Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier Alterations
Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Though MASH is closely tied to metabolic risk factors, the underlying pathogenic mechanisms remain scarcely understood. Rece...
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Elsevier
2025-01-01
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| Series: | Gastro Hep Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S277257232400195X |
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| author | Alia Hadefi Morgane Leprovots Gilles Dinsart Maryam Marefati Marjorie Vermeersch Daniel Monteyne David Pérez-Morga Anne Lefort Frédérick Libert Laurine Verset Claire Liefferinckx Christophe Moreno Jacques Devière Eric Trépo Marie-Isabelle Garcia |
| author_facet | Alia Hadefi Morgane Leprovots Gilles Dinsart Maryam Marefati Marjorie Vermeersch Daniel Monteyne David Pérez-Morga Anne Lefort Frédérick Libert Laurine Verset Claire Liefferinckx Christophe Moreno Jacques Devière Eric Trépo Marie-Isabelle Garcia |
| author_sort | Alia Hadefi |
| collection | DOAJ |
| description | Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Though MASH is closely tied to metabolic risk factors, the underlying pathogenic mechanisms remain scarcely understood. Recent research has emphasized the importance of the gut-liver axis in its pathogenesis, an aspect less explored in human studies. Here, we investigated whether the duodenal epithelium of MASH patients could exhibit intrinsic dysfunctions. Methods: Duodenal epithelial organoids were generated from 16 MASH patients and 14 healthy controls. Biopsies and patient-derived organoid transcriptomes were then analyzed to evaluate if specific intestinal pathways were differentially modulated in MASH subjects. Functional assays were performed to assess the duodenal epithelial absorptive potential and barrier functionality. Results: Organoid formation efficiency was similar between control-derived duodenal epithelial organoids and MASH-derived duodenal epithelial organoids (MDEOs) (71% and 69%, respectively). Despite global heterogeneity in growth patterns, MDEOs frequently exhibited cystic spheroid morphology. MDEOs displayed altered digestive potential associated with reduced mature absorptive cell fate, but they retained their lipid metabolic capacity, possibly mediated by lipid oxidation in stem/progenitor cells. Additionally, MDEOs misexpressed components of tight and adherens junctions and desmosomes compared to controls. However, MDEOs maintained pore and leak pathway integrity, indicating that the duodenal epithelial barrier remained functionally preserved under tested conditions. Conclusion: This study provides evidence that the duodenal epithelium of MASH patients exhibits significant alterations in its nutrition-related and barrier functions. This study sheds light on the intricate dynamics of duodenal epithelial alterations in MASH, highlighting potential therapeutic avenues for restoring intestinal functions. |
| format | Article |
| id | doaj-art-e0f51ba5b9a74f0f9787f1845ce6a233 |
| institution | Kabale University |
| issn | 2772-5723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Gastro Hep Advances |
| spelling | doaj-art-e0f51ba5b9a74f0f9787f1845ce6a2332025-02-10T04:35:30ZengElsevierGastro Hep Advances2772-57232025-01-0144100599Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier AlterationsAlia Hadefi0Morgane Leprovots1Gilles Dinsart2Maryam Marefati3Marjorie Vermeersch4Daniel Monteyne5David Pérez-Morga6Anne Lefort7Frédérick Libert8Laurine Verset9Claire Liefferinckx10Christophe Moreno11Jacques Devière12Eric Trépo13Marie-Isabelle Garcia14IRIBHM, Jacques E. Dumont, Faculty of Medicine, Université Libre de Bruxelles ULB, Brussels, Belgium; Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, BelgiumIRIBHM, Jacques E. Dumont, Faculty of Medicine, Université Libre de Bruxelles ULB, Brussels, BelgiumIRIBHM, Jacques E. Dumont, Faculty of Medicine, Université Libre de Bruxelles ULB, Brussels, BelgiumIRIBHM, Jacques E. Dumont, Faculty of Medicine, Université Libre de Bruxelles ULB, Brussels, BelgiumCenter for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), Charleroi, BelgiumCenter for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), Charleroi, BelgiumCenter for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), Charleroi, BelgiumBRIGHTcore ULB-VUB and Institute of Interdisciplinary Research in Human and Molecular Biology (IRIBHM), Université Libre de Bruxelles, Brussels, BelgiumBRIGHTcore ULB-VUB and Institute of Interdisciplinary Research in Human and Molecular Biology (IRIBHM), Université Libre de Bruxelles, Brussels, BelgiumInstitut Jules Bordet, Hôpital Universitaire de Bruxelles, Centre d’Anatomie pathologique, rue Meylermeersch, Brussels, BelgiumDepartment of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, BelgiumDepartment of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, BelgiumDepartment of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, BelgiumDepartment of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, BelgiumIRIBHM, Jacques E. Dumont, Faculty of Medicine, Université Libre de Bruxelles ULB, Brussels, Belgium; Correspondence: Address correspondence to: Marie-Isabelle Garcia, PhD, Université Libre de Bruxelles, IRIBHM, GHoPaT Group, Room C5-140, Route de Lennik, Brussels 8081070, Belgium.Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Though MASH is closely tied to metabolic risk factors, the underlying pathogenic mechanisms remain scarcely understood. Recent research has emphasized the importance of the gut-liver axis in its pathogenesis, an aspect less explored in human studies. Here, we investigated whether the duodenal epithelium of MASH patients could exhibit intrinsic dysfunctions. Methods: Duodenal epithelial organoids were generated from 16 MASH patients and 14 healthy controls. Biopsies and patient-derived organoid transcriptomes were then analyzed to evaluate if specific intestinal pathways were differentially modulated in MASH subjects. Functional assays were performed to assess the duodenal epithelial absorptive potential and barrier functionality. Results: Organoid formation efficiency was similar between control-derived duodenal epithelial organoids and MASH-derived duodenal epithelial organoids (MDEOs) (71% and 69%, respectively). Despite global heterogeneity in growth patterns, MDEOs frequently exhibited cystic spheroid morphology. MDEOs displayed altered digestive potential associated with reduced mature absorptive cell fate, but they retained their lipid metabolic capacity, possibly mediated by lipid oxidation in stem/progenitor cells. Additionally, MDEOs misexpressed components of tight and adherens junctions and desmosomes compared to controls. However, MDEOs maintained pore and leak pathway integrity, indicating that the duodenal epithelial barrier remained functionally preserved under tested conditions. Conclusion: This study provides evidence that the duodenal epithelium of MASH patients exhibits significant alterations in its nutrition-related and barrier functions. This study sheds light on the intricate dynamics of duodenal epithelial alterations in MASH, highlighting potential therapeutic avenues for restoring intestinal functions.http://www.sciencedirect.com/science/article/pii/S277257232400195XMASHStem CellsCell AdhesionOrganoidsIntestine |
| spellingShingle | Alia Hadefi Morgane Leprovots Gilles Dinsart Maryam Marefati Marjorie Vermeersch Daniel Monteyne David Pérez-Morga Anne Lefort Frédérick Libert Laurine Verset Claire Liefferinckx Christophe Moreno Jacques Devière Eric Trépo Marie-Isabelle Garcia Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier Alterations Gastro Hep Advances MASH Stem Cells Cell Adhesion Organoids Intestine |
| title | Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier Alterations |
| title_full | Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier Alterations |
| title_fullStr | Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier Alterations |
| title_full_unstemmed | Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier Alterations |
| title_short | Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier Alterations |
| title_sort | duodenal organoids from metabolic dysfunction associated steatohepatitis patients exhibit absorptive and barrier alterations |
| topic | MASH Stem Cells Cell Adhesion Organoids Intestine |
| url | http://www.sciencedirect.com/science/article/pii/S277257232400195X |
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