Pub Date : 2026-01-08DOI: 10.1136/gutjnl-2025-336715
Christoph Ammer-Herrmenau, Richard Meier, Kai L Antweiler, Thomas Asendorf, Silke Cameron, Gabriele Capurso, Marko Damm, Linh Dang, Fabian Frost, Jacob Hamm, Albrecht Hoffmeister, Yana Kocheva, Christian Meinhardt, Lukasz Nawacki, Vitor Nunes, Arpad Panyko, María Lourdes Ruiz-Rebollo, Cesáreo Flórez-Pardo, Veit Phillip, Aldis Pukitis, Diana Vaselane, Ecaterina Rinja, Vasile Sandru, Arlett Schaefer, Rahel Scholz, Julian Seelig, Simon Sirtl, Volker Ellenrieder, Albrecht Neesse
Background: Postdischarge morbidity and mortality is high in acute pancreatitis (AP) and pathophysiological mechanisms remain poorly understood.
Objectives: We aim to investigate the composition of gut microbiota and clinical long-term outcomes of prospectively enrolled patients with AP to predict postdischarge complications.
Design: In this long-term follow-up study, we analysed clinical and microbiome data of 277 patients from the prospective multicentre Pancreatitis-Microbiome As Predictor of Severity trial. The primary endpoint was the association of the microbial composition with postdischarge mortality, recurrent AP (RAP), progression to chronic pancreatitis, pancreatic exocrine insufficiency, diabetes mellitus (DM) and pancreatic ductal adenocarcinoma.
Results: Buccal (n=238) and rectal (n=249) swabs were analysed by 16S rRNA and metagenomics sequencing using Oxford Nanopore Technologies. Median follow-up was 2.8 years. Distance-based redundancy analysis with canonical analysis of principal coordinates showed significant differences for β-diversity (Bray-Curtis) for postdischarge mortality (p=0.04), RAP (p=0.02) and DM (p=0.03). A ridge regression model including 11 differentially abundant species predicted postdischarge DM with an area under the receiving operating characteristic of 94.8% and 86.2% in the matched and entire cohort, respectively. Using this classifier, a positive predictive value of 66.6%, a negative predictive value of 96% and an accuracy of 95% was achieved.
Conclusion: Our data indicate that the admission microbiome of patients with AP correlates with postdischarge complications independent from multiple risk factors such as AP severity, smoking or alcohol. Microbiota at admission show excellent capacity to predict postdischarge DM and may thus open new stratification tools for a tailored risk assessment in the future.
{"title":"Gut microbiota predict development of postdischarge diabetes mellitus in acute pancreatitis.","authors":"Christoph Ammer-Herrmenau, Richard Meier, Kai L Antweiler, Thomas Asendorf, Silke Cameron, Gabriele Capurso, Marko Damm, Linh Dang, Fabian Frost, Jacob Hamm, Albrecht Hoffmeister, Yana Kocheva, Christian Meinhardt, Lukasz Nawacki, Vitor Nunes, Arpad Panyko, María Lourdes Ruiz-Rebollo, Cesáreo Flórez-Pardo, Veit Phillip, Aldis Pukitis, Diana Vaselane, Ecaterina Rinja, Vasile Sandru, Arlett Schaefer, Rahel Scholz, Julian Seelig, Simon Sirtl, Volker Ellenrieder, Albrecht Neesse","doi":"10.1136/gutjnl-2025-336715","DOIUrl":"10.1136/gutjnl-2025-336715","url":null,"abstract":"<p><strong>Background: </strong>Postdischarge morbidity and mortality is high in acute pancreatitis (AP) and pathophysiological mechanisms remain poorly understood.</p><p><strong>Objectives: </strong>We aim to investigate the composition of gut microbiota and clinical long-term outcomes of prospectively enrolled patients with AP to predict postdischarge complications.</p><p><strong>Design: </strong>In this long-term follow-up study, we analysed clinical and microbiome data of 277 patients from the prospective multicentre Pancreatitis-Microbiome As Predictor of Severity trial. The primary endpoint was the association of the microbial composition with postdischarge mortality, recurrent AP (RAP), progression to chronic pancreatitis, pancreatic exocrine insufficiency, diabetes mellitus (DM) and pancreatic ductal adenocarcinoma.</p><p><strong>Results: </strong>Buccal (n=238) and rectal (n=249) swabs were analysed by 16S rRNA and metagenomics sequencing using Oxford Nanopore Technologies. Median follow-up was 2.8 years. Distance-based redundancy analysis with canonical analysis of principal coordinates showed significant differences for β-diversity (Bray-Curtis) for postdischarge mortality (p=0.04), RAP (p=0.02) and DM (p=0.03). A ridge regression model including 11 differentially abundant species predicted postdischarge DM with an area under the receiving operating characteristic of 94.8% and 86.2% in the matched and entire cohort, respectively. Using this classifier, a positive predictive value of 66.6%, a negative predictive value of 96% and an accuracy of 95% was achieved.</p><p><strong>Conclusion: </strong>Our data indicate that the admission microbiome of patients with AP correlates with postdischarge complications independent from multiple risk factors such as AP severity, smoking or alcohol. Microbiota at admission show excellent capacity to predict postdischarge DM and may thus open new stratification tools for a tailored risk assessment in the future.</p><p><strong>Trial registration number: </strong>NCT04777812.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"316-325"},"PeriodicalIF":25.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145632684","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}
BACKGROUNDInflammatory bowel disease (IBD) arises from complex interactions among diet, host and gut microbiome. Although diet influences intestinal inflammation, the microbial and metabolic pathways involved, and their differences between Crohn's disease (CD) and ulcerative colitis (UC), the two main subtypes of IBD remain unclear.OBJECTIVETo investigate how the gut microbiome mediates the effects of habitual diet on inflammatory activity in IBD.DESIGNThis longitudinal study included 198 adults (100 healthy controls, 49 CD, 49 UC), participants completed a validated food frequency questionnaire. Dietary quality was evaluated using established indices (Alternative Mediterranean Diet, Healthy Eating Index-2015, Índice de Alimentación Saludable, Mean Adequacy Ratio, Plant-Based Dietary Indexes, Healthy Food Diversity). Participants also provided two stool samples (baseline and 6 months). Shotgun metagenomics (n=366) enabled taxonomic and functional profiling. Causal mediation analyses were used to identify microbial features mediating the effect of diet on inflammation.RESULTSIBD patients exhibited lower dietary diversity, fibre intake and nutritional adequacy compared with controls. Microbiome diversity was lowest in CD, intermediate in UC and correlated positively with higher intake of fibre, fruit, vegetables and nuts, and negative with processed foods and sugary beverages. Causal mediation analyses revealed that in CD, coffee, whole wheat bread and healthier diets lowered the Harvey-Bradshaw index through specific bacterial species and metabolites. In UC, Mediterranean-like diets, fruits and coffee reduced C reactive protein via greater microbial richness, reduced dysbiosis and short-chain fatty acid-related functions.CONCLUSIONDiet quality influences inflammation in IBD through distinct microbiome pathways: specific taxa and metabolites mediate effects in CD, whereas microbial richness and global composition drive protection in UC.
背景：炎症性肠病（IBD）是饮食、宿主和肠道微生物群之间复杂相互作用的结果。尽管饮食影响肠道炎症、所涉及的微生物和代谢途径，以及它们在克罗恩病（CD）和溃疡性结肠炎（UC）之间的差异，但IBD的两种主要亚型仍不清楚。目的探讨肠道菌群如何介导习惯性饮食对IBD炎症活性的影响。设计本纵向研究包括198名成年人（100名健康对照，49名乳糜泻，49名UC），参与者完成了一份有效的食物频率问卷。采用既定指标（替代地中海饮食、健康饮食指数-2015、Índice de Alimentación Saludable、平均充足率、植物性饮食指数、健康食品多样性）评估饮食质量。参与者还提供了两个粪便样本（基线和6个月）。霰弹枪宏基因组学（n=366）实现了分类和功能分析。因果中介分析用于确定微生物特征介导饮食对炎症的影响。结果与对照组相比，sibd患者表现出较低的饮食多样性、纤维摄入量和营养充足性。微生物组多样性在乳糜泻组最低，UC组居中，与纤维、水果、蔬菜和坚果摄入量高呈正相关，与加工食品和含糖饮料呈负相关。因果中介分析显示，在乳糜泻中，咖啡、全麦面包和更健康的饮食通过特定的细菌种类和代谢物降低了哈维-布拉德肖指数。在UC中，地中海式饮食、水果和咖啡通过增加微生物丰富度、减少生态失调和短链脂肪酸相关功能来减少C反应蛋白。结论饮食质量通过不同的微生物组途径影响IBD的炎症：特定的分类群和代谢物介导CD的作用，而微生物丰富度和整体组成驱动UC的保护。
{"title":"Distinct microbial mediators link diet to inflammation in Crohn's disease and ulcerative colitis.","authors":"Luis Mayorga,Arnau Noguera Segura,Laura Campderros,Marc Pons-Tarin,Zaida Soler,Sara Vega-Abellaneda,Gerard Serrano-Gomez,Claudia Herrera-deGuise,Virginia Robles-Alonso,Natalia Borruel,Chaysavanh Manichanh","doi":"10.1136/gutjnl-2025-337480","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337480","url":null,"abstract":"BACKGROUNDInflammatory bowel disease (IBD) arises from complex interactions among diet, host and gut microbiome. Although diet influences intestinal inflammation, the microbial and metabolic pathways involved, and their differences between Crohn's disease (CD) and ulcerative colitis (UC), the two main subtypes of IBD remain unclear.OBJECTIVETo investigate how the gut microbiome mediates the effects of habitual diet on inflammatory activity in IBD.DESIGNThis longitudinal study included 198 adults (100 healthy controls, 49 CD, 49 UC), participants completed a validated food frequency questionnaire. Dietary quality was evaluated using established indices (Alternative Mediterranean Diet, Healthy Eating Index-2015, Índice de Alimentación Saludable, Mean Adequacy Ratio, Plant-Based Dietary Indexes, Healthy Food Diversity). Participants also provided two stool samples (baseline and 6 months). Shotgun metagenomics (n=366) enabled taxonomic and functional profiling. Causal mediation analyses were used to identify microbial features mediating the effect of diet on inflammation.RESULTSIBD patients exhibited lower dietary diversity, fibre intake and nutritional adequacy compared with controls. Microbiome diversity was lowest in CD, intermediate in UC and correlated positively with higher intake of fibre, fruit, vegetables and nuts, and negative with processed foods and sugary beverages. Causal mediation analyses revealed that in CD, coffee, whole wheat bread and healthier diets lowered the Harvey-Bradshaw index through specific bacterial species and metabolites. In UC, Mediterranean-like diets, fruits and coffee reduced C reactive protein via greater microbial richness, reduced dysbiosis and short-chain fatty acid-related functions.CONCLUSIONDiet quality influences inflammation in IBD through distinct microbiome pathways: specific taxa and metabolites mediate effects in CD, whereas microbial richness and global composition drive protection in UC.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"14 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907565","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}
OBJECTIVEImmune checkpoint inhibitors (ICIs) have revolutionised cancer treatment and patients' survival. However, ICIs also cause severe immune-related adverse events, notably colitis, resulting in ICIs therapy discontinuation and tumour immunotherapy failure. This study investigates long myosin light chain kinase 1 (MLCK1), a known regulator of tight junction and gut permeability, to elucidate the mechanisms underlying ICI-mediated colitis and identify approaches to reduce this toxicity.DESIGNThis study employed an integrated approach, using clinical samples, in vivo models and in vitro organoid systems. Biopsies from patients with ICIs colitis were profiled using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. To recapitulate human ICIs colitis, we used a wild mouse microbiota (WildR) model, alongside various genetically modified and tumour-bearing models (including melanoma and MC38). Furthermore, mechanisms were investigated through organoid-immune cell co-cultures. Finally, surface plasmon resonance, microscale thermophoresis, full-spectrum flow cytometry, bulk RNA sequencing, immunostaining, ELISA and gut permeability assays were performed to comprehensively delineate the underlying molecular mechanism.RESULTSTight junction integrity was compromised in both human ICIs colitis and our WildR mouse model. We determined that this barrier dysfunction is driven by activation of the MLCK1-mediated leak pathway following ICI treatment. Using murine models, we identified tumour necrosis factor secreted by CD8+ and CD4+ T cells as an upstream regulator that induces colitis through this MLCK-dependent mechanism, as genetic deletion of MLCK preserved the tight junction structure and ameliorated the inflammation and ICIs colitis. Furthermore, a pharmacological screen identified the small molecule Epicatechin, which blocks MLCK1-FKBP8 interaction and inhibits the recruitment of MLCK1 to the perijunctional actomyosin ring and prevents the intestinal barrier loss. Finally, treatment with Epicatechin mitigated ICI-induced colitis without compromising the antitumour efficacy of the immunotherapy.CONCLUSIONSThese findings suggest that MLCK1-dependent tight junction regulation is essential for ICIs colitis, positioning barrier restoration as a potential therapeutic strategy.
{"title":"Targeting MLCK1 uncouples immune checkpoint inhibitor-induced colitis from antitumour immunity.","authors":"Lei Xiong,Jianshang Huang,Yunsheng Dong,Wei Han,Wei-Ting Kuo,Wentao Xu,Yiran Han,Chenchen An,Rumeng Zhu,Nina Zhu,Hanqi Xia,Abduxukur Rahman,Sainan Tang,Chonggui Jiang,Junhao Zhao,Wangxiang Pei,Juan Wang,Xianda Wang,Jiayi Song,Zihan Wang,Shanshan Wu,Hui Zhang,Honghai Xu,Baoming Wu,Qiansheng Huang,Bin Bao,Qiao Mei,Huaqing Zhu,Lanlan Hou,Suthat Liangpunsakul,Feng Cao,Honglei Weng,Bei Tan,Jerrold R Turner,Hua Wang,Li Zuo","doi":"10.1136/gutjnl-2025-337780","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337780","url":null,"abstract":"OBJECTIVEImmune checkpoint inhibitors (ICIs) have revolutionised cancer treatment and patients' survival. However, ICIs also cause severe immune-related adverse events, notably colitis, resulting in ICIs therapy discontinuation and tumour immunotherapy failure. This study investigates long myosin light chain kinase 1 (MLCK1), a known regulator of tight junction and gut permeability, to elucidate the mechanisms underlying ICI-mediated colitis and identify approaches to reduce this toxicity.DESIGNThis study employed an integrated approach, using clinical samples, in vivo models and in vitro organoid systems. Biopsies from patients with ICIs colitis were profiled using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. To recapitulate human ICIs colitis, we used a wild mouse microbiota (WildR) model, alongside various genetically modified and tumour-bearing models (including melanoma and MC38). Furthermore, mechanisms were investigated through organoid-immune cell co-cultures. Finally, surface plasmon resonance, microscale thermophoresis, full-spectrum flow cytometry, bulk RNA sequencing, immunostaining, ELISA and gut permeability assays were performed to comprehensively delineate the underlying molecular mechanism.RESULTSTight junction integrity was compromised in both human ICIs colitis and our WildR mouse model. We determined that this barrier dysfunction is driven by activation of the MLCK1-mediated leak pathway following ICI treatment. Using murine models, we identified tumour necrosis factor secreted by CD8+ and CD4+ T cells as an upstream regulator that induces colitis through this MLCK-dependent mechanism, as genetic deletion of MLCK preserved the tight junction structure and ameliorated the inflammation and ICIs colitis. Furthermore, a pharmacological screen identified the small molecule Epicatechin, which blocks MLCK1-FKBP8 interaction and inhibits the recruitment of MLCK1 to the perijunctional actomyosin ring and prevents the intestinal barrier loss. Finally, treatment with Epicatechin mitigated ICI-induced colitis without compromising the antitumour efficacy of the immunotherapy.CONCLUSIONSThese findings suggest that MLCK1-dependent tight junction regulation is essential for ICIs colitis, positioning barrier restoration as a potential therapeutic strategy.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"14 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907555","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":"Refining watch-and-wait in low rectal cancer after neoadjuvant chemoradiotherapy: pilot study of endoscopic full-thickness resection.","authors":"Zhipeng Qi,Mingyan Cai,Ayimukedisi Yalikong,Haixing Wang,Xian Zhang,De-Xiang Zhu,Yunshi Zhong","doi":"10.1136/gutjnl-2025-336549","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336549","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"9 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907562","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 : 2026-01-06DOI: 10.1136/gutjnl-2025-337099
George J Webster
{"title":"Commentary on: gutjnl-2025-335548.R2-endoscopic retrograde cholangiopancreatography (ERCP) services across the UK.","authors":"George J Webster","doi":"10.1136/gutjnl-2025-337099","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337099","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"15 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907567","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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