Pub Date : 2025-04-23DOI: 10.1136/gutjnl-2025-335220
Yihui Chen,Riccardo Ballarò,Marta Sans,Fredrik Ivar Thege,Mingxin Zuo,Rongzhang Dou,Jimin Min,Michele Yip-Schneider,J Zhang,Ranran Wu,Ehsan Irajizad,Yuki Makino,Kimal I Rajapakshe,Hamid K Rudsari,Mark W Hurd,Ricardo A León-Letelier,Hiroyuki Katayama,Edwin Ostrin,Jody Vykoukal,Jennifer B Dennison,Kim-Anh Do,Samir M Hanash,Robert A Wolff,Paolo A Guerrero,Michael Kim,C Max Schmidt,Anirban Maitra,Johannes F Fahrmann
BACKGROUNDWe conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC).OBJECTIVEWe aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC.DESIGNMatrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition.RESULTSMALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice.CONCLUSIONOur work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.
{"title":"Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers.","authors":"Yihui Chen,Riccardo Ballarò,Marta Sans,Fredrik Ivar Thege,Mingxin Zuo,Rongzhang Dou,Jimin Min,Michele Yip-Schneider,J Zhang,Ranran Wu,Ehsan Irajizad,Yuki Makino,Kimal I Rajapakshe,Hamid K Rudsari,Mark W Hurd,Ricardo A León-Letelier,Hiroyuki Katayama,Edwin Ostrin,Jody Vykoukal,Jennifer B Dennison,Kim-Anh Do,Samir M Hanash,Robert A Wolff,Paolo A Guerrero,Michael Kim,C Max Schmidt,Anirban Maitra,Johannes F Fahrmann","doi":"10.1136/gutjnl-2025-335220","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335220","url":null,"abstract":"BACKGROUNDWe conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC).OBJECTIVEWe aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC.DESIGNMatrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition.RESULTSMALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice.CONCLUSIONOur work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"24 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872114","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 : 2025-04-23DOI: 10.1136/gutjnl-2025-335329
Yi-Chia Lee
{"title":"Single-biopsy epigenetic profiling reveals persistent DNA methylation and gastric cancer risk after Helicobacter pylori eradication.","authors":"Yi-Chia Lee","doi":"10.1136/gutjnl-2025-335329","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335329","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"17 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872003","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":"Unravelling the causality between inflammatory bowel disease and polycystic ovary syndrome mediated by gut microbiota and blood metabolism: insights from two prospective cohort studies.","authors":"Zhaoman Wan,Xueyu Hao,Feiling Huang,Hanqiao Dai,Yubo Fan,Tianyao Chu,Hongyan Chen,Min Cui,Hong Yang,Xinlei Zhang,Rong Chen,Peng Zhang","doi":"10.1136/gutjnl-2024-334693","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334693","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"38 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857282","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 : 2025-04-16DOI: 10.1136/gutjnl-2024-334445
Manuel B. Braga-Neto, Taha Qazi, Clifton Fulmer, Stefan D. Holubar, Claudio Fiocchi, Andrei I. Ivanov, Florian Rieder
Pouchitis, defined as inflammation of the ileal pouch, is the most common complication following restorative proctocolectomy for refractory ulcerative colitis. Antibiotics remain the first line of therapy for pouchitis, but the majority of patients develop subsequent episodes and some are refractory to antibiotic therapy. This highlights the need for more effective treatment options and points to a more complex pathophysiology beyond the role of th pouch microbiome, similar to what is seen in inflammatory bowel disease. In this review, we outline the putative mechanisms of pouchitis, including genetic predisposition, microbiome alterations, dysfunction of the intestinal barrier and the immune system and review the available animal models of pouchitis. In addition, we introduce the concept of pouchitis as a possible transmural disease and discuss the potential role of non-immune cells, including stromal cells, in perpetuating inflammation and intestinal barrier dysfunction. We discuss future directions, implications for novel therapies and propose novel multicellular disease models that can better capture the complexity of pouchitis pathogenesis.
{"title":"Cellular and molecular mechanisms in the pathogenesis of pouchitis: more than just the microbiota","authors":"Manuel B. Braga-Neto, Taha Qazi, Clifton Fulmer, Stefan D. Holubar, Claudio Fiocchi, Andrei I. Ivanov, Florian Rieder","doi":"10.1136/gutjnl-2024-334445","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334445","url":null,"abstract":"Pouchitis, defined as inflammation of the ileal pouch, is the most common complication following restorative proctocolectomy for refractory ulcerative colitis. Antibiotics remain the first line of therapy for pouchitis, but the majority of patients develop subsequent episodes and some are refractory to antibiotic therapy. This highlights the need for more effective treatment options and points to a more complex pathophysiology beyond the role of th pouch microbiome, similar to what is seen in inflammatory bowel disease. In this review, we outline the putative mechanisms of pouchitis, including genetic predisposition, microbiome alterations, dysfunction of the intestinal barrier and the immune system and review the available animal models of pouchitis. In addition, we introduce the concept of pouchitis as a possible transmural disease and discuss the potential role of non-immune cells, including stromal cells, in perpetuating inflammation and intestinal barrier dysfunction. We discuss future directions, implications for novel therapies and propose novel multicellular disease models that can better capture the complexity of pouchitis pathogenesis.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"29 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841350","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}
Background Precision cancer risk stratification for gastric cancer is urgently needed for the growing number of healthy people after Helicobacter pylori eradication. The epimutation burden in non-malignant tissues has been associated with cancer risk in multiple cross-sectional studies. Objective To confirm the clinical usefulness of a DNA methylation marker for epimutation burden, and to identify a cut-off methylation level for a super-high-risk population. Design Healthy people after H. pylori eradication with open-type atrophy were prospectively recruited. DNA methylation levels of a marker gene, RIMS1 , were measured in biopsy specimens from gastric antrum and body. The primary endpoint was the incidence rate of gastric cancer in quartiles of the methylation levels. Results 1624 participants had at least one endoscopic follow-up with a median follow-up of 4.05 years, and a primary gastric cancer developed in 27 participants. The highest quartile of RIMS1 methylation levels had a higher incidence rate (972.8 per 100 000 person-years) than the lowest quartile (127.1). Cox regression analysis revealed a univariate HR of 7.7 (95% CI 1.8–33.7) and an age- and sex-adjusted HR of 5.7 (95% CI 1.3–25.5). As a secondary objective, a cut-off methylation level of 25.7% (95% CI 1.7–7.7) was obtained to identify a population with a super-high risk based on the number needed to screen of 1000. Conclusion A DNA methylation marker can risk-stratify healthy people after H. pylori eradication even though all of them have clinically high risk. Individuals with super-high risk will need more frequent gastric cancer screening than currently recommended. Trial registration number UMIN-CTR000016894. No data are available. The anonymised data will be available after the follow-up analysis in 2027.
{"title":"Precision risk stratification of primary gastric cancer after eradication of H. pylori by a DNA methylation marker: a multicentre prospective study","authors":"Harumi Yamada, Seiichiro Abe, Hadrien Charvat, Takayuki Ando, Masahiro Maeda, Kazunari Murakami, Shiro Oka, Takao Maekita, Mitsushige Sugimoto, Takahisa Furuta, Mitsuru Kaise, Nobutake Yamamichi, Hiroyuki Takamaru, Akiko Sasaki, Ichiro Oda, Sohachi Nanjo, Nobuhiro Suzuki, Toshiro Sugiyama, Masaaki Kodama, Kazuhiro Mizukami, Masanori Ito, Takahiro Kotachi, Taichi Shimazu, Seiichiro Yamamoto, Toshikazu Ushijima","doi":"10.1136/gutjnl-2025-335039","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335039","url":null,"abstract":"Background Precision cancer risk stratification for gastric cancer is urgently needed for the growing number of healthy people after Helicobacter pylori eradication. The epimutation burden in non-malignant tissues has been associated with cancer risk in multiple cross-sectional studies. Objective To confirm the clinical usefulness of a DNA methylation marker for epimutation burden, and to identify a cut-off methylation level for a super-high-risk population. Design Healthy people after H. pylori eradication with open-type atrophy were prospectively recruited. DNA methylation levels of a marker gene, RIMS1 , were measured in biopsy specimens from gastric antrum and body. The primary endpoint was the incidence rate of gastric cancer in quartiles of the methylation levels. Results 1624 participants had at least one endoscopic follow-up with a median follow-up of 4.05 years, and a primary gastric cancer developed in 27 participants. The highest quartile of RIMS1 methylation levels had a higher incidence rate (972.8 per 100 000 person-years) than the lowest quartile (127.1). Cox regression analysis revealed a univariate HR of 7.7 (95% CI 1.8–33.7) and an age- and sex-adjusted HR of 5.7 (95% CI 1.3–25.5). As a secondary objective, a cut-off methylation level of 25.7% (95% CI 1.7–7.7) was obtained to identify a population with a super-high risk based on the number needed to screen of 1000. Conclusion A DNA methylation marker can risk-stratify healthy people after H. pylori eradication even though all of them have clinically high risk. Individuals with super-high risk will need more frequent gastric cancer screening than currently recommended. Trial registration number UMIN-CTR000016894. No data are available. The anonymised data will be available after the follow-up analysis in 2027.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"1 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836690","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 : 2025-04-10DOI: 10.1136/gutjnl-2024-333687
Gunnar Baatrup, Thomas Bjørsum-Meyer, Lasse Kaalby, Benedicte Schelde-Olesen, Morten Kobaek-Larsen, Anastasios Koulaouzidis, Rasmus Kroijer, Issam Al-Najami, Niels Buch, Anders Høgh, Niels Qvist, Marianne Kirstine Thygesen, Ulrik Deding
Background Colonoscopy is among the standard tests for colorectal cancer (CRC) screening. However, uptake varies, and alternatives such as colon capsule endoscopy (CCE) are available. The uptake and detection rate of clinically significant neoplasia with CCE, compared with colonoscopy, remain unclear in this setting. Objective The primary objective of this study was to compare the detection rates of advanced neoplasia between CCE and colonoscopy, using a pathway in which the study group could choose between the two procedures, while the control group was offered only colonoscopy. Design A randomised, intention-to-treat trial was conducted among Danish CRC screening participants who tested positive with a faecal immunochemical test (FIT). The trial compared the detection rate of advanced neoplasia (primary outcome) and the uptake rate of both approaches between the two arms. Results A total of 473 684 invitations were sent to 396 676 individuals, with 62.6% returning the test. Among them, 11 075 tests were positive (4.5%), with no significant differences between the two study groups. Among FIT-positive cases, the uptake for colonoscopy was 91.1% in the control arm and 91.7% in the study arm, where participants had a choice of methods. In the study arm, 45.8% preferred CCE, 11.4% preferred colonoscopy and 42.8% had no preference and underwent colonoscopy. Ultimately, 69.9% of patients who initially opted for CCE were later referred for colonoscopy. The rate of advanced neoplasia detection was similar between the groups: 0.67% in the study arm versus 0.64% in the control arm. Conclusion Offering CCE as an alternative to colonoscopy did not significantly alter the detection rate of advanced neoplasia, nor did it increase uptake in a screening programme with high adherence to colonoscopy following a positive FIT test. Instead, it led to a very high rate of secondary colonoscopies. Therefore, CCE cannot be recommended in this setting. Trial registration number [NCT04049357][1] (ClinicalTrials.gov) No data are available. The data from the current study will not be publicly available as this is not permitted by Danish legislation. All data are stored at secure, logged governmental servers at ‘Statistics Denmark’. Upon justified request to the corresponding author, aggregated additional results can be shared within 2 years from the publication date. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04049357&atom=%2Fgutjnl%2Fearly%2F2025%2F04%2F10%2Fgutjnl-2024-333687.atom
{"title":"Choice of colon capsule or colonoscopy versus default colonoscopy in FIT positive patients in the Danish screening programme: a parallel group randomised controlled trial","authors":"Gunnar Baatrup, Thomas Bjørsum-Meyer, Lasse Kaalby, Benedicte Schelde-Olesen, Morten Kobaek-Larsen, Anastasios Koulaouzidis, Rasmus Kroijer, Issam Al-Najami, Niels Buch, Anders Høgh, Niels Qvist, Marianne Kirstine Thygesen, Ulrik Deding","doi":"10.1136/gutjnl-2024-333687","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333687","url":null,"abstract":"Background Colonoscopy is among the standard tests for colorectal cancer (CRC) screening. However, uptake varies, and alternatives such as colon capsule endoscopy (CCE) are available. The uptake and detection rate of clinically significant neoplasia with CCE, compared with colonoscopy, remain unclear in this setting. Objective The primary objective of this study was to compare the detection rates of advanced neoplasia between CCE and colonoscopy, using a pathway in which the study group could choose between the two procedures, while the control group was offered only colonoscopy. Design A randomised, intention-to-treat trial was conducted among Danish CRC screening participants who tested positive with a faecal immunochemical test (FIT). The trial compared the detection rate of advanced neoplasia (primary outcome) and the uptake rate of both approaches between the two arms. Results A total of 473 684 invitations were sent to 396 676 individuals, with 62.6% returning the test. Among them, 11 075 tests were positive (4.5%), with no significant differences between the two study groups. Among FIT-positive cases, the uptake for colonoscopy was 91.1% in the control arm and 91.7% in the study arm, where participants had a choice of methods. In the study arm, 45.8% preferred CCE, 11.4% preferred colonoscopy and 42.8% had no preference and underwent colonoscopy. Ultimately, 69.9% of patients who initially opted for CCE were later referred for colonoscopy. The rate of advanced neoplasia detection was similar between the groups: 0.67% in the study arm versus 0.64% in the control arm. Conclusion Offering CCE as an alternative to colonoscopy did not significantly alter the detection rate of advanced neoplasia, nor did it increase uptake in a screening programme with high adherence to colonoscopy following a positive FIT test. Instead, it led to a very high rate of secondary colonoscopies. Therefore, CCE cannot be recommended in this setting. Trial registration number [NCT04049357][1] (ClinicalTrials.gov) No data are available. The data from the current study will not be publicly available as this is not permitted by Danish legislation. All data are stored at secure, logged governmental servers at ‘Statistics Denmark’. Upon justified request to the corresponding author, aggregated additional results can be shared within 2 years from the publication date. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04049357&atom=%2Fgutjnl%2Fearly%2F2025%2F04%2F10%2Fgutjnl-2024-333687.atom","PeriodicalId":12825,"journal":{"name":"Gut","volume":"183 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819248","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 : 2025-04-10DOI: 10.1136/gutjnl-2025-335476
Ziwen Zheng, Liyun Wang
We read with great interest the study by Digby et al , which presents an innovative approach towards improving colorectal cancer (CRC) risk stratification by combining faecal haemoglobin (f-Hb), iron-deficiency anaemia (IDA) and age.1 The authors’ recommendations to refine thresholds for referral and optimise colonoscopy resources offer valuable insights. However, several aspects still need to be discussed. First, we commend the effort to combine f-Hb with IDA and age for risk prediction. However, the study relies on a single analyser (HM-JACKarc), which raises questions about the generalisability of findings across different healthcare systems using other platforms …
{"title":"Perspective on enhancing CRC risk prediction","authors":"Ziwen Zheng, Liyun Wang","doi":"10.1136/gutjnl-2025-335476","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335476","url":null,"abstract":"We read with great interest the study by Digby et al , which presents an innovative approach towards improving colorectal cancer (CRC) risk stratification by combining faecal haemoglobin (f-Hb), iron-deficiency anaemia (IDA) and age.1 The authors’ recommendations to refine thresholds for referral and optimise colonoscopy resources offer valuable insights. However, several aspects still need to be discussed. First, we commend the effort to combine f-Hb with IDA and age for risk prediction. However, the study relies on a single analyser (HM-JACKarc), which raises questions about the generalisability of findings across different healthcare systems using other platforms …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"183 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819330","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}
Background Injured or reactive biliary epithelial cells participate in most chronic liver injuries in a process referred to as ductular reaction, which involves multicellular interactions with marked local infiltration of macrophages and fibrogenic cell activation. The direct roles of biliary epithelial cells in shaping their cellular niche remain unknown. Objective We aimed at investigating the effects of biliary epithelial cell-derived acute phase response protein orosomucoid 2 (ORM2) in shaping monocyte/macrophage response to liver injury. Design Transcriptome data sets from human and mouse livers were used, results were confirmed with multiplex immunofluorescence. A multicellular biliary-niche-on-a-chip derived from primary liver and blood cells (wild-type, Mdr2 −/− mice) was established to model ductular reaction. Human blood cells collected from healthy donors and intrahepatic cholangiocyte organoids derived from normal and cirrhotic liver patients were used. Results Our transcriptome data set and multiplex immunofluorescence analyses indicated a previously unrecognised involvement of the acute phase response protein ORM2 in ductular reactions in both human and mouse livers. ORM2 gene expression was increased in biliatresone-challenged, bile acid-challenged and acetaminophen-challenged cholangiocytes. Cholangiocyte-derived ORM2 induced unique transcriptome changes and functional adaptation of liver macrophages. ORM2-activated macrophages exacerbated cholangiocyte cell stress and Orm2 expression, but also tended to promote fibrogenic activation of hepatic stellate cells. Mechanistically, ORM2 effects were mediated by an inositol 1,4,5-trisphosphate receptor type 2-dependent calcium pathway. Conclusion This study reveals a paracrine communication circuit during ductular reaction, in which reactive cholangiocyte-derived ORM2 reprogrammes liver macrophages, participating in a pathogenic remodelling of the immune biliary niche. Data are available in a public, open access repository. Data are available upon reasonable request. The transcriptome sequencing data based on mouse primary liver macrophages is accessible from GEO database (ID: GSE273509). Data and technical details associated with this study are provided within the manuscript or available as supplementary materials. Further information may be provided upon reasonable request to the corresponding author.
{"title":"Reactive cholangiocyte-derived ORM2 drives a pathogenic modulation of the injured biliary niche through macrophage reprogramming","authors":"Hanyang Liu, Guo Yin, Bianca Franco Leonardi, Tian Lan, Yeni Ait Ahmed, Hilmar Berger, Marlene Sophia Kohlhepp, Natalja Amiridze, Natalia Martagón Calderón, Carla Frau, Ludovic Vallier, Milad Rezvani, Frank Tacke, Adrien Guillot","doi":"10.1136/gutjnl-2024-334425","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334425","url":null,"abstract":"Background Injured or reactive biliary epithelial cells participate in most chronic liver injuries in a process referred to as ductular reaction, which involves multicellular interactions with marked local infiltration of macrophages and fibrogenic cell activation. The direct roles of biliary epithelial cells in shaping their cellular niche remain unknown. Objective We aimed at investigating the effects of biliary epithelial cell-derived acute phase response protein orosomucoid 2 (ORM2) in shaping monocyte/macrophage response to liver injury. Design Transcriptome data sets from human and mouse livers were used, results were confirmed with multiplex immunofluorescence. A multicellular biliary-niche-on-a-chip derived from primary liver and blood cells (wild-type, Mdr2 −/− mice) was established to model ductular reaction. Human blood cells collected from healthy donors and intrahepatic cholangiocyte organoids derived from normal and cirrhotic liver patients were used. Results Our transcriptome data set and multiplex immunofluorescence analyses indicated a previously unrecognised involvement of the acute phase response protein ORM2 in ductular reactions in both human and mouse livers. ORM2 gene expression was increased in biliatresone-challenged, bile acid-challenged and acetaminophen-challenged cholangiocytes. Cholangiocyte-derived ORM2 induced unique transcriptome changes and functional adaptation of liver macrophages. ORM2-activated macrophages exacerbated cholangiocyte cell stress and Orm2 expression, but also tended to promote fibrogenic activation of hepatic stellate cells. Mechanistically, ORM2 effects were mediated by an inositol 1,4,5-trisphosphate receptor type 2-dependent calcium pathway. Conclusion This study reveals a paracrine communication circuit during ductular reaction, in which reactive cholangiocyte-derived ORM2 reprogrammes liver macrophages, participating in a pathogenic remodelling of the immune biliary niche. Data are available in a public, open access repository. Data are available upon reasonable request. The transcriptome sequencing data based on mouse primary liver macrophages is accessible from GEO database (ID: GSE273509). Data and technical details associated with this study are provided within the manuscript or available as supplementary materials. Further information may be provided upon reasonable request to the corresponding author.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"30 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805656","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 : 2025-04-08DOI: 10.1136/gutjnl-2024-334412
Luca Maccioni, Yukun Guan, Mariia Kim, Maria A Parra, Brandon Peiffer, Yaojie Fu, Yang Wang, Yu-Hong Lin, Bryan Mackowiak, Dechun Feng, Andrew Cameron, Zhaoli Sun, George Kunos, Peter Stärkel, Bin Gao
Background Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure. Objective We examined the regulation of intestinal and intrahepatic CD8+ T lymphocytes and their contribution to ALD. Design ALD patients were recruited for evaluation of intestinal and liver T cells. Single-cell RNA sequencing (scRNA seq) was performed to analyse intrahepatic and peripheral T cells in ALD. Wildtype, CD8-specific Bcl2 transgenic ( Cd8 Bcl-2), and Cd8 −/− mice were subjected to chronic-plus-binge ethanol feeding. Results In ALD patients, duodenal CD8+ T cells were selectively reduced and negatively correlated with liver injury and bacterial translocation markers, while intrahepatic CD8+ T cells were markedly increased. ScRNA seq analysis of ALD patient livers revealed several populations of CD8+ T cells expressing activation and survival genes (eg, Bcl2 ). Transcriptomics and functional studies revealed a key role of prosurvival BCL2 in this opposite regulation of CD8+ T cells. Mechanistically, chronic-plus-binge ethanol feeding reduced CD8+ T cells specifically in the duodenum where ethanol levels are high. Inducing BCL2 in CD8+ T cells reversed ethanol-induced loss of duodenal CD8+ T cells, improved gut barrier function and ameliorated ALD, while CD8 deficiency was linked to enhanced neutrophil and macrophage infiltration in the liver, exacerbating ALD in mice. Conclusions ALD is associated with loss of duodenal CD8+ T cells but elevation of intrahepatic CD8+ T cells, which aggravates and ameliorates ALD, respectively. Restoration of survival and functions of intestinal and intrahepatic CD8+ T cells may represent a novel therapeutic strategy for ALD patients. All data relevant to the study are included in the article or uploaded as supplementary information. Some of the data are available on reasonable request.
{"title":"Opposite regulation of intestinal and intrahepatic CD8+ T cells controls alcohol-associated liver disease progression","authors":"Luca Maccioni, Yukun Guan, Mariia Kim, Maria A Parra, Brandon Peiffer, Yaojie Fu, Yang Wang, Yu-Hong Lin, Bryan Mackowiak, Dechun Feng, Andrew Cameron, Zhaoli Sun, George Kunos, Peter Stärkel, Bin Gao","doi":"10.1136/gutjnl-2024-334412","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334412","url":null,"abstract":"Background Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure. Objective We examined the regulation of intestinal and intrahepatic CD8+ T lymphocytes and their contribution to ALD. Design ALD patients were recruited for evaluation of intestinal and liver T cells. Single-cell RNA sequencing (scRNA seq) was performed to analyse intrahepatic and peripheral T cells in ALD. Wildtype, CD8-specific Bcl2 transgenic ( Cd8 Bcl-2), and Cd8 −/− mice were subjected to chronic-plus-binge ethanol feeding. Results In ALD patients, duodenal CD8+ T cells were selectively reduced and negatively correlated with liver injury and bacterial translocation markers, while intrahepatic CD8+ T cells were markedly increased. ScRNA seq analysis of ALD patient livers revealed several populations of CD8+ T cells expressing activation and survival genes (eg, Bcl2 ). Transcriptomics and functional studies revealed a key role of prosurvival BCL2 in this opposite regulation of CD8+ T cells. Mechanistically, chronic-plus-binge ethanol feeding reduced CD8+ T cells specifically in the duodenum where ethanol levels are high. Inducing BCL2 in CD8+ T cells reversed ethanol-induced loss of duodenal CD8+ T cells, improved gut barrier function and ameliorated ALD, while CD8 deficiency was linked to enhanced neutrophil and macrophage infiltration in the liver, exacerbating ALD in mice. Conclusions ALD is associated with loss of duodenal CD8+ T cells but elevation of intrahepatic CD8+ T cells, which aggravates and ameliorates ALD, respectively. Restoration of survival and functions of intestinal and intrahepatic CD8+ T cells may represent a novel therapeutic strategy for ALD patients. All data relevant to the study are included in the article or uploaded as supplementary information. Some of the data are available on reasonable request.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"93 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805645","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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