Pub Date : 2024-10-23DOI: 10.1038/s44355-024-00009-5
Hong Mao, Larissa D. Kruse, Ruomei Li, Ana Oteiza, Eike C. Struck, Jasmin Schürstedt, Wolfgang Hübner, Victoria C. Cogger, David Le Couteur, Deanna L. Wolfson, Thomas Huser, Balpreet Singh Ahluwalia, Cristina Øie, Peter A. G. McCourt
Atherogenesis is associated with elevated plasma levels of oxidized low-density lipoproteins (oxLDL). In vivo, oxLDL causes liver endothelial swelling, and disrupts liver sinusoidal endothelial cell (LSECs) fenestrations. We mapped the nanoscale kinetics of these changes in vitro in isolated rat LSECs challenged with oxLDL and monitored viability with endocytosis and cytotoxicity assays. OxLDL disrupted LSEC ultrastructure – increasing oxLDL concentrations and oxidation levels caused sieve plate loss, fenestration fusion, and gap formation. Importantly, these effects were not uniform across all LSECs. LSECs retained the ability to endocytose ligands irrespective of the presence of oxLDL. However, increasing oxidation levels and concentrations of oxLDL inhibited LSEC mediated degradation of endocytosed ligands. Viability was unaffected by any oxLDL challenge. In conclusion, oxLDL disrupts LSEC ultrastructural morphology in vitro but LSECs remain viable and mostly maintain the scavenging function during oxLDL challenge.
{"title":"Impact of oxidized low-density lipoprotein on rat liver sinusoidal endothelial cell morphology and function","authors":"Hong Mao, Larissa D. Kruse, Ruomei Li, Ana Oteiza, Eike C. Struck, Jasmin Schürstedt, Wolfgang Hübner, Victoria C. Cogger, David Le Couteur, Deanna L. Wolfson, Thomas Huser, Balpreet Singh Ahluwalia, Cristina Øie, Peter A. G. McCourt","doi":"10.1038/s44355-024-00009-5","DOIUrl":"10.1038/s44355-024-00009-5","url":null,"abstract":"Atherogenesis is associated with elevated plasma levels of oxidized low-density lipoproteins (oxLDL). In vivo, oxLDL causes liver endothelial swelling, and disrupts liver sinusoidal endothelial cell (LSECs) fenestrations. We mapped the nanoscale kinetics of these changes in vitro in isolated rat LSECs challenged with oxLDL and monitored viability with endocytosis and cytotoxicity assays. OxLDL disrupted LSEC ultrastructure – increasing oxLDL concentrations and oxidation levels caused sieve plate loss, fenestration fusion, and gap formation. Importantly, these effects were not uniform across all LSECs. LSECs retained the ability to endocytose ligands irrespective of the presence of oxLDL. However, increasing oxidation levels and concentrations of oxLDL inhibited LSEC mediated degradation of endocytosed ligands. Viability was unaffected by any oxLDL challenge. In conclusion, oxLDL disrupts LSEC ultrastructural morphology in vitro but LSECs remain viable and mostly maintain the scavenging function during oxLDL challenge.","PeriodicalId":501708,"journal":{"name":"npj Gut and Liver","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44355-024-00009-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1038/s44355-024-00007-7
Sonia-Emilia Selicean, Eric Felli, Cong Wang, Yeldos Nulan, Juan José Lozano, Sergi Guixé-Muntet, Horia Ștefănescu, Jaime Bosch, Annalisa Berzigotti, Jordi Gracia-Sancho
Chronic liver disease (CLD) is characterised by liver sinusoidal endothelial cells (LSECs) dysfunction. Mechanical forces and inflammation are among the leading factors. ETS-related gene (ERG) is an endothelial-specific transcription factor, involved in maintaining cell quiescence and homeostasis. Our study aimed to understand the expression and modulation of ERG in CLD. ERG expression was characterised and correlated to clinical data in human liver cirrhosis at different disease stages. ERG dynamics in response to stiffness and inflammation were investigated in primary healthy and cirrhotic rat LSEC and in human umbilical vein endothelial cells (HUVECs). ERG is markedly downregulated in cirrhosis independently of disease stage or aetiology and its expression is modulated by substrate stiffness in ECs. Inflammation downregulates ERG in cells on physiological stiffness, but not on high stiffness, suggesting a complementary role of inflammation and stiffness in suppressing ERG. This study outlines ERG as an LSEC inflammation and stiffness-responsive transcription factor in cirrhosis.
{"title":"Stiffness-induced modulation of ERG transcription factor in chronic liver disease","authors":"Sonia-Emilia Selicean, Eric Felli, Cong Wang, Yeldos Nulan, Juan José Lozano, Sergi Guixé-Muntet, Horia Ștefănescu, Jaime Bosch, Annalisa Berzigotti, Jordi Gracia-Sancho","doi":"10.1038/s44355-024-00007-7","DOIUrl":"10.1038/s44355-024-00007-7","url":null,"abstract":"Chronic liver disease (CLD) is characterised by liver sinusoidal endothelial cells (LSECs) dysfunction. Mechanical forces and inflammation are among the leading factors. ETS-related gene (ERG) is an endothelial-specific transcription factor, involved in maintaining cell quiescence and homeostasis. Our study aimed to understand the expression and modulation of ERG in CLD. ERG expression was characterised and correlated to clinical data in human liver cirrhosis at different disease stages. ERG dynamics in response to stiffness and inflammation were investigated in primary healthy and cirrhotic rat LSEC and in human umbilical vein endothelial cells (HUVECs). ERG is markedly downregulated in cirrhosis independently of disease stage or aetiology and its expression is modulated by substrate stiffness in ECs. Inflammation downregulates ERG in cells on physiological stiffness, but not on high stiffness, suggesting a complementary role of inflammation and stiffness in suppressing ERG. This study outlines ERG as an LSEC inflammation and stiffness-responsive transcription factor in cirrhosis.","PeriodicalId":501708,"journal":{"name":"npj Gut and Liver","volume":" ","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44355-024-00007-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s44355-024-00006-8
Emily C. Hoedt, Georgia Carroll, Bree Stephensen, Katie Togher, Mark Morrison, Veral Vishnoi, Samwel Makanyengo, Brian Draganic, Brendan McManus, Louise Clarke, Kalpesh Shah, Stephen R. Smith, Nicholas J. Talley, Simon Keely, Peter Pockney
Anastomotic leaks (AL) are the most severe complications of colorectal surgery. The cause of AL is unclear, but recent studies have implicated the intestinal microbiota in its development. We aimed to determine whether there is an identifiable microbial pattern in the mucosal microbiota associated with AL. A pragmatic series of 162 patients undergoing colorectal resection with anastomosis had swabs taken from the proximal and distal mucosa of the bowel resection immediately after the tissue was excised. DNA was extracted for 16S rRNA amplicon gene sequencing and a subset for metagenomic shotgun sequencing (MGS). The AL rate in the cohort was approximately 15% (25/162). The alpha diversity measures from the intraoperative swabs were all significantly increased for AL, and there were significant differences in the beta diversity measures for AL from both the 16S and MGS datasets. The predictive power of AL was more sensitive when both proximal and distal communities were considered, and the species-level classifier AUC-ROC was stronger for the MGS dataset than for the 16S data (AUC = 0.92 and 0.76, respectively). We also report, for the first time, the functional changes in intraoperative AL microbes and noted an increase in the relative abundance of pathways with fermentation end products. This result was also found in our murine model of anastomoses (n = 20). At the time of surgery, the mucosal microbiota of the anastomotic extremities exhibits subtle differences at the species level and altered fermentation capacity, which may be associated with AL outcomes. A greater understanding of these insights could improve AL prognosis and preoperative management to reduce the occurrence of this life-threatening condition.
吻合口漏（AL）是结直肠手术最严重的并发症。AL的病因尚不清楚，但最近的研究表明肠道微生物群与AL的发生有关。我们旨在确定与 AL 相关的粘膜微生物群是否存在可识别的微生物模式。我们对 162 名接受吻合术结直肠切除术的患者进行了务实的系列研究，在切除肠道组织后立即从切除肠道的近端和远端粘膜上采集拭子。提取的 DNA 用于 16S rRNA 扩增子基因测序，一部分用于元基因组枪式测序（MGS）。队列中的 AL 率约为 15%（25/162）。术中拭子的α多样性测量值在AL时均显著增加，16S和MGS数据集的β多样性测量值在AL时也有显著差异。当同时考虑近端和远端群落时，AL 的预测能力更加灵敏，MGS 数据集的物种级分类器 AUC-ROC 比 16S 数据更强（AUC = 0.92 和 0.76，分别为 0.92 和 0.76）。我们还首次报告了术中 AL 微生物的功能变化，并注意到发酵终产物通路的相对丰度有所增加。这一结果也出现在我们的吻合口小鼠模型中（n = 20）。手术时，吻合口肢体粘膜微生物群在物种水平上表现出微妙的差异，发酵能力也发生了改变，这可能与 AL 的结果有关。进一步了解这些观点可以改善 AL 的预后和术前管理，从而减少这种危及生命的疾病的发生。
{"title":"The Microleaks study: 16S community profile and metagenomic shotgun sequencing signatures associated with anastomotic leak","authors":"Emily C. Hoedt, Georgia Carroll, Bree Stephensen, Katie Togher, Mark Morrison, Veral Vishnoi, Samwel Makanyengo, Brian Draganic, Brendan McManus, Louise Clarke, Kalpesh Shah, Stephen R. Smith, Nicholas J. Talley, Simon Keely, Peter Pockney","doi":"10.1038/s44355-024-00006-8","DOIUrl":"10.1038/s44355-024-00006-8","url":null,"abstract":"Anastomotic leaks (AL) are the most severe complications of colorectal surgery. The cause of AL is unclear, but recent studies have implicated the intestinal microbiota in its development. We aimed to determine whether there is an identifiable microbial pattern in the mucosal microbiota associated with AL. A pragmatic series of 162 patients undergoing colorectal resection with anastomosis had swabs taken from the proximal and distal mucosa of the bowel resection immediately after the tissue was excised. DNA was extracted for 16S rRNA amplicon gene sequencing and a subset for metagenomic shotgun sequencing (MGS). The AL rate in the cohort was approximately 15% (25/162). The alpha diversity measures from the intraoperative swabs were all significantly increased for AL, and there were significant differences in the beta diversity measures for AL from both the 16S and MGS datasets. The predictive power of AL was more sensitive when both proximal and distal communities were considered, and the species-level classifier AUC-ROC was stronger for the MGS dataset than for the 16S data (AUC = 0.92 and 0.76, respectively). We also report, for the first time, the functional changes in intraoperative AL microbes and noted an increase in the relative abundance of pathways with fermentation end products. This result was also found in our murine model of anastomoses (n = 20). At the time of surgery, the mucosal microbiota of the anastomotic extremities exhibits subtle differences at the species level and altered fermentation capacity, which may be associated with AL outcomes. A greater understanding of these insights could improve AL prognosis and preoperative management to reduce the occurrence of this life-threatening condition.","PeriodicalId":501708,"journal":{"name":"npj Gut and Liver","volume":" ","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44355-024-00006-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02DOI: 10.1038/s44355-024-00005-9
Shintaro Akiyama, Joëlle St-Pierre, Cindy Traboulsi, Alexa Silfen, Victoria Rai, Tina G. Rodriguez, Amarachi I. Erondu, Joshua M. Steinberg, Seth R. Shaffer, Britt Christensen, David T. Rubin
We have previously demonstrated that histological normalization in ulcerative colitis (UC) is associated with superior maintenance of remission outcomes. This single-center, retrospective case-control study assessed outcomes after the therapeutic de-escalation in UC patients who have achieved histologic normalization. A total of 111 patients were included, of which 24 underwent de-escalation, and 87 patients without therapeutic changes. The most commonly withdrawn therapy was aminosalicylates (50%), followed by immunomodulators (37.5%), and biologics (12.5%). Fourteen patients remained on therapies after de-escalation, including aminosalicylate (9/14), immunomodulators (3/14), and biologics (3/14), while 10 patients were not on any therapy immediately after withdrawal. Median follow-up was 43 months in the de-escalation group and 47 months in the control. The rates of clinical, endoscopic, and histologic recurrence were not significantly different between the two groups, nor was the proportion of patients who subsequently required additional therapies after withdrawal (P = 0.133). Clinical and endo-histologic recurrence rates were the lowest in patients who withdrew immunomodulators (0% and 14.3%, respectively). We demonstrate the clinical stability of therapeutic withdrawal in UC patients with histologic normalization.
{"title":"Patients with ulcerative colitis who have normalized histology are clinically stable after de-escalation of therapy","authors":"Shintaro Akiyama, Joëlle St-Pierre, Cindy Traboulsi, Alexa Silfen, Victoria Rai, Tina G. Rodriguez, Amarachi I. Erondu, Joshua M. Steinberg, Seth R. Shaffer, Britt Christensen, David T. Rubin","doi":"10.1038/s44355-024-00005-9","DOIUrl":"10.1038/s44355-024-00005-9","url":null,"abstract":"We have previously demonstrated that histological normalization in ulcerative colitis (UC) is associated with superior maintenance of remission outcomes. This single-center, retrospective case-control study assessed outcomes after the therapeutic de-escalation in UC patients who have achieved histologic normalization. A total of 111 patients were included, of which 24 underwent de-escalation, and 87 patients without therapeutic changes. The most commonly withdrawn therapy was aminosalicylates (50%), followed by immunomodulators (37.5%), and biologics (12.5%). Fourteen patients remained on therapies after de-escalation, including aminosalicylate (9/14), immunomodulators (3/14), and biologics (3/14), while 10 patients were not on any therapy immediately after withdrawal. Median follow-up was 43 months in the de-escalation group and 47 months in the control. The rates of clinical, endoscopic, and histologic recurrence were not significantly different between the two groups, nor was the proportion of patients who subsequently required additional therapies after withdrawal (P = 0.133). Clinical and endo-histologic recurrence rates were the lowest in patients who withdrew immunomodulators (0% and 14.3%, respectively). We demonstrate the clinical stability of therapeutic withdrawal in UC patients with histologic normalization.","PeriodicalId":501708,"journal":{"name":"npj Gut and Liver","volume":" ","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44355-024-00005-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1038/s44355-024-00004-w
Xiao-Dong Zhou, Vincent Wai-Sun Wong, Ming-Hua Zheng
Developing drugs for metabolic dysfunction-associated steatohepatitis (MASH) has been a surprisingly challenging task. To effectively treat MASH, the drug should address the three key issues associated with these conditions: fat accumulation, inflammation, and fibrosis. However, no therapeutic drugs have been able to meet all the required criteria, especially when it comes to improving fibrosis. With FDA approval, resmetirom, a liver-targeted thyroid hormone receptor-β (THRβ) selective agonist, changes the MASH drug development landscape. The activation of THRβ is known to improve MASH by controlling fat synthesis, regulating fatty acid oxidation, cholesterol metabolism, mitochondrial function, and reducing inflammation and fibrosis. Glucagon-like peptide-1 (GLP-1) agonists, employed to treat diabetes and obesity, has been tested on MASH patients and is widely regarded as the preferred treatment for MASH. GLP-1 agonists are regarded as the primary contenders for resmetirom. Some even suggest that GLP-1 agonists might have the potential to supplant MASH therapy in its entirety. It should be noted that while GLP-1 agonists positively impact metabolism upstream of the liver, this may not subsequently improve the fibrotic liver injury within the tested treatment duration. Combining the therapeutic approaches of GLP-1 agonists (which target extrahepatic mechanisms for metabolic disorders) with resmetirom (which target intrahepatic mechanisms for MASH and liver fibrosis) seems like a promising strategy for addressing fat accumulation, inflammation, and fibrosis associated with MASH.
{"title":"Resmetirom and GLP-1 agonists for MASH: complementary rather than exclusive","authors":"Xiao-Dong Zhou, Vincent Wai-Sun Wong, Ming-Hua Zheng","doi":"10.1038/s44355-024-00004-w","DOIUrl":"10.1038/s44355-024-00004-w","url":null,"abstract":"Developing drugs for metabolic dysfunction-associated steatohepatitis (MASH) has been a surprisingly challenging task. To effectively treat MASH, the drug should address the three key issues associated with these conditions: fat accumulation, inflammation, and fibrosis. However, no therapeutic drugs have been able to meet all the required criteria, especially when it comes to improving fibrosis. With FDA approval, resmetirom, a liver-targeted thyroid hormone receptor-β (THRβ) selective agonist, changes the MASH drug development landscape. The activation of THRβ is known to improve MASH by controlling fat synthesis, regulating fatty acid oxidation, cholesterol metabolism, mitochondrial function, and reducing inflammation and fibrosis. Glucagon-like peptide-1 (GLP-1) agonists, employed to treat diabetes and obesity, has been tested on MASH patients and is widely regarded as the preferred treatment for MASH. GLP-1 agonists are regarded as the primary contenders for resmetirom. Some even suggest that GLP-1 agonists might have the potential to supplant MASH therapy in its entirety. It should be noted that while GLP-1 agonists positively impact metabolism upstream of the liver, this may not subsequently improve the fibrotic liver injury within the tested treatment duration. Combining the therapeutic approaches of GLP-1 agonists (which target extrahepatic mechanisms for metabolic disorders) with resmetirom (which target intrahepatic mechanisms for MASH and liver fibrosis) seems like a promising strategy for addressing fat accumulation, inflammation, and fibrosis associated with MASH.","PeriodicalId":501708,"journal":{"name":"npj Gut and Liver","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44355-024-00004-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s44355-024-00003-x
Christopher Kasia, Andres Duarte-Rojo
The purpose of this review is to highlight common and best practices in liver transplant evaluation and management, particularly on how to best optimize a patient to become a successful recipient. There is an increasing armamentarium of pharmacologic, procedural, and behavioral interventions that has grown in body of evidence and use in clinical practice to best prepare patients for liver transplant. This includes tools in the management of common decompensations in liver disease, such as hepatic encephalopathy or ascites, as well as associated medical comorbidities that are also encountered in the general population. Aside from management of decompensations, a holistic approach to pre-operative care, including prehabilitation, is becoming increasingly more important to improve sarcopenia, frailty, and quality of life through an exercise program and nutritional modifications. Social determinants of health have become an increasingly recognized barrier to equitable LT access and have garnered increasing attention in the last several years. The road to liver transplantation is a multi-disciplinary patient-centered journey. The complications of decompensated disease require thoughtful decision making as it pertains to management and is a careful balance to avoid the creation of iatrogenic complications which can impact clinical stability and candidacy. Further investment in the management of behavioral modifications and lifestyle is an essential part of the treatment process.
{"title":"Optimizing the liver transplant candidate","authors":"Christopher Kasia, Andres Duarte-Rojo","doi":"10.1038/s44355-024-00003-x","DOIUrl":"10.1038/s44355-024-00003-x","url":null,"abstract":"The purpose of this review is to highlight common and best practices in liver transplant evaluation and management, particularly on how to best optimize a patient to become a successful recipient. There is an increasing armamentarium of pharmacologic, procedural, and behavioral interventions that has grown in body of evidence and use in clinical practice to best prepare patients for liver transplant. This includes tools in the management of common decompensations in liver disease, such as hepatic encephalopathy or ascites, as well as associated medical comorbidities that are also encountered in the general population. Aside from management of decompensations, a holistic approach to pre-operative care, including prehabilitation, is becoming increasingly more important to improve sarcopenia, frailty, and quality of life through an exercise program and nutritional modifications. Social determinants of health have become an increasingly recognized barrier to equitable LT access and have garnered increasing attention in the last several years. The road to liver transplantation is a multi-disciplinary patient-centered journey. The complications of decompensated disease require thoughtful decision making as it pertains to management and is a careful balance to avoid the creation of iatrogenic complications which can impact clinical stability and candidacy. Further investment in the management of behavioral modifications and lifestyle is an essential part of the treatment process.","PeriodicalId":501708,"journal":{"name":"npj Gut and Liver","volume":" ","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44355-024-00003-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-10DOI: 10.1038/s44355-024-00001-z
Giulia Ilaria Bagarolo, Shruti Bhargava, Robert Schierwagen, Wenyi Gu, Vera Jankowski, Josefin Soppert, Emona Barzakova, Federica Cascone, Olaf Tyc, Christiane Kuhl, Heidi Noels, Jonel Trebicka, Joachim Jankowski
Portal hypertension develops in patients with advanced chronic liver diseases (CLD), especially cirrhosis and is associated with complications, such as gastrointestinal bleeding and ascites resulting in high mortality. The transjugular intrahepatic portosystemic shunt (TIPS) is a treatment option for portal hypertension, aiming to decrease portal venous pressure by establishing an artificial passage for blood from the gastrointestinal tract to the liver vein. This study focuses on the differences in the molecular composition of plasma samples from patients with portal hypertension before and after TIPS intervention to identify and characterise potential mediators influencing gut-liver cross-talk. The plasma of 23 patients displaying advanced CLD with portal hypertension was collected from peripheral veins before and after TIPS treatment and analysed using a well-established non-targeted chromatography-mass spectrometric (LC-MS) approach. Sialomucin core protein 24(CD164)(160–180), meckelin(99-118), Histone-lysine N-methyltransferase(MLL3)(3019-3045) and transient receptor potential cation channel subfamily V member 5(TRPV5)(614-630) were identified to be downregulated after the TIPS treatment. In addition, the metabolites 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), uric acid, dopamine, homoarginine, leucylproline and 5-methyluridine were significantly decreased after TIPS, whereas one yet unidentified low molecular-weight metabolite showed an increase after the medical procedure. In conclusion, these substances are novel potential biomarkers for portal hypertension in patients with CLD, with mechanistic clues of involvement in regulating pathological gut-liver cross-talk.
{"title":"Alterations of the peptidomic composition of peripheral plasma after portal hypertension correction by transjugular intrahepatic portosystemic shunt","authors":"Giulia Ilaria Bagarolo, Shruti Bhargava, Robert Schierwagen, Wenyi Gu, Vera Jankowski, Josefin Soppert, Emona Barzakova, Federica Cascone, Olaf Tyc, Christiane Kuhl, Heidi Noels, Jonel Trebicka, Joachim Jankowski","doi":"10.1038/s44355-024-00001-z","DOIUrl":"10.1038/s44355-024-00001-z","url":null,"abstract":"Portal hypertension develops in patients with advanced chronic liver diseases (CLD), especially cirrhosis and is associated with complications, such as gastrointestinal bleeding and ascites resulting in high mortality. The transjugular intrahepatic portosystemic shunt (TIPS) is a treatment option for portal hypertension, aiming to decrease portal venous pressure by establishing an artificial passage for blood from the gastrointestinal tract to the liver vein. This study focuses on the differences in the molecular composition of plasma samples from patients with portal hypertension before and after TIPS intervention to identify and characterise potential mediators influencing gut-liver cross-talk. The plasma of 23 patients displaying advanced CLD with portal hypertension was collected from peripheral veins before and after TIPS treatment and analysed using a well-established non-targeted chromatography-mass spectrometric (LC-MS) approach. Sialomucin core protein 24(CD164)(160–180), meckelin(99-118), Histone-lysine N-methyltransferase(MLL3)(3019-3045) and transient receptor potential cation channel subfamily V member 5(TRPV5)(614-630) were identified to be downregulated after the TIPS treatment. In addition, the metabolites 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), uric acid, dopamine, homoarginine, leucylproline and 5-methyluridine were significantly decreased after TIPS, whereas one yet unidentified low molecular-weight metabolite showed an increase after the medical procedure. In conclusion, these substances are novel potential biomarkers for portal hypertension in patients with CLD, with mechanistic clues of involvement in regulating pathological gut-liver cross-talk.","PeriodicalId":501708,"journal":{"name":"npj Gut and Liver","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44355-024-00001-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141298825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-29DOI: 10.1038/s44355-024-00002-y
Andrew O. Agbaje
Evidence on the long-term relationship of sedentary time (ST), light physical activity (LPA) and moderate-to-vigorous PA (MVPA) with liver steatosis, fibrosis, cirrhosis, and changes in liver enzymes in the paediatric population is limited. This study examined the associations of cumulative ST, LPA and MVPA from childhood with longitudinal changes in liver indices and enzymes. From the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, 2684 children aged 11 years who had at least one follow-up time-points accelerometer-measured ST, LPA and MVPA over a period of 13 years, and liver indices and enzymes measures at age 24 years clinic visit were included. Liver steatosis and fibrosis were assessed by transient elastography and staged as fibrosis stage F0-F4 and steatosis grade (S0-S3) at age 24 years. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (GGT) were assayed at ages 17 and 24 years. Longitudinal associations were examined using generalized linear mixed-effect models, while mediation analyses were conducted with structural equation models. Among 2684 children (mean [SD] age, 11.75 [0.24] years; 1537 [57.3%] females]), the prevalence of liver steatosis at age 17 years was 2.6% and 20.5% at age 24 years. The cumulative 1-minute/day increase in ST from ages 11–24 years was associated with higher odds of liver cirrhosis (odds ratio 1.004 [95% CI 1.002–1.005] p < 0.001) and severe liver steatosis (1.001 [1.001–1.002] p = 0.002) at age 24 years. Increased ST from childhood was directly associated with progressively increased ALT, AST and GGT from ages 17 to 24 years. Cumulative 1-min/day LPA was associated with lower odds of liver cirrhosis (0.990 [0.990–0.991] p < 0.001) and severe liver steatosis (0.999 [0.998–0.999] p < 0.001) at age 24 years, as well as decreased liver enzymes. Cumulative 1-min/day MVPA was associated with associated with lower odds of severe liver steatosis (0.996 [0.994–0.998] p < 0.001) but not liver cirrhosis at age 24 years. MVPA effect on lowering liver steatosis was significantly suppressed (64% suppression) by increased fat mass. In conclusion, increasing LPA, sustaining MVPA and decreasing ST from childhood may independently attenuate and reverse the risk of severe liver steatosis and liver cirrhosis by young adulthood.
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