ratio (TSR) is a potential prognostic indicator, yet hindered by quantification challenges and conflicting reports.OBJECTIVETo determine whether TSR follows a non-linear prognostic pattern and to develop an artificial intelligence (AI)-powered framework for standardised TSR assessment and prognosis prediction in hepatocellular carcinoma (HCC).DESIGNWe integrated whole-slide image (WSI) data with clinical variables across a retrospective cohort (n=392) and The Cancer Genome Atlas dataset (n=168). Restricted cubic splines were used to interrogate non-linear hazard dynamics, with biological validation via transcriptomics and immunohistochemistry. An AI-driven foundation model framework was developed for TSR quantification and multimodal prognostic modelling.RESULTSOur analysis unveiled an inverted U-shaped non-linear relationship between TSR and mortality, identifying a risk initiation threshold at 0.188 and a peak at 0.268. Transcriptomics analysis indicated that this high-risk phenotype is characterised by active tumour proliferation, stromal activation and tumour microenvironment crosstalk. Technically, AI-derived TSR showed strong correlation with expert assessment (R² >0.9). Furthermore, we developed a novel 'Token-Guided Multimodal Fusion' architecture to integrate WSI, TSR and clinical variables as high-dimensional tokens directly into the computational logic. Consequently, our multimodal framework demonstrated prognostic accuracy (area under the curve >0.80) compared with unimodal baselines.CONCLUSIONThis study redefines TSR assessment, shifting from manual estimation to high-dimensional semantic reasoning. By identifying the non-linear prognostic mechanics of the stroma, our token-guided framework offers a biologically interpretable solution for HCC. We suggest that the future of computational pathology may lie not in simple quantification, but in the semantic fusion of human domain knowledge with AI reasoning.
{"title":"Token-guided multimodal prognosis in hepatocellular carcinoma: a framework steered by tumour-stroma ratio.","authors":"He-Yu Huang,Kun Wu,Li-Mei Qu,Xiao-Dong Sun,Ming-Yue Li,Feng Wei,Ping Zhang,Alfred Wei Chieh Kow,Yu-Guo Chen,Mei-Shan Jin,Liang Guo,Wei Qiu,Meng Wang,Xiao-Ju Shi,Jun-Feng Ye,Chuan-Hao Hu,Yue-Xuan Zhao,Yu Huang,Zhong-Qi Fan,Yu-Shan Zheng,Feng-Ying Xie,Guo-Yue Lv","doi":"10.1136/gutjnl-2025-337945","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337945","url":null,"abstract":"BACKGROUNDThe tumour-stroma ratio (TSR) is a potential prognostic indicator, yet hindered by quantification challenges and conflicting reports.OBJECTIVETo determine whether TSR follows a non-linear prognostic pattern and to develop an artificial intelligence (AI)-powered framework for standardised TSR assessment and prognosis prediction in hepatocellular carcinoma (HCC).DESIGNWe integrated whole-slide image (WSI) data with clinical variables across a retrospective cohort (n=392) and The Cancer Genome Atlas dataset (n=168). Restricted cubic splines were used to interrogate non-linear hazard dynamics, with biological validation via transcriptomics and immunohistochemistry. An AI-driven foundation model framework was developed for TSR quantification and multimodal prognostic modelling.RESULTSOur analysis unveiled an inverted U-shaped non-linear relationship between TSR and mortality, identifying a risk initiation threshold at 0.188 and a peak at 0.268. Transcriptomics analysis indicated that this high-risk phenotype is characterised by active tumour proliferation, stromal activation and tumour microenvironment crosstalk. Technically, AI-derived TSR showed strong correlation with expert assessment (R² >0.9). Furthermore, we developed a novel 'Token-Guided Multimodal Fusion' architecture to integrate WSI, TSR and clinical variables as high-dimensional tokens directly into the computational logic. Consequently, our multimodal framework demonstrated prognostic accuracy (area under the curve >0.80) compared with unimodal baselines.CONCLUSIONThis study redefines TSR assessment, shifting from manual estimation to high-dimensional semantic reasoning. By identifying the non-linear prognostic mechanics of the stroma, our token-guided framework offers a biologically interpretable solution for HCC. We suggest that the future of computational pathology may lie not in simple quantification, but in the semantic fusion of human domain knowledge with AI reasoning.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"89 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478589","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}
Pub Date : 2026-03-18DOI: 10.1136/gutjnl-2026-338723
Antonio Tursi
{"title":"Optimal use of rifaximin in diverticular disease of the colon: use less for use better.","authors":"Antonio Tursi","doi":"10.1136/gutjnl-2026-338723","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338723","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"28 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478591","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}
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