Pub Date : 2025-12-19DOI: 10.1136/gutjnl-2025-337514
Qingzhou Kong,Baobao Wang,Yueyue Li,Rui Ji,Yanqing Li
{"title":"Endoscopic gastroenterostomy for malignant gastric outlet obstruction: the need for reintervention is variable.","authors":"Qingzhou Kong,Baobao Wang,Yueyue Li,Rui Ji,Yanqing Li","doi":"10.1136/gutjnl-2025-337514","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-337514","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"4 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786370","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 : 2025-12-19DOI: 10.1136/gutjnl-2024-333309
Sabela Lens,Alice R Burton,Jessica Davies,Maelle Locatelli,Mireia García-López,Anna Pocurull,Anna Jeffery-Smith,Nikolai Novikov,Simon P Fletcher,Xavier Forns,Sofía Pérez-Del-Pulgar,Mala K Maini
BACKGROUNDWithdrawal of prolonged nucleos(t)ide analogue (NA) treatment results in hepatitis B surface antigen (HBsAg) loss in some subjects with chronic hepatitis B (CHB), potentially revealing immune correlates of functional cure.OBJECTIVEWe investigated whether baseline or longitudinal changes in humoral immunity correlated with outcome of discontinuing prolonged NA treatment.DESIGNGlobal memory B cells (MBC) and T follicular helper cells (Tfh) were analysed by flow cytometry. HBs (small surface)/HBc (core)-MBC were quantified by ex-vivo bait staining and function assessed by cultured ELISpots (enzyme-linked immunosorbent spots). Immune parameters assessed at end-of-treatment (EOT), 12 and 48 weeks after treatment withdrawal (and at 4-8 years in a subset) were correlated with intrahepatic and longitudinal serum viral markers and alanine transaminase (ALT).RESULTSIndividuals on prolonged NA had comparable frequencies of HBc-MBC and HBs-MBC, although the latter were PD-1hi and functionally defective. Following treatment withdrawal, increases in class-switched HBc-MBC were frequently temporally linked with hepatic flares. Subjects achieving HBsAg loss had an increase in activated global MBC detectable at EOT that become more marked by week 48, accompanied by significant increases in plasmablasts. HBs-MBC in those with HBsAg loss showed significant reductions in PD-1, trends to increased activation (CD71) and function and a more robust correlation with Tfh, compared with HBsAg persistence. MBC changes were maintained 4-8 years after HBsAg seroconversion.CONCLUSIONDifferences in global and HBs-specific B cell immunity associate with HBsAg loss, whereas HBc-MBC temporally associates with flares, following withdrawal of prolonged NA treatment. Our results underscore the need to further explore the potential of B cell targets for monitoring and enhancing HBV functional cure in larger cohorts.
{"title":"Tracking B cell immunity during perturbation of hepatitis B infection induced by treatment withdrawal.","authors":"Sabela Lens,Alice R Burton,Jessica Davies,Maelle Locatelli,Mireia García-López,Anna Pocurull,Anna Jeffery-Smith,Nikolai Novikov,Simon P Fletcher,Xavier Forns,Sofía Pérez-Del-Pulgar,Mala K Maini","doi":"10.1136/gutjnl-2024-333309","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333309","url":null,"abstract":"BACKGROUNDWithdrawal of prolonged nucleos(t)ide analogue (NA) treatment results in hepatitis B surface antigen (HBsAg) loss in some subjects with chronic hepatitis B (CHB), potentially revealing immune correlates of functional cure.OBJECTIVEWe investigated whether baseline or longitudinal changes in humoral immunity correlated with outcome of discontinuing prolonged NA treatment.DESIGNGlobal memory B cells (MBC) and T follicular helper cells (Tfh) were analysed by flow cytometry. HBs (small surface)/HBc (core)-MBC were quantified by ex-vivo bait staining and function assessed by cultured ELISpots (enzyme-linked immunosorbent spots). Immune parameters assessed at end-of-treatment (EOT), 12 and 48 weeks after treatment withdrawal (and at 4-8 years in a subset) were correlated with intrahepatic and longitudinal serum viral markers and alanine transaminase (ALT).RESULTSIndividuals on prolonged NA had comparable frequencies of HBc-MBC and HBs-MBC, although the latter were PD-1hi and functionally defective. Following treatment withdrawal, increases in class-switched HBc-MBC were frequently temporally linked with hepatic flares. Subjects achieving HBsAg loss had an increase in activated global MBC detectable at EOT that become more marked by week 48, accompanied by significant increases in plasmablasts. HBs-MBC in those with HBsAg loss showed significant reductions in PD-1, trends to increased activation (CD71) and function and a more robust correlation with Tfh, compared with HBsAg persistence. MBC changes were maintained 4-8 years after HBsAg seroconversion.CONCLUSIONDifferences in global and HBs-specific B cell immunity associate with HBsAg loss, whereas HBc-MBC temporally associates with flares, following withdrawal of prolonged NA treatment. Our results underscore the need to further explore the potential of B cell targets for monitoring and enhancing HBV functional cure in larger cohorts.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"9 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785759","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 : 2025-12-18DOI: 10.1136/gutjnl-2025-335398
Wolfgang Marx,Chao Suo,Thusharika Dissanayaka,Suzan Maleki,Liam Nguyen,Nikolaj Travica,Mohammadreza Mohebbi,Mojtaba Lotfaliany,Murat Yucel,Amelia J McGuinness,Michael Berk,Hajara Aslam,Felice N Jacka
BACKGROUNDFermented foods are a promising yet underexplored intervention for influencing brain function and mental health through the gut-brain axis.OBJECTIVEThe objective of this study was to evaluate the impact of a dairy product fermented with probiotic bacteria on aspects of brain structure and function.DESIGNIn a triple-blind, randomised, placebo-controlled trial, 40 healthy women aged 18-55 years were randomised to consume either 130 g per day of a fermented probiotic yoghurt or a placebo for 8 weeks. The primary outcome was the between-group differential change from baseline to week 8 in left hippocampal metabolites, measured using magnetic resonance spectroscopy. Secondary outcomes included changes in brain structure and function, faecal microbiome composition and functional potential, mental health, gastrointestinal symptoms, memory and blood markers of oxidative stress and inflammation.RESULTSThere was a between-group difference in the change in average left hippocampal glutathione concentration (mean difference in change: -0.49; 95% CI -0.95 to -0.04), as well as brain volume in the hippocampus and nucleus accumbens, although these results did not withstand correction for multiple comparisons. There were between-group differences in the change in average functional connectivity between the left hippocampus and left frontal pole. There was also a significant between-group change in gut microbiome beta diversity. There were no differences in other secondary measures.CONCLUSIONThis study provides preliminary evidence that a probiotic fermented dairy product can modulate hippocampal-related outcomes.TRIAL REGISTRATION NUMBERACTRN12622000622707.
{"title":"Effects of a probiotic fermented dairy product on hippocampal metabolites, structure and function: an 8-week randomised, placebo-controlled trial in healthy women.","authors":"Wolfgang Marx,Chao Suo,Thusharika Dissanayaka,Suzan Maleki,Liam Nguyen,Nikolaj Travica,Mohammadreza Mohebbi,Mojtaba Lotfaliany,Murat Yucel,Amelia J McGuinness,Michael Berk,Hajara Aslam,Felice N Jacka","doi":"10.1136/gutjnl-2025-335398","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335398","url":null,"abstract":"BACKGROUNDFermented foods are a promising yet underexplored intervention for influencing brain function and mental health through the gut-brain axis.OBJECTIVEThe objective of this study was to evaluate the impact of a dairy product fermented with probiotic bacteria on aspects of brain structure and function.DESIGNIn a triple-blind, randomised, placebo-controlled trial, 40 healthy women aged 18-55 years were randomised to consume either 130 g per day of a fermented probiotic yoghurt or a placebo for 8 weeks. The primary outcome was the between-group differential change from baseline to week 8 in left hippocampal metabolites, measured using magnetic resonance spectroscopy. Secondary outcomes included changes in brain structure and function, faecal microbiome composition and functional potential, mental health, gastrointestinal symptoms, memory and blood markers of oxidative stress and inflammation.RESULTSThere was a between-group difference in the change in average left hippocampal glutathione concentration (mean difference in change: -0.49; 95% CI -0.95 to -0.04), as well as brain volume in the hippocampus and nucleus accumbens, although these results did not withstand correction for multiple comparisons. There were between-group differences in the change in average functional connectivity between the left hippocampus and left frontal pole. There was also a significant between-group change in gut microbiome beta diversity. There were no differences in other secondary measures.CONCLUSIONThis study provides preliminary evidence that a probiotic fermented dairy product can modulate hippocampal-related outcomes.TRIAL REGISTRATION NUMBERACTRN12622000622707.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"27 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777425","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 : 2025-12-18DOI: 10.1136/gutjnl-2024-332243
Annika Osswald, Esther Wortmann, David Wylensek, Stephanie Kuhls, Olivia I Coleman, Kenneth Peuker, Anne Strigli, Quinten R Ducarmon, Martin Larralde, Wei Liang, Nicole S Treichel, Fabian Schumacher, Colin Volet, Silke Matysik, Karin Kleigrewe, Michael Gigl, Sascha Rohn, Chun-Jun Guo, Burkhard Kleuser, Gerhard Liebisch, Angelika Schnieke, Jason M Ridlon, Rizlan Bernier-Latmani, Georg Zeller, Sebastian Zeissig, Dirk Haller, Krzysztof Flisikowski, Thomas Clavel, Soeren Ocvirk
Background: Western diet and associated production of secondary bile acids (BAs) have been linked to the development of sporadic colorectal cancer (CRC). Despite observational studies showing that secondary BAs produced by 7α-dehydroxylating (7αDH+) gut bacteria are increased in CRC, a causal proof of their tumour-promoting effects is lacking.
Objective: Investigate the causal role of BAs produced by 7αDH+ gut bacteria in CRC.
Design: We performed feeding studies in a porcine model of CRC combined with multi-omics analyses and gnotobiotic mouse models colonised with 7αDH+ bacteria or a genetically modified strain to demonstrate causality.
Results: Western diet exacerbated the CRC phenotype in APC1311/+ pigs. This was accompanied by increased levels of the secondary BA deoxycholic acid (DCA) and higher colonic epithelial cell proliferation. The latter was counteracted by the BA-scavenging drug colestyramine. Metagenomic analysis across multiple human cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in faeces of patients with CRC. Addition of these specific 7αDH+ bacteria (C. scindens/Extibacter muris) to defined communities of gut bacteria led to DCA production and increased colon tumour burden in mouse models of chemically or genetically induced CRC. A mutant strain of Faecalicatena contorta lacking 7αDH caused fewer colonic tumours in azoxymethane/dextran sodium sulfate treated mice and triggered less epithelial cell proliferation in human colon organoids compared with wild-type F. contorta.
Conclusion: This work provides functional evidence for the causal role of secondary BAs produced by gut bacteria through 7αDH in CRC under adverse dietary conditions, opening avenues for future preventive strategies.
{"title":"Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer.","authors":"Annika Osswald, Esther Wortmann, David Wylensek, Stephanie Kuhls, Olivia I Coleman, Kenneth Peuker, Anne Strigli, Quinten R Ducarmon, Martin Larralde, Wei Liang, Nicole S Treichel, Fabian Schumacher, Colin Volet, Silke Matysik, Karin Kleigrewe, Michael Gigl, Sascha Rohn, Chun-Jun Guo, Burkhard Kleuser, Gerhard Liebisch, Angelika Schnieke, Jason M Ridlon, Rizlan Bernier-Latmani, Georg Zeller, Sebastian Zeissig, Dirk Haller, Krzysztof Flisikowski, Thomas Clavel, Soeren Ocvirk","doi":"10.1136/gutjnl-2024-332243","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332243","url":null,"abstract":"<p><strong>Background: </strong>Western diet and associated production of secondary bile acids (BAs) have been linked to the development of sporadic colorectal cancer (CRC). Despite observational studies showing that secondary BAs produced by 7α-dehydroxylating (7αDH+) gut bacteria are increased in CRC, a causal proof of their tumour-promoting effects is lacking.</p><p><strong>Objective: </strong>Investigate the causal role of BAs produced by 7αDH+ gut bacteria in CRC.</p><p><strong>Design: </strong>We performed feeding studies in a porcine model of CRC combined with multi-omics analyses and gnotobiotic mouse models colonised with 7αDH+ bacteria or a genetically modified strain to demonstrate causality.</p><p><strong>Results: </strong>Western diet exacerbated the CRC phenotype in <i>APC</i> <sup>1311/+</sup> pigs. This was accompanied by increased levels of the secondary BA deoxycholic acid (DCA) and higher colonic epithelial cell proliferation. The latter was counteracted by the BA-scavenging drug colestyramine. Metagenomic analysis across multiple human cohorts revealed higher occurrence of <i>bai</i> (BA inducible) operons from <i>Clostridium scindens</i> and close relatives in faeces of patients with CRC. Addition of these specific 7αDH+ bacteria (<i>C. scindens</i>/<i>Extibacter muris</i>) to defined communities of gut bacteria led to DCA production and increased colon tumour burden in mouse models of chemically or genetically induced CRC. A mutant strain of <i>Faecalicatena contorta</i> lacking 7αDH caused fewer colonic tumours in azoxymethane/dextran sodium sulfate treated mice and triggered less epithelial cell proliferation in human colon organoids compared with wild-type <i>F. contorta</i>.</p><p><strong>Conclusion: </strong>This work provides functional evidence for the causal role of secondary BAs produced by gut bacteria through 7αDH in CRC under adverse dietary conditions, opening avenues for future preventive strategies.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781132","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 : 2025-12-17DOI: 10.1136/gutjnl-2025-336758
Marine Fidelle,Laurence Zitvogel
{"title":"Tryptophan metabolite indole-3-acetate: a new culprit in irinotecan-induced gut epithelial injury.","authors":"Marine Fidelle,Laurence Zitvogel","doi":"10.1136/gutjnl-2025-336758","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336758","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"17 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771396","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}
BACKGROUNDMetabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) has been reported to be less responsive to immune checkpoint inhibitors, which may be associated with metabolic reprogramming of tumour cells and abnormal tumour microenvironment.OBJECTIVEHere, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumour microenvironment.DESIGNHepatocyte-specific phosphatase and tensin homologue (Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametrical flow cytometry were performed to analyse the immune landscape alterations. Untargeted metabolomics was conducted to elucidate the hepatic metabolism dysregulation.RESULTSPCK1 is downregulated in tumour tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumour-infiltrating CD8+ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8+ T cells and activate the p38 mitogen-activated protein kinase pathway by directly interacting with the BTB and CNC homology 1 transcription factor, ultimately leading to CD8+ T cells dysfunction. Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD-1 treatment increases the antitumour capability of CD8+ T cells and suppresses MASH-HCC development.CONCLUSIONThis study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8+ T cell dysfunction via 12-HETE-p38 signalling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD-1 immunotherapy in MASH-HCC.
{"title":"PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction.","authors":"Kang Wu,Luo Li,Yi Liu,Kai Wang,Jianghong Zheng,Huijun Liang,Fengli Xu,Renming Liu,Chang Chen,Luyi Huang,Haijun Deng,Xiaojian Han,Shi Chen,Zhirong Zhang,Xinyu Liu,Qiang He,Xiaosong Li,Aishun Jin,Ailong Huang,Ni Tang","doi":"10.1136/gutjnl-2024-334562","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334562","url":null,"abstract":"BACKGROUNDMetabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) has been reported to be less responsive to immune checkpoint inhibitors, which may be associated with metabolic reprogramming of tumour cells and abnormal tumour microenvironment.OBJECTIVEHere, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumour microenvironment.DESIGNHepatocyte-specific phosphatase and tensin homologue (Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametrical flow cytometry were performed to analyse the immune landscape alterations. Untargeted metabolomics was conducted to elucidate the hepatic metabolism dysregulation.RESULTSPCK1 is downregulated in tumour tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumour-infiltrating CD8+ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8+ T cells and activate the p38 mitogen-activated protein kinase pathway by directly interacting with the BTB and CNC homology 1 transcription factor, ultimately leading to CD8+ T cells dysfunction. Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD-1 treatment increases the antitumour capability of CD8+ T cells and suppresses MASH-HCC development.CONCLUSIONThis study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8+ T cell dysfunction via 12-HETE-p38 signalling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD-1 immunotherapy in MASH-HCC.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"82 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771431","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}
BACKGROUNDIntestinal fibrosis, a hallmark complication of Crohn's disease (CD), frequently progresses to stricture formation and surgical intervention. Fibroblast metabolic reprogramming is important in organ fibrosis. However, its role in intestinal fibrogenesis of CD remains elusive.OBJECTIVEWe aim to explore the metabolic reprogramming of fibroblasts and its upstream regulators during intestinal fibrosis of CD.DESIGNWe performed metabolome, single-cell RNA sequencing and spatial transcriptome on paired mucosal and submucosal tissue from the strictured and adjacent non-strictured intestinal segments. The candidate metabolite and metabolic enzymes were verified in primary human intestinal myofibroblasts (HIMFs) and dextran sulfate sodium-induced intestinal fibrotic mice. Next, we identified fibrosis-associated circPLCE1 to regulate the pentose phosphate pathway (PPP) using the circRNA transcriptome. Finally, we studied the functions and mechanisms of circPLCE1 using metabolome, transcriptome, metabolic flux, seahorse assay and RNA pull-down assay in HIMFs and fibroblast-specific circPLCE1 knockdown mice.RESULTSMultilayer integrated analysis identified activation of PPP in fibroblasts during intestinal fibrosis of CD. Specifically, xylulokinase (XYLB)-generated xylulose-5-phosphate (Xu5P) promoted extracellular matrix synthesis by epigenetic upregulation of collagen transcription. Moreover, downregulation of circPLCE1 in fibroblasts activated PPP, resulting in increased glycolysis, nicotinamide adenine dinucleotide phosphate production and aggravated intestinal fibrosis in vitro and in vivo. Mechanistically, circPLCE1 directly bound the domain-I of XYLB and competitively inhibited its enzymatic activity. Decreased circPLCE1 restored XYLB activity and accumulation of Xu5P in intestinal fibrosis.CONCLUSIONOur findings delineate a circPLCE1/XYLB/Xu5P axis in fibroblasts which orchestrates PPP and fibrogenesis, unveiling a novel therapeutic target for intestinal fibrosis of CD.
{"title":"Fibroblast pentose phosphate pathway activation upon decreased circPLCE1 exacerbates intestinal fibrosis in Crohn's disease.","authors":"Longyuan Zhou,Jing Nie,Zhiyin Feng,Rongchang Li,Pingxin Zhang,Sinan Lin,Yao Zhang,Florian Rieder,Changhao Chen,Minhu Chen,Ren Mao","doi":"10.1136/gutjnl-2025-336415","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336415","url":null,"abstract":"BACKGROUNDIntestinal fibrosis, a hallmark complication of Crohn's disease (CD), frequently progresses to stricture formation and surgical intervention. Fibroblast metabolic reprogramming is important in organ fibrosis. However, its role in intestinal fibrogenesis of CD remains elusive.OBJECTIVEWe aim to explore the metabolic reprogramming of fibroblasts and its upstream regulators during intestinal fibrosis of CD.DESIGNWe performed metabolome, single-cell RNA sequencing and spatial transcriptome on paired mucosal and submucosal tissue from the strictured and adjacent non-strictured intestinal segments. The candidate metabolite and metabolic enzymes were verified in primary human intestinal myofibroblasts (HIMFs) and dextran sulfate sodium-induced intestinal fibrotic mice. Next, we identified fibrosis-associated circPLCE1 to regulate the pentose phosphate pathway (PPP) using the circRNA transcriptome. Finally, we studied the functions and mechanisms of circPLCE1 using metabolome, transcriptome, metabolic flux, seahorse assay and RNA pull-down assay in HIMFs and fibroblast-specific circPLCE1 knockdown mice.RESULTSMultilayer integrated analysis identified activation of PPP in fibroblasts during intestinal fibrosis of CD. Specifically, xylulokinase (XYLB)-generated xylulose-5-phosphate (Xu5P) promoted extracellular matrix synthesis by epigenetic upregulation of collagen transcription. Moreover, downregulation of circPLCE1 in fibroblasts activated PPP, resulting in increased glycolysis, nicotinamide adenine dinucleotide phosphate production and aggravated intestinal fibrosis in vitro and in vivo. Mechanistically, circPLCE1 directly bound the domain-I of XYLB and competitively inhibited its enzymatic activity. Decreased circPLCE1 restored XYLB activity and accumulation of Xu5P in intestinal fibrosis.CONCLUSIONOur findings delineate a circPLCE1/XYLB/Xu5P axis in fibroblasts which orchestrates PPP and fibrogenesis, unveiling a novel therapeutic target for intestinal fibrosis of CD.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"166 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746693","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}
BACKGROUNDAssociating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively induces rapid liver hypertrophy in patients with initially unresectable liver tumours, yet the immunological mechanisms remain unclear.OBJECTIVEWe aim to elucidate the immune alterations and underlying mechanisms driving liver regeneration following ALPPS.DESIGNThe cohort study included single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on remnant liver tissues from ALPPS patients. Neutrophil infiltration was validated by flow cytometry and histological analyses in the world's largest ALPPS clinical cohort and mouse ALPPS models. Functional validation, including neutrophil depletion, matrix metalloproteinase 9 (MMP9) inhibition and CD177 blockade, as well as Cd177 knockout and CD177+ neutrophil infusion in vivo.RESULTSscRNA-seq revealed substantial neutrophil infiltration following stage 1 ALPPS. Depletion of neutrophils impaired liver regeneration. Among subsets, CD177+ neutrophils were metabolically active with enhanced neutrophil extracellular traps formation and secreted MMP9. MMP9 inhibition disrupted extracellular matrix (ECM) degradation and hepatocyte growth factor alpha (HGF-α) release, impairing regeneration. CD177+ neutrophils interacted with endothelial cells via CD177-PECAM1 to facilitate transmigration, while hepatic stellate cell-derived CXCL8 promoted neutrophil chemotaxis via CXCL8-CXCR1/2. Cd177 deficiency attenuated neutrophil infiltration and regenerative growth, while CD177+ neutrophil infusion restored regeneration, which was abolished in Cd177-/- mice.CONCLUSIONSCD177+ neutrophils drive liver regeneration by promoting endothelial transmigration, ECM degradation and HGF-α release. These findings reveal a neutrophil-mediated mechanism driving surgical liver regeneration and support the potential of CD177+ neutrophil infusion to establish a proregenerative hepatic environment for therapeutic strategies in liver failure.
{"title":"CD177 + neutrophils drive extracellular matrix remodelling and HGF-alpha release in ALPPS-induced liver regeneration.","authors":"Jiayan Yan,Ao Huang,Shiyu Zhang,Na Yao,Junfeng Huang,Zhifeng Jiang,Jiayi Wang,Feiyu Chen,Qichao Yu,Jianwen Cheng,Senquan Zhang,Tianyi Li,Rongshan Gao,Runze Miao,Rongkui Luo,Shaolai Zhou,Yuan Ji,Zheng Wang,Dongmei Gao,Zhenbin Ding,Zhaoyou Tang,Jia Fan,Miguel A Esteban,Hans Jürgen Schlitt,Xinrong Yang,Jian Zhou","doi":"10.1136/gutjnl-2025-336300","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336300","url":null,"abstract":"BACKGROUNDAssociating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively induces rapid liver hypertrophy in patients with initially unresectable liver tumours, yet the immunological mechanisms remain unclear.OBJECTIVEWe aim to elucidate the immune alterations and underlying mechanisms driving liver regeneration following ALPPS.DESIGNThe cohort study included single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on remnant liver tissues from ALPPS patients. Neutrophil infiltration was validated by flow cytometry and histological analyses in the world's largest ALPPS clinical cohort and mouse ALPPS models. Functional validation, including neutrophil depletion, matrix metalloproteinase 9 (MMP9) inhibition and CD177 blockade, as well as Cd177 knockout and CD177+ neutrophil infusion in vivo.RESULTSscRNA-seq revealed substantial neutrophil infiltration following stage 1 ALPPS. Depletion of neutrophils impaired liver regeneration. Among subsets, CD177+ neutrophils were metabolically active with enhanced neutrophil extracellular traps formation and secreted MMP9. MMP9 inhibition disrupted extracellular matrix (ECM) degradation and hepatocyte growth factor alpha (HGF-α) release, impairing regeneration. CD177+ neutrophils interacted with endothelial cells via CD177-PECAM1 to facilitate transmigration, while hepatic stellate cell-derived CXCL8 promoted neutrophil chemotaxis via CXCL8-CXCR1/2. Cd177 deficiency attenuated neutrophil infiltration and regenerative growth, while CD177+ neutrophil infusion restored regeneration, which was abolished in Cd177-/- mice.CONCLUSIONSCD177+ neutrophils drive liver regeneration by promoting endothelial transmigration, ECM degradation and HGF-α release. These findings reveal a neutrophil-mediated mechanism driving surgical liver regeneration and support the potential of CD177+ neutrophil infusion to establish a proregenerative hepatic environment for therapeutic strategies in liver failure.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"22 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746697","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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