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Özdirik B, Berger H, Tonetti FR, Cabré N, Treichel N, Clavel T, Tacke F, Sigal M, Schnabl B. Faecal Cytolysin is Associated With Worse Survival in Patients With Primary Sclerosing Cholangitis. Liver Int 2025; 45:e16181. [PMID: 40083245 DOI: 10.1111/liv.16181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 03/16/2025]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy without treatment options beyond liver transplantation. The gut-liver axis, especially the role of gut microbes, has emerged as a crucial pathway contributing to PSC pathogenesis. Recent research has revealed Enterococcus (E.) faecalis and its virulence factor cytolysin to increase mortality risk in patients with alcohol-associated hepatitis. Thus, we studied the role of enterococci, particularly E. faecalis and its virulence factor genes cytolysin and gelatinase, in faecal samples from patients with PSC. METHODS To assess the relevance of Enterococcus species, we performed 16S rRNA gene amplicon analysis in faecal samples from 60 patients with PSC. We validated our findings by qPCR of faecal microbial DNA in an extended cohort of 105 patients with PSC, 104 patients with inflammatory bowel disease (IBD) and 68 healthy subjects. RESULTS High-throughput 16S rRNA amplicon analysis revealed an increased relative abundance of enterococci in PSC patients compared with healthy controls and IBD patients, respectively, (p < 0.0001). PSC patients with high enterococci abundance had a decreased probability of transplant-free survival (p = 0.028). E. faecalis and its virulence factors cytolysin and gelatinase were more abundant in patients with PSC. Higher faecal cytolysin was associated with lower overall survival (p = 0.04), while survival was independent of gelatinase levels. CONCLUSION Our data highlight the association of E. faecalis and faecal cytolysin with lower survival in patients with PSC. These data should prompt further research into the pathogenic role of cytolysin-positive E. faecalis, and to explore its role as a potential therapeutic target.
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Affiliation(s)
- Burcin Özdirik
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Hilmar Berger
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fernanda Raya Tonetti
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Noemí Cabré
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Nicole Treichel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
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Ronca V, Gerussi A, Collins P, Parente A, Oo YH, Invernizzi P. The liver as a central "hub" of the immune system: pathophysiological implications. Physiol Rev 2025; 105:493-539. [PMID: 39297676 DOI: 10.1152/physrev.00004.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 01/16/2025] Open
Abstract
The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.
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Affiliation(s)
- Vincenzo Ronca
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Paul Collins
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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Ning M, Lu D, Liang D, Ren PG. Single-cell RNA sequencing advances in revealing the development and progression of MASH: the identifications and interactions of non-parenchymal cells. Front Mol Biosci 2025; 12:1513993. [PMID: 40201243 PMCID: PMC11976672 DOI: 10.3389/fmolb.2025.1513993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 03/05/2025] [Indexed: 04/10/2025] Open
Abstract
Developing drugs for the treatment of Metabolic Associated Steatohepatitis (MASH) has always been a significant challenge. Researchers have been dedicated to exploring drugs and therapeutic strategies to alleviate disease progression, but treatments remain limited. This is partly due to the complexity of the pathophysiological processes, and inadequate knowledge of the cellular and molecular mechanisms in MASH. Especially, the liver non-parenchymal cells (NPCs) like Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells which play critical roles in live function, immune responses, fibrosis and disease progression. Deciphering how these cells function in MASH, would help understand the pathophysiological processes and find potential drug targets. In recent years, new technologies have been developed for single-cell transcriptomic sequencing, making cell-specific transcriptome profiling a reality in healthy and diseased livers. In this review, we discussed how the use of single-cell transcriptomic sequencing provided us with an in-depth understanding of the heterogeneous, cellular interactions among non-parenchymal cells and tried to highlight recent discoveries in MASH by this technology. It is hoped that the summarized features and markers of various subclusters in this review could provide a technical reference for further experiments and a theoretical basis for clinical applications.
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Affiliation(s)
- Meng Ning
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen, China
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Donghui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Dong Liang
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Pei-Gen Ren
- Center for Cancer Immunology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
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Schneider KM, Kummen M, Trivedi PJ, Hov JR. Role of microbiome in autoimmune liver diseases. Hepatology 2024; 80:965-987. [PMID: 37369002 PMCID: PMC11407779 DOI: 10.1097/hep.0000000000000506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/25/2023] [Indexed: 06/29/2023]
Abstract
The microbiome plays a crucial role in integrating environmental influences into host physiology, potentially linking it to autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. All autoimmune liver diseases are associated with reduced diversity of the gut microbiome and altered abundance of certain bacteria. However, the relationship between the microbiome and liver diseases is bidirectional and varies over the course of the disease. This makes it challenging to dissect whether such changes in the microbiome are initiating or driving factors in autoimmune liver diseases, secondary consequences of disease and/or pharmacological intervention, or alterations that modify the clinical course that patients experience. Potential mechanisms include the presence of pathobionts, disease-modifying microbial metabolites, and more nonspecific reduced gut barrier function, and it is highly likely that the effect of these change during the progression of the disease. Recurrent disease after liver transplantation is a major clinical challenge and a common denominator in these conditions, which could also represent a window to disease mechanisms of the gut-liver axis. Herein, we propose future research priorities, which should involve clinical trials, extensive molecular phenotyping at high resolution, and experimental studies in model systems. Overall, autoimmune liver diseases are characterized by an altered microbiome, and interventions targeting these changes hold promise for improving clinical care based on the emerging field of microbiota medicine.
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Affiliation(s)
| | - Martin Kummen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Palak J. Trivedi
- National Institute for Health and Care Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, UK
| | - Johannes R. Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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5
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Cornillet M, Geanon D, Bergquist A, Björkström NK. Immunobiology of primary sclerosing cholangitis. Hepatology 2024:01515467-990000000-01014. [PMID: 39226402 DOI: 10.1097/hep.0000000000001080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 08/21/2024] [Indexed: 09/05/2024]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, the presence of autoantibodies, the strong clinical link with inflammatory bowel disease, and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue residency and knowledge gained from novel technologies, including single-cell RNA sequencing and spatial transcriptomics. This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.
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Affiliation(s)
- Martin Cornillet
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Daniel Geanon
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Annika Bergquist
- Unit of Gastroenterology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K Björkström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Gao J, Lan T, Kostallari E, Guo Y, Lai E, Guillot A, Ding B, Tacke F, Tang C, Shah VH. Angiocrine signaling in sinusoidal homeostasis and liver diseases. J Hepatol 2024; 81:543-561. [PMID: 38763358 PMCID: PMC11906189 DOI: 10.1016/j.jhep.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/29/2024] [Accepted: 05/10/2024] [Indexed: 05/21/2024]
Abstract
The hepatic sinusoids are composed of liver sinusoidal endothelial cells (LSECs), which are surrounded by hepatic stellate cells (HSCs) and contain liver-resident macrophages called Kupffer cells, and other patrolling immune cells. All these cells communicate with each other and with hepatocytes to maintain sinusoidal homeostasis and a spectrum of hepatic functions under healthy conditions. Sinusoidal homeostasis is disrupted by metabolites, toxins, viruses, and other pathological factors, leading to liver injury, chronic liver diseases, and cirrhosis. Alterations in hepatic sinusoids are linked to fibrosis progression and portal hypertension. LSECs are crucial regulators of cellular crosstalk within their microenvironment via angiocrine signaling. This review discusses the mechanisms by which angiocrine signaling orchestrates sinusoidal homeostasis, as well as the development of liver diseases. Here, we summarise the crosstalk between LSECs, HSCs, hepatocytes, cholangiocytes, and immune cells in health and disease and comment on potential novel therapeutic methods for treating liver diseases.
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Affiliation(s)
- Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Lan
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China; Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yangkun Guo
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Enjiang Lai
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Bisen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Trivedi PJ, Hirschfield GM, Adams DH, Vierling JM. Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts. Gastroenterology 2024; 166:995-1019. [PMID: 38342195 DOI: 10.1053/j.gastro.2024.01.049] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 01/21/2024] [Accepted: 01/28/2024] [Indexed: 02/13/2024]
Abstract
Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom.
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - David H Adams
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
| | - John M Vierling
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, Texas.
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Marrella V, Nicchiotti F, Cassani B. Microbiota and Immunity during Respiratory Infections: Lung and Gut Affair. Int J Mol Sci 2024; 25:4051. [PMID: 38612860 PMCID: PMC11012346 DOI: 10.3390/ijms25074051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/29/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Bacterial and viral respiratory tract infections are the most common infectious diseases, leading to worldwide morbidity and mortality. In the past 10 years, the importance of lung microbiota emerged in the context of pulmonary diseases, although the mechanisms by which it impacts the intestinal environment have not yet been fully identified. On the contrary, gut microbial dysbiosis is associated with disease etiology or/and development in the lung. In this review, we present an overview of the lung microbiome modifications occurring during respiratory infections, namely, reduced community diversity and increased microbial burden, and of the downstream consequences on host-pathogen interaction, inflammatory signals, and cytokines production, in turn affecting the disease progression and outcome. Particularly, we focus on the role of the gut-lung bidirectional communication in shaping inflammation and immunity in this context, resuming both animal and human studies. Moreover, we discuss the challenges and possibilities related to novel microbial-based (probiotics and dietary supplementation) and microbial-targeted therapies (antibacterial monoclonal antibodies and bacteriophages), aimed to remodel the composition of resident microbial communities and restore health. Finally, we propose an outlook of some relevant questions in the field to be answered with future research, which may have translational relevance for the prevention and control of respiratory infections.
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Affiliation(s)
- Veronica Marrella
- UOS Milan Unit, Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, 20138 Milan, Italy;
- IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Federico Nicchiotti
- Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, 20089 Milan, Italy;
| | - Barbara Cassani
- IRCCS Humanitas Research Hospital, 20089 Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, 20089 Milan, Italy;
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Stumme F, Steffens N, Steglich B, Mathies F, Nawrocki M, Sabihi M, Soukou-Wargalla S, Göke E, Kempski J, Fründt T, Weidemann S, Schramm C, Gagliani N, Huber S, Bedke T. A protective effect of inflammatory bowel disease on the severity of sclerosing cholangitis. Front Immunol 2024; 15:1307297. [PMID: 38510236 PMCID: PMC10950911 DOI: 10.3389/fimmu.2024.1307297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/12/2024] [Indexed: 03/22/2024] Open
Abstract
Background Primary sclerosing cholangitis (PSC) is a chronic liver disease marked by inflammation of the bile ducts and results in the development of strictures and fibrosis. A robust clinical correlation exists between PSC and inflammatory bowel disease (IBD). At present, published data are controversial, and it is yet unclear whether IBD drives or attenuates PSC. Methods Mdr2-deficient mice or DDC-fed mice were used as experimental models for sclerosing cholangitis. Additionally, colitis was induced in mice with experimental sclerosing cholangitis, either through infection with Citrobacter rodentium or by feeding with DSS. Lastly, fibrosis levels were determined through FibroScan analysis in people with PSC and PSC-IBD. Results Using two distinct experimental models of colitis and two models of sclerosing cholangitis, we found that colitis does not aggravate liver pathology, but rather reduces liver inflammation and liver fibrosis. Likewise, people with PSC-IBD have decreased liver fibrosis compared to those with PSC alone. Conclusions We found evidence that intestinal inflammation attenuates liver pathology. This study serves as a basis for further research on the pathogenesis of PSC and PSC-IBD, as well as the molecular mechanism responsible for the protective effect of IBD on PSC development. This study could lead to the discovery of novel therapeutic targets for PSC.
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Affiliation(s)
- Friederike Stumme
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Niklas Steffens
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Babett Steglich
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Mathies
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mikolaj Nawrocki
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Morsal Sabihi
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Shiwa Soukou-Wargalla
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Emilia Göke
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Kempski
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorben Fründt
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Center of Diagnostics, Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tanja Bedke
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Rodrigues SG, van der Merwe S, Krag A, Wiest R. Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases. Semin Immunol 2024; 71:101859. [PMID: 38219459 DOI: 10.1016/j.smim.2023.101859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Schalk van der Merwe
- Department of Gastroenterology and Hepatology, University hospital Gasthuisberg, University of Leuven, Belgium
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark, University of Southern Denmark, Odense, Denmark
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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11
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Sutton H, Karpen SJ, Kamath BM. Pediatric Cholestatic Diseases: Common and Unique Pathogenic Mechanisms. ANNUAL REVIEW OF PATHOLOGY 2024; 19:319-344. [PMID: 38265882 DOI: 10.1146/annurev-pathmechdis-031521-025623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2024]
Abstract
Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert. Bile acid (BA) synthesis and excretion, the formation and flow of bile, and the enterohepatic reuptake of BAs all function to maintain the circulation of BAs, a key molecule in lipid digestion, metabolic and cellular signaling, and, as discussed in the review, a crucial mediator in the pathogenesis of cholestasis. Disruption of one or several of these steps can result in the accumulation of toxic BAs in bile ducts and hepatocytes leading to inflammation, fibrosis, and, over time, biliary and hepatic cirrhosis. Biliary atresia, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and Alagille syndrome are four of the most common pediatric cholestatic conditions. Through understanding the commonalities and differences in these diseases, the important cellular mechanistic underpinnings of cholestasis can be greater appreciated.
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Affiliation(s)
- Harry Sutton
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
| | - Saul J Karpen
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Binita M Kamath
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
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12
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Eladham MW, Selvakumar B, Saheb Sharif-Askari N, Saheb Sharif-Askari F, Ibrahim SM, Halwani R. Unraveling the gut-Lung axis: Exploring complex mechanisms in disease interplay. Heliyon 2024; 10:e24032. [PMID: 38268584 PMCID: PMC10806295 DOI: 10.1016/j.heliyon.2024.e24032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 12/18/2023] [Accepted: 01/02/2024] [Indexed: 01/26/2024] Open
Abstract
The link between gut and lung starts as early as during organogenesis. Even though they are anatomically distinct, essential bidirectional crosstalk via complex mechanisms supports GLA. Emerging studies have demonstrated the association of gut and lung diseases via multifaceted mechanisms. Advancements in omics and metagenomics technologies revealed a potential link between gut and lung microbiota, adding further complexity to GLA. Despite substantial studies on GLA in various disease models, mechanisms beyond microbial dysbiosis regulating the interplay between gut and lung tissues during disease conditions are not thoroughly reviewed. This review outlines disease specific GLA mechanisms, emphasizing research gaps with a focus on gut-to-lung direction based on current GLA literature. Moreover, the review discusses potential gut microbiota and their products like metabolites, immune modulators, and non-bacterial contributions as a basis for developing treatment strategies for lung diseases. Advanced experimental methods, modern diagnostic tools, and technological advancements are also highlighted as crucial areas for improvement in developing novel therapeutic approaches for GLA-related diseases. In conclusion, this review underscores the importance of exploring additional mechanisms within the GLA to gain a deeper understanding that could aid in preventing and treating a wide spectrum of lung diseases.
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Affiliation(s)
- Mariam Wed Eladham
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Balachandar Selvakumar
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Narjes Saheb Sharif-Askari
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Fatemeh Saheb Sharif-Askari
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Pharmacy Practice and Pharmaceutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
| | | | - Rabih Halwani
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Prince Abdullah Ben Khaled Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Saudi Arabia
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13
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Migliorisi G, Vella G, Dal Buono A, Gabbiadini R, Busacca A, Loy L, Bezzio C, Vinciguerra P, Armuzzi A. Ophthalmological Manifestations in Inflammatory Bowel Diseases: Keep an Eye on It. Cells 2024; 13:142. [PMID: 38247834 PMCID: PMC10814681 DOI: 10.3390/cells13020142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 12/31/2023] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases (IBD) are multifactorial chronic inflammatory disorders affecting the gastrointestinal tract. However, a broad spectrum of extraintestinal manifestations (EIMs) is associated with IBD, affecting several organs and systems, such as the skin, musculoskeletal and hepatobiliary systems, and, not least, the eye. Approximately 10% of IBD patients can develop ocular EIMs (O-EIMs) with a higher prevalence in Crohn's disease (CD). Eye-redness, photophobia, pain, and blurred vision are the common symptoms, with a wide rate of severity and clinical impact on the quality of life. This narrative review aims to summarize the prevalence, pathogenesis, and current evidence-based management of O-EIMs, underlying the importance of a holistic approach and specialties collaboration for a prompt diagnosis and treatment. METHODS PubMed was searched up to December 2023 to identify relevant studies investigating the pathogenesis, epidemiology, and treatment of O-EIMs in IBD patients. RESULTS The mechanisms underlying O-EIMs are partially unknown, encompassing immune dysregulation, shared antigens between the eye and the gut, genetic predisposition, and systemic inflammation driven by high levels of interleukins and cytokines in IBD patients. The complexity of O-EIMs' pathogenesis reflects in the management of these conditions, varying from topical and systemic steroids to immunomodulatory molecules and biologic therapy, such as anti-tumor necrosis factor (TNF)-alpha. A multidisciplinary approach is the backbone of the management of O-EIMs.
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Affiliation(s)
- Giulia Migliorisi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
| | - Giovanna Vella
- Department of Ophtalmology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Arianna Dal Buono
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
| | - Roberto Gabbiadini
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
| | - Anita Busacca
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
| | - Laura Loy
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
| | - Cristina Bezzio
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
| | - Paolo Vinciguerra
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
- Department of Ophtalmology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (G.M.); (A.D.B.); (R.G.); (A.B.); (L.L.); (C.B.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
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14
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Gordon H, Wichmann K, Lewis A, Sanders T, Wildemann M, Hoti I, Hornsby E, Kok KB, Silver A, Lindsay JO, Stagg AJ. Human Intestinal Dendritic Cells Can Overcome Retinoic Acid Signaling to Generate Proinflammatory CD4 T Cells with Both Gut and Skin Homing Properties. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:96-106. [PMID: 37955427 DOI: 10.4049/jimmunol.2300340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 09/18/2023] [Indexed: 11/14/2023]
Abstract
Retinoic acid, produced by intestinal dendritic cells (DCs), promotes T cell trafficking to the intestinal mucosa by upregulating α4β7 integrin and inhibiting the generation of cutaneous leukocyte Ag (CLA) required for skin entry. In the present study, we report that activation of human naive CD4 T cells in an APC-free system generates cells expressing α4β7 alone; in contrast, activation by intestinal DCs that produce retinoic acid and induce high levels of α4β7 also results in CLA expression, generating CLA+α4β7+ "dual tropic" cells, with both gut and skin trafficking potential, that also express high levels of α4β1 integrin. DC generation of CLA+α4β7+ T cells is associated with upregulation of FUT7, a fucosyltransferase involved in CLA generation; requires cell contact; and is enhanced by IL-12/IL-23. The blood CD4+ T cell population contains CLA+α4β7+ cells, which are significantly enriched for cells capable of IFN-γ, IL-17, and TNF-α production compared with conventional CLA-α4β7+ cells. Dual tropic lymphocytes are increased in intestinal tissue from patients with Crohn's disease, and single-cell RNA-sequencing analysis identifies a transcriptionally distinct cluster of FUT7-expressing cells present only in inflamed tissue; expression of genes associated with cell proliferation suggests that these cells are undergoing local activation. The expression of multiple trafficking molecules by CLA+α4β7+ T cells can enable their recruitment by alternative pathways to both skin and gut; they may contribute to both intestinal and cutaneous manifestations of inflammatory bowel disease.
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Affiliation(s)
- Hannah Gordon
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
| | - Katherine Wichmann
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
| | - Amy Lewis
- Centre for Genomics and Child Health, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
| | - Theodore Sanders
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
| | - Martha Wildemann
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
| | - Inva Hoti
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
| | - Eve Hornsby
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
| | - K Bel Kok
- Department of Gastroenterology, Barts Health NHS Trust, London, United Kingdom
| | - Andrew Silver
- Centre for Genomics and Child Health, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
- Department of Gastroenterology, Barts Health NHS Trust, London, United Kingdom
| | - Andrew J Stagg
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine and dentistry, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
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Özdirik B, Schnabl B. Microbial Players in Primary Sclerosing Cholangitis: Current Evidence and Concepts. Cell Mol Gastroenterol Hepatol 2023; 17:423-438. [PMID: 38109970 PMCID: PMC10837305 DOI: 10.1016/j.jcmgh.2023.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with progressive biliary inflammation, destruction of the biliary tract, and fibrosis, resulting in liver cirrhosis and end-stage liver disease. To date, liver transplantation is the only definitive treatment option for PSC. The precise etiology of PSC remains elusive, but it is widely accepted to involve a complex interplay between genetic predisposition, immunologic dysfunction, and environmental influence. In recent years, the gut-liver axis has emerged as a crucial pathway contributing to the pathogenesis of PSC, with particular focus on the role of gut microbiota. However, the role of the fungal microbiome or mycobiome has been overlooked for years, resulting in a lack of comprehensive studies on its involvement in PSC. In this review, we clarify the present clinical and mechanistic data and concepts concerning the gut bacterial and fungal microbiota in the context of PSC. This review sheds light on the role of specific microbes and elucidates the dynamics of bacterial and fungal populations. Moreover, we discuss the latest insights into microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism.
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Affiliation(s)
- Burcin Özdirik
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California.
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Mousavere I, Kalampokis G, Fousekis F, Karayiannis P, Baltayiannis G, Christodoulou D. An overview of recent treatment options for primary sclerosing cholangitis. Ann Gastroenterol 2023; 36:589-598. [PMID: 38023975 PMCID: PMC10662072 DOI: 10.20524/aog.2023.0834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 09/26/2023] [Indexed: 12/01/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic hepatic dysfunction characterized by inflammatory and tissue-degenerative strictures of the biliary tree, leading to cirrhosis and cholangiocarcinoma. The pathophysiological mechanisms involve immune-mediated responses. Numerous treatment modalities targeting the inflammatory aspects have been suggested, but a consensus on the best treatment option is lacking. This study aims to review the most up-to-date treatment options for PSC.
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Affiliation(s)
- Ioanna Mousavere
- Department of Gastroenterology, University Hospital of Ioannina, Greece (Ioanna Mousavere, Fotios Fousekis, Gerasimos Baltayiannis, Dimitrios Christodoulou)
| | - Georgios Kalampokis
- Department of Internal Medicine, University Hospital of Ioannina, Greece (Georgios Kalampokis, Gerasimos Baltayiannis, Dimitrios Christodoulou)
| | - Fotios Fousekis
- Department of Gastroenterology, University Hospital of Ioannina, Greece (Ioanna Mousavere, Fotios Fousekis, Gerasimos Baltayiannis, Dimitrios Christodoulou)
| | - Peter Karayiannis
- Department of Microbiology and Molecular Virology, University of Nicosia, Cyprus (Peter Karayiannis)
| | - Gerasimos Baltayiannis
- Department of Gastroenterology, University Hospital of Ioannina, Greece (Ioanna Mousavere, Fotios Fousekis, Gerasimos Baltayiannis, Dimitrios Christodoulou)
| | - Dimitrios Christodoulou
- Department of Gastroenterology, University Hospital of Ioannina, Greece (Ioanna Mousavere, Fotios Fousekis, Gerasimos Baltayiannis, Dimitrios Christodoulou)
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17
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He R, Zhao S, Cui M, Chen Y, Ma J, Li J, Wang X. Cutaneous manifestations of inflammatory bowel disease: basic characteristics, therapy, and potential pathophysiological associations. Front Immunol 2023; 14:1234535. [PMID: 37954590 PMCID: PMC10637386 DOI: 10.3389/fimmu.2023.1234535] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease typically involving the gastrointestinal tract but not limited to it. IBD can be subdivided into Crohn's disease (CD) and ulcerative colitis (UC). Extraintestinal manifestations (EIMs) are observed in up to 47% of patients with IBD, with the most frequent reports of cutaneous manifestations. Among these, pyoderma gangrenosum (PG) and erythema nodosum (EN) are the two most common skin manifestations in IBD, and both are immune-related inflammatory skin diseases. The presence of cutaneous EIMs may either be concordant with intestinal disease activity or have an independent course. Despite some progress in research on EIMs, for instance, ectopic expression of gut-specific mucosal address cell adhesion molecule-1 (MAdCAM-1) and chemokine CCL25 on the vascular endothelium of the portal tract have been demonstrated in IBD-related primary sclerosing cholangitis (PSC), little is understood about the potential pathophysiological associations between IBD and cutaneous EIMs. Whether cutaneous EIMs are inflammatory events with a commonly shared genetic background or environmental risk factors with IBD but independent of IBD or are the result of an extraintestinal extension of intestinal inflammation, remains unclear. The review aims to provide an overview of the two most representative cutaneous manifestations of IBD, describe IBD's epidemiology, clinical characteristics, and histology, and discuss the immunopathophysiology and existing treatment strategies with biologic agents, with a focus on the potential pathophysiological associations between IBD and cutaneous EIMs.
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Affiliation(s)
- Ronghua He
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Subei Zhao
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingyu Cui
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yanhao Chen
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jinrong Ma
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jintao Li
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaodong Wang
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
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18
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Zhang J, Wang H, Liu J, Fu L, Peng S. ANXA1 is identified as a key gene associated with high risk and T cell infiltration in primary sclerosing cholangitis. Hum Genomics 2023; 17:86. [PMID: 37735492 PMCID: PMC10512524 DOI: 10.1186/s40246-023-00534-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 09/12/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, with unclear pathogenesis. Although immune disorders, especially T cell infiltration, are thought to play a vital role in PSC, the specific pathogenesis mechanisms remain incompletely understood. This study evaluated the potential key gene associated with the PSC pathogenesis and analyzed the associations of the key gene with prognosis and immune cell infiltration by combining bioinformatics analysis and experimental verification. METHODS Transcriptome data of PSC and normal human liver tissues (GSE159676) were obtained from the gene expression omnibus database. Differentially expressed genes (DEGs) were identified, and differences in biological states were analyzed. A protein-protein interaction (PPI) network was constructed. Hub genes were identified, and their expression was verified using transcriptome data of mice fed 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and Mdr2-/- mice (GSE179993, GSE80776), as well as by immunohistochemistry staining on clinical samples. The correlations between the key gene and other factors were evaluated by Pearson's correlation coefficient. Immune cell infiltration into human liver (GSE159676) was analyzed by xCell and verified by immunofluorescence staining on PSC liver samples. RESULTS Of the 185 DEGs identified, 113 were upregulated and 72 were downregulated genes in PSC. Genes associated with immune cell infiltration and fibrosis were significantly enriched in PSC. PPI network showed close interactions among DEGs. A module strongly associated with immune infiltration was identified, with annexin A1 (ANXA1) being the core gene. High expression of ANXA1 in PSC was confirmed in two public datasets and by immunohistochemistry staining on clinical samples. High ANXA1 expression was strongly associated with high-risk score for PSC. Also, ANXA1 expression was positively associated with chemokines and chemokine receptors and with the infiltration of immune cells, especially T cells, into liver with PSC. Immune infiltration, fibrosis, and cancer-related processes were markedly enriched in PSC with high expression of ANXA1. CONCLUSION ANXA1 is a key gene associated with high risk and infiltration of immune cells, especially T cells, in PSC. These findings provide new insight into the key biomarker of PSC and suggest that targeting ANXA1 may be a valuable strategy for the treatment of PSC.
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Affiliation(s)
- Jian Zhang
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Huiwen Wang
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Jinqing Liu
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Lei Fu
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China.
| | - Shifang Peng
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China.
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Sharma P, Joshi RV, Pritchard R, Xu K, Eicher MA. Therapeutic Antibodies in Medicine. Molecules 2023; 28:6438. [PMID: 37764213 PMCID: PMC10535987 DOI: 10.3390/molecules28186438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/05/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10-15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery.
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Affiliation(s)
- Prerna Sharma
- Geisinger Commonwealth School of Medicine, Scranton, PA 18509, USA
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20
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Nanjundappa RH, Christen U, Umeshappa CS. Distinct immune surveillance in primary biliary cholangitis and primary sclerosing cholangitis is linked with discrete cholangiocarcinoma risk. Hepatol Commun 2023; 7:e0218. [PMID: 37555943 PMCID: PMC10412426 DOI: 10.1097/hc9.0000000000000218] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/10/2023] [Indexed: 08/10/2023] Open
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are 2 major liver autoimmune diseases. PBC is common in women and primarily affects intrahepatic small bile duct epithelial cells, known as cholangiocytes. In contrast, PSC is dominant in men and primarily affects medium and big intrahepatic and extrahepatic bile duct epithelial cells. Cholangiocarcinoma (CCA) is a malignancy arising from cholangiocytes, and its incidence is increasing worldwide in both men and women. Numerous retrospective and clinical studies have suggested that PBC patients rarely develop CCA compared to PSC patients. CCA is accountable for the higher deaths in PSC patients due to ineffective therapies and our inability to diagnose the disease at an early stage. Therefore, it is paramount to understand the differences in immune surveillance mechanisms that render PBC patients more resistant while PSC patients are susceptible to CCA development. Here, we review several potential mechanisms contributing to differences in the susceptibility to CCA in PBC versus PSC patients.
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Affiliation(s)
- Roopa H. Nanjundappa
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Urs Christen
- Department of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Channakeshava S. Umeshappa
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Pediatrics, IWK Health Center, Halifax, Nova Scotia, Canada
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21
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Gordon H, Rodger B, Lindsay JO, Stagg AJ. Recruitment and Residence of Intestinal T Cells - Lessons for Therapy in Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1326-1341. [PMID: 36806613 DOI: 10.1093/ecco-jcc/jjad027] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Indexed: 02/23/2023]
Abstract
Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.
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Affiliation(s)
- Hannah Gordon
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Beverley Rodger
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Andrew J Stagg
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
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22
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Mohammadi M, Attar A, Mohammadbeigi M, Peymani A, Bolori S, Fardsanei F. The possible role of Helicobacter pylori in liver diseases. Arch Microbiol 2023; 205:281. [PMID: 37430019 DOI: 10.1007/s00203-023-03602-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/15/2023] [Accepted: 05/29/2023] [Indexed: 07/12/2023]
Abstract
According to previous studies, Helicobacter pylori infection is associated with liver disease. In order to better understand the risk of acquiring various liver diseases, we reviewed current knowledge on the impact of H. pylori on the onset, intensification, and progression of various liver diseases caused by the infection of H. pylori. It has been estimated that between 50 and 90% of people worldwide have been infected with H. pylori. The bacterium is mostly responsible for inflamed gastric mucosa, ulcers, and cancers associated with the gastric mucosa. Through the active antioxidant system in H. pylori, the bacteria can neutralize free radicals by synthesizing VacA, a toxin that causes cell damage and apoptosis. Furthermore, there is a possibility that CagA genes may play a role in cancer development. People who have been infected with H. pylori are likely to develop lesions in the skin, the circulation system, and the pancreas. Moreover, transferring blood from the stomach may allow H. pylori to colonize the liver. The bacterium worsened liver function during autoimmune inflammation, toxic injury, chronic HCV infection, chronic HBV infection, and liver cirrhosis. Increasing portal pressure, hyperammonemia, and esophageal varices may be associated with H pylori infection. As a result, it is crucial to diagnose and treat this infection in patients with H. pylori.
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Affiliation(s)
- Mahnaz Mohammadi
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Adeleh Attar
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Mohammadbeigi
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amir Peymani
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Shahin Bolori
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Fatemeh Fardsanei
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.
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23
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Dervishi E, Hailemariam D, Goldansaz SA, Ametaj BN. Early-Life Exposure to Lipopolysaccharide Induces Persistent Changes in Gene Expression Profiles in the Liver and Spleen of Female FVB/N Mice. Vet Sci 2023; 10:445. [PMID: 37505851 PMCID: PMC10384579 DOI: 10.3390/vetsci10070445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/28/2023] [Accepted: 07/05/2023] [Indexed: 07/29/2023] Open
Abstract
The objective of this study was to investigate how subcutaneous (sc) lipopolysaccharide (LPS) administration affects the gene expression profiles of insulin signaling as well as innate and adaptive immunity genes in mouse livers and spleens. FVB/N female mice were randomly assigned to one of two treatment groups at 5 weeks of age: (1) a six-week subcutaneous injection of saline at 11 μL/h (control-CON), or (2) a six-week subcutaneous injection of LPS from Escherichia coli 0111:B4 at 0.1 μg/g body weight at 11 μL/h. At 106 weeks (i.e., 742 days) after the last treatment, mice were euthanized. Following euthanasia, liver and spleen samples were collected, snap frozen, and stored at -80 °C until gene expression profiling. LPS upregulated nine genes in the liver, according to the findings (Pparg, Frs3, Kras, Raf1, Gsk3b, Rras2, Hk2, Pik3r2, and Myd88). With a 4.18-fold increase over the CON group, Pparg was the most up-regulated gene in the liver. Based on the annotation cluster analysis, LPS treatment upregulated liver genes which are involved in pathways associated with hepatic steatosis, B- and T-cell receptor signaling, chemokine signaling, as well as other types of cancers such as endometrial cancer, prostate cancer, and colorectal cancer. LPS increased the spleen expression of Ccl11, Ccl25, Il6, Cxcl5, Pparg, Tlr4, Nos2, Cxcl11, Il1a, Ccl17, and Fcgr3, all of which are involved in innate and adaptive immune responses and the regulation of cytokine production. Furthermore, functional analysis revealed that cytokine-cytokine receptor interaction and chemokine signaling pathways were the most enriched in LPS-treated mice spleen tissue. Our findings support the notion that early-life LPS exposure can result in long-term changes in gene expression profiling in the liver and spleen tissues of FVB/N female mice.
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Affiliation(s)
- Elda Dervishi
- Department of Agricultural Food, and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Dagnachew Hailemariam
- Department of Agricultural Food, and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Seyed Ali Goldansaz
- Department of Agricultural Food, and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Burim N Ametaj
- Department of Agricultural Food, and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
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24
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Lee SH, Moon SJ, Woo SH, Ahn G, Kim WK, Lee CH, Hwang JH. CrebH protects against liver injury associated with colonic inflammation via modulation of exosomal miRNA. Cell Biosci 2023; 13:116. [PMID: 37370191 DOI: 10.1186/s13578-023-01065-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Hepatic liver disease, including primary sclerosing cholangitis (PSC), is a serious extraintestinal manifestations of colonic inflammation. Cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CrebH) is a transcription factor expressed mostly in the liver and small intestine. However, CrebH's roles in the gut-liver axis remain unknown. METHODS Inflammatory bowel disease (IBD) and PSC disease models were established in wild-type and CrebH-/- mice treated with dextran sulfate sodium, dinitrobenzene sulfonic acid, and diethoxycarbonyl dihydrocollidine diet, respectively. RNA sequencing were conducted to investigate differential gene expression. Exosomes were isolated from plasma and culture media. miRNA expression profiling was performed using the NanoString nCounter Mouse miRNA Panel. Effects of miR-29a-3p on adhesion molecule expression were investigated in bEnd.3 brain endothelial cells. RESULTS CrebH-/- mice exhibited accelerated liver injury without substantial differences in the gut after administration of dextran sulfate sodium (DSS), and had similar features to PSC, including enlarged bile ducts, enhanced inflammation, and aberrant MAdCAM-1 expression. Furthermore, RNA-sequencing analysis showed that differentially expressed genes in the liver of CrebH-/- mice after DSS overlapped significantly with genes changed in PSC-liver. Analysis of plasma exosome miRNA isolated from WT and CrebH-/- mice indicates that CrebH can contribute to the exosomal miRNA profile. We also identified miR-29a-3p as an effective mediator for MAdCAM-1 expression. Administration of plasma exosome from CrebH-/- mice led to prominent inflammatory signals in the liver of WT mice with inflammatory bowel disease (IBD). CONCLUSIONS CrebH deficiency led to increased susceptibility to IBD-induced liver diseases via enhanced expression of adhesion molecules and concomitant infiltration of T lymphocytes. Exosomes can contribute to the progression of IBD-induced liver injury in CrebH-/- mice. These study provide novel insights into the role of CrebH in IBD-induced liver injury.
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Affiliation(s)
- Sang-Hee Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- Department of Biology, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon, 34520, Korea
| | - Sung-Je Moon
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
| | - Seung Hee Woo
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- Department of Biology and Microbiology, Changwon National University, 20 Chanwondaehak-ro, Uichan-gu, Chanwon-si, Gyeonsangnam-do, 51140, Korea
| | - Gwangsook Ahn
- Department of Biology, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon, 34520, Korea
| | - Won Kon Kim
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
- Metabolic Regulation Research Center, KRIBB, 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea.
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
| | - Jung Hwan Hwang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea.
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
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25
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Feliu V, Gomez-Roca C, Michelas M, Thébault N, Lauzéral-Vizcaino F, Salvioni A, Scandella L, Sarot E, Valle C, Balança CC, Scarlata CM, Delord JP, Ayyoub M, Devaud C. Distant antimetastatic effect of enterotropic colon cancer-derived α4β7 +CD8 + T cells. Sci Immunol 2023; 8:eadg8841. [PMID: 37289857 DOI: 10.1126/sciimmunol.adg8841] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/29/2023] [Indexed: 06/10/2023]
Abstract
Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here, we show, in metastatic CRC preclinical models, that orthotopically implanted primary colon tumors exert a colon-specific antimetastatic effect on distant hepatic lesions. Enterotropic α4β7 integrin-expressing neoantigen-specific CD8 T cells were key components of the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved control of liver lesions by anti-PD-L1 proof-of-concept immunotherapy and generated protective immune memory, whereas partial depletion of α4β7+ cells abrogated control of metastases. Last, in patients with metastatic CRC, response to ICB was associated with expression of α4β7 integrin in metastases and with circulating α4β7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut-primed tumor-specific α4β7+ CD8 T cells.
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Affiliation(s)
- Virginie Feliu
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Carlos Gomez-Roca
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Marie Michelas
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Noémie Thébault
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Françoise Lauzéral-Vizcaino
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Anna Salvioni
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Lise Scandella
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Emeline Sarot
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Carine Valle
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Camille-Charlotte Balança
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Clara-Maria Scarlata
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Jean-Pierre Delord
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Maha Ayyoub
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
| | - Christel Devaud
- Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, Institut Claudius Regaud, Toulouse, France
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26
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Saner FH, Frey A, Stüben BO, Hoyer DP, Willuweit K, Daniel M, Rashidi-Alavieh J, Treckmann JW, Schmidt HH. Transplantation for Primary Sclerosing Cholangitis: Outcomes and Recurrence. J Clin Med 2023; 12:jcm12103405. [PMID: 37240511 DOI: 10.3390/jcm12103405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/07/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is characterized by inflammation of the whole bile duct system. Liver transplantation is only approved as a curative treatment when it comes to end-stage liver disease. The aim of our study was to assess morbidity, survival rates and PSC recurrence and the impact of donor characteristics in long-term follow-up. This was an IRB-approved retrospective study. A total of 82 patients were identified who were transplanted between January 2010 and December 2021 for PSC. Among these patients, 76 adult liver transplant PSC patients and their corresponding donors were analyzed. Three pediatric cases and three adult patients with a follow-up within <1 year were excluded from further analysis. Median (range) age was 47 years (18-70) with a median (range) lab-MELD of 16 (7-40). Median (range) ICU and hospital stays were 4.6 days (0-147) and 21 days (1-176), respectively. The majority of patients suffered from Crohn's disease or ulcerative colitis as a concomitant comorbidity (65.8%). The ten-year survival rate was 74.6%. A significantly lower lab-MELD score was identified in patients surviving for > 10 years (15 vs. 22, p = 0.004). Most patients (65%) passed in the first year following transplantation, with primary non-function (PNF), sepsis and arterial thrombosis being the most common causes of death. Donor characteristics did not affect patient survival. Patients with PSC show excellent 10-year survival rates. While the lab-MELD score significantly affected long term outcomes, donor characteristics did not affect survival rates.
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Affiliation(s)
- Fuat H Saner
- Department of General- and Visceral- and Transplant Surgery, Essen University Medical Center, 45147 Essen, Germany
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia
| | - Alexandra Frey
- Department of Gastroenterology, Hepatology and Transplantation Medicine, Essen University Medical Center, 45147 Essen, Germany
| | - Björn-Ole Stüben
- Department of General- and Visceral- and Transplant Surgery, Essen University Medical Center, 45147 Essen, Germany
| | - Dieter P Hoyer
- Department of General- and Visceral- and Transplant Surgery, Essen University Medical Center, 45147 Essen, Germany
| | - Katharina Willuweit
- Department of Gastroenterology, Hepatology and Transplantation Medicine, Essen University Medical Center, 45147 Essen, Germany
| | - Martina Daniel
- Department of Gastroenterology, Hepatology and Transplantation Medicine, Essen University Medical Center, 45147 Essen, Germany
| | - Jassin Rashidi-Alavieh
- Department of Gastroenterology, Hepatology and Transplantation Medicine, Essen University Medical Center, 45147 Essen, Germany
| | - Jurgen W Treckmann
- Department of General- and Visceral- and Transplant Surgery, Essen University Medical Center, 45147 Essen, Germany
| | - Hartmut H Schmidt
- Department of Gastroenterology, Hepatology and Transplantation Medicine, Essen University Medical Center, 45147 Essen, Germany
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27
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Bozward A, Ce M, Dell'oro L, Oo YH, Ronca V. Breakdown in hepatic tolerance and its relation to autoimmune liver diseases. Minerva Gastroenterol (Torino) 2023; 69:10-22. [PMID: 33793157 DOI: 10.23736/s2724-5985.21.02853-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The liver is a complex immunological organ. It has both immunogenic and tolerogenic capacity. Tolerogenic potential of human liver with its protective firewalls is required to guard the body against the continuous influx of microbial product from the gut via the sinusoids and biliary tree. Immunotolerance and anergic state is maintained by a combined effort of both immune cells, parenchyma cells, epithelial and endothelial cells. Despite this, an unknown trigger can ignite the pathway towards breakdown in hepatic tolerance leading to autoimmune liver diseases. Understanding the initial stimulus which causes the hepatic immune system to switch from the regulatory arm towards self-reactive effector arm remains challenging. Dissecting this pathology using the current technological advances is crucial to develop curative immune based therapy in autoimmune liver diseases. We discuss the hepatic immune cells and non-immune cells which maintain liver tolerance and the evidence of immune system barrier breach which leads to autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis.
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Affiliation(s)
- Amber Bozward
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK
| | - Maurizio Ce
- Department of Health Sciences, University of Milan, Milan, Italy
| | | | - Ye H Oo
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
| | - Vincenzo Ronca
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK - .,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
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28
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Habeeb TAAM, Hussain A, Podda M, Cianci P, Ramshaw B, Safwat K, Amr WM, Wasefy T, Fiad AA, Mansour MI, Moursi AM, Osman G, Qasem A, Fawzy M, Alsaad MIA, Kalmoush AE, Nassar MS, Mustafa FM, Badawy MHM, Hamdy A, Elbelkasi H, Mousa B, Metwalli AEM, Mawla WA, Elaidy MM, Baghdadi MA, Raafat A. Hepatobiliary manifestations following two-stages elective laparoscopic restorative proctocolectomy for patients with ulcerative colitis: A prospective observational study. World J Gastrointest Surg 2023; 15:234-248. [PMID: 36896298 PMCID: PMC9988646 DOI: 10.4240/wjgs.v15.i2.234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/05/2023] [Accepted: 02/03/2023] [Indexed: 02/27/2023] Open
Abstract
BACKGROUND Hepatobiliary manifestations occur in ulcerative colitis (UC) patients. The effect of laparoscopic restorative proctocolectomy (LRP) with ileal pouch anal anastomosis (IPAA) on hepatobiliary manifestations is debated.
AIM To evaluate hepatobiliary changes after two-stages elective laparoscopic restorative proctocolectomy for patients with UC.
METHODS Between June 2013 and June 2018, 167 patients with hepatobiliary symptoms underwent two-stage elective LRP for UC in a prospective observational study. Patients with UC and having at least one hepatobiliary manifestation who underwent LRP with IPAA were included in the study. The patients were followed up for four years to assess the outcomes of hepatobiliary manifestations.
RESULTS The patients' mean age was 36 ± 8 years, and males predominated (67.1%). The most common hepatobiliary diagnostic method was liver biopsy (85.6%), followed by Magnetic resonance cholangiopancreatography (63.5%), Antineutrophil cytoplasmic antibodies (62.5%), abdominal ultrasonography (35.9%), and Endoscopic retrograde cholangiopancreatography (6%). The most common hepatobiliary symptom was Primary sclerosing cholangitis (PSC) (62.3%), followed by fatty liver (16.8%) and gallbladder stone (10.2%). 66.4% of patients showed a stable course after surgery. Progressive or regressive courses occurred in 16.8% of each. Mortality was 6%, and recurrence or progression of symptoms required surgery for 15%. Most PSC patients (87.5%) had a stable course, and only 12.5% became worse. Two-thirds (64.3%) of fatty liver patients showed a regressive course, while one-third (35.7%) showed a stable course. Survival rates were 98.8%, 97%, 95.8%, and 94% at 12 mo, 24 mo, 36 mo, and at the end of the follow-up.
CONCLUSION In patients with UC who had LRP, there is a positive impact on hepatobiliary disease. It caused an improvement in PSC and fatty liver disease. The most prevalent unchanged course was PSC, while the most common improvement was fatty liver disease.
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Affiliation(s)
- Tamer A A M Habeeb
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | | | - Mauro Podda
- Department of Surgical Science, University of Cagliari, Cagliari 2432, Italy
| | - Pasquale Cianci
- Department of Medical and Surgical Sciences, Università degli studi di Foggia, Foggia 546, Italy
| | - Bruce Ramshaw
- MD CQInsights PBC, Co-founder & CEO, Tennessee, TN 37010, United States
| | - Khaled Safwat
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Wesam M Amr
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Tamer Wasefy
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Alaa A Fiad
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Mohamed Ibrahim Mansour
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Adel Mahmoud Moursi
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Gamal Osman
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Anass Qasem
- Department of Internal Medicine, Zagazig University, Zagazig 2355, Egypt
| | - Mohamed Fawzy
- Department of Internal Medicine, Suez University, Suez 235, Egypt
| | | | | | | | - Fawzy M Mustafa
- Department of General Surgery, Al-azhar University, Cairo 285, Egypt
| | | | - Ahmed Hamdy
- Department of Hepato-Bilio-Pancreatic (HBP) Surgery, National Hepatology and Tropical Medicine Research Institute, Cairo 285, Egypt
| | - Hamdi Elbelkasi
- Department of General Surgery, Mataryia Teaching Hospital, Cairo 285, Egypt
| | - Bassam Mousa
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Abd-Elrahman M Metwalli
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Walid A Mawla
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Mostafa M Elaidy
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Muhammad Ali Baghdadi
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
| | - Ahmed Raafat
- Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig 44759, Sharkia, Egypt
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29
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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Little R, Kamath BM, Ricciuto A. Liver Disease in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:129-149. [DOI: 10.1007/978-3-031-14744-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Voskens C, Stoica D, Rosenberg M, Vitali F, Zundler S, Ganslmayer M, Knott H, Wiesinger M, Wunder J, Kummer M, Siegmund B, Schnoy E, Rath T, Hartmann A, Hackstein H, Schuler-Thurner B, Berking C, Schuler G, Atreya R, Neurath MF. Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis. Gut 2023; 72:49-53. [PMID: 35428657 PMCID: PMC9763232 DOI: 10.1136/gutjnl-2022-327075] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available. DESIGN The patient received a single infusion of 1×106 autologous, ex vivo expanded, polyclonal Tregs per kilogram of body weight, and the clinical, biochemical, endoscopic and histological responses were assessed 4 and 12 weeks after adoptive Treg transfer. RESULTS The patient showed clinical, biochemical, endoscopic and histological signs of response until week 12 after adoptive Treg transfer, which was associated with an enrichment of intestinal CD3+/FoxP3+ and CD3+/IL-10+ T cells and increased mucosal transforming growth factor beta and amphiregulin levels. Moreover, there was marked improvement of PSC with reduction of liver enzymes. This pronounced effect lasted for 4 weeks before values started to increase again. CONCLUSION These findings suggest that adoptive Treg therapy might be effective in refractory UC and might open new avenues for clinical trials in PSC. TRIAL REGISTRATION NUMBER NCT04691232.
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Affiliation(s)
- Caroline Voskens
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Diane Stoica
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Marita Rosenberg
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Francesco Vitali
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Sebastian Zundler
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Marion Ganslmayer
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Heike Knott
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Manuel Wiesinger
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Jutta Wunder
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Mirko Kummer
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Elisabeth Schnoy
- Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany
| | - Timo Rath
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, Erlangen University Hospital, Erlangen, Germany
| | - Holger Hackstein
- Department of Transfusion Medicine, Erlangen University Hospital, Erlangen, Germany
| | - Beatrice Schuler-Thurner
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Carola Berking
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Gerold Schuler
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Raja Atreya
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Markus F Neurath
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
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Ortiz-López N, Fuenzalida C, Dufeu MS, Pinto-León A, Escobar A, Poniachik J, Roblero JP, Valenzuela-Pérez L, Beltrán CJ. The immune response as a therapeutic target in non-alcoholic fatty liver disease. Front Immunol 2022; 13:954869. [PMID: 36300120 PMCID: PMC9589255 DOI: 10.3389/fimmu.2022.954869] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 09/21/2022] [Indexed: 08/25/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex and heterogeneous disorder considered a liver-damaging manifestation of metabolic syndrome. Its prevalence has increased in the last decades due to modern-day lifestyle factors associated with overweight and obesity, making it a relevant public health problem worldwide. The clinical progression of NAFLD is associated with advanced forms of liver injury such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). As such, diverse pharmacological strategies have been implemented over the last few years, principally focused on metabolic pathways involved in NAFLD progression. However, a variable response rate has been observed in NAFLD patients, which is explained by the interindividual heterogeneity of susceptibility to liver damage. In this scenario, it is necessary to search for different therapeutic approaches. It is worth noting that chronic low-grade inflammation constitutes a central mechanism in the pathogenesis and progression of NAFLD, associated with abnormal composition of the intestinal microbiota, increased lymphocyte activation in the intestine and immune effector mechanisms in liver. This review aims to discuss the current knowledge about the role of the immune response in NAFLD development. We have focused mainly on the impact of altered gut-liver-microbiota axis communication on immune cell activation in the intestinal mucosa and the role of subsequent lymphocyte homing to the liver in NAFLD development. We further discuss novel clinical trials that addressed the control of the liver and intestinal immune response to complement current NAFLD therapies.
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Affiliation(s)
- Nicolás Ortiz-López
- Laboratory of Immunogastroenterology, Unit of Gastroenterology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
- School of Medicine, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Catalina Fuenzalida
- Laboratory of Immunogastroenterology, Unit of Gastroenterology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
- School of Medicine, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - María Soledad Dufeu
- Laboratory of Immunogastroenterology, Unit of Gastroenterology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
- School of Medicine, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Araceli Pinto-León
- Laboratory of Immunogastroenterology, Unit of Gastroenterology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
| | | | - Jaime Poniachik
- Unit of Gastroenterology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Juan Pablo Roblero
- Unit of Gastroenterology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Lucía Valenzuela-Pérez
- Laboratory of Immunogastroenterology, Unit of Gastroenterology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
- School of Medicine, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Caroll J. Beltrán
- Laboratory of Immunogastroenterology, Unit of Gastroenterology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
- School of Medicine, Faculty of Medicine, Universidad de Chile, Santiago, Chile
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Zhang S, Lu S, Li Z. Extrahepatic factors in hepatic immune regulation. Front Immunol 2022; 13:941721. [PMID: 36052075 PMCID: PMC9427192 DOI: 10.3389/fimmu.2022.941721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
The liver is a site of complex immune activity. The hepatic immune system tolerates harmless immunogenic loads in homeostasis status, shelters liver function, while maintaining vigilance against possible infectious agents or tissue damage and providing immune surveillance at the same time. Activation of the hepatic immunity is initiated by a diverse repertoire of hepatic resident immune cells as well as non-hematopoietic cells, which can sense "danger signals" and trigger robust immune response. Factors that mediate the regulation of hepatic immunity are elicited not only in liver, but also in other organs, given the dual blood supply of the liver via both portal vein blood and arterial blood. Emerging evidence indicates that inter-organ crosstalk between the liver and other organs such as spleen, gut, lung, adipose tissue, and brain is involved in the pathogenesis of liver diseases. In this review, we present the features of hepatic immune regulation, with particular attention to the correlation with factors from extrahepatic organ. We describe the mechanisms by which other organs establish an immune association with the liver and then modulate the hepatic immune response. We discuss their roles and distinct mechanisms in liver homeostasis and pathological conditions from the cellular and molecular perspective, highlighting their potential for liver disease intervention. Moreover, we review the available animal models and methods for revealing the regulatory mechanisms of these extrahepatic factors. With the increasing understanding of the mechanisms by which extrahepatic factors regulate liver immunity, we believe that this will provide promising targets for liver disease therapy.
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Affiliation(s)
- Shaoying Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Shemin Lu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China
| | - Zongfang Li
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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Intestinal homeostasis in autoimmune liver diseases. Chin Med J (Engl) 2022; 135:1642-1652. [PMID: 36193976 PMCID: PMC9509077 DOI: 10.1097/cm9.0000000000002291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
ABSTRACT Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system. Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease (AILD). Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis. Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD. Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation. Additionally, the gut and liver are continuously exposed to microbial metabolic products, mediating variable effects on liver immune pathologies. Importantly, microbiota-specific or associated immune responses, either hepatic or systemic, are abnormal in AILD. Comprehensive knowledge about host-microbiota interactions, included but not limited to this review, facilitates novel clinical practice from a microbiome-based perspective. However, many challenges and controversies remain in the microbiota field of AILD, and there is an urgent need for future investigations.
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Buness JG, Ali AH, Tabibian JH, Buness CW, Cox KL, Lindor KD. Potential Association of Doxycycline With the Onset of Primary Sclerosing Cholangitis: A Case Series. Am J Ther 2022; 29:e437-e443. [PMID: 31567143 DOI: 10.1097/mjt.0000000000001065] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. AREAS OF UNCERTAINTY The etiopathogenesis of PSC remains an enigma. DATA SOURCES We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed. RESULTS We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months. THERAPEUTIC HYPOTHESIS We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.
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Affiliation(s)
- James Gage Buness
- Arizona College of Osteopathic Medicine, Midwestern University, Downers Grove, IL
| | - Ahmad Hassan Ali
- Division of Hepatology, Mayo Clinic, Phoenix, AZ
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Los Angeles, CA
| | - Cynthia W Buness
- National Patient Advocate Foundation, Arizona State University, Phoenix, AZ; and
| | - Kenneth L Cox
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Stanford University, Palo Alto, CA
| | - Keith D Lindor
- Arizona College of Osteopathic Medicine, Midwestern University, Downers Grove, IL
- Division of Hepatology, Mayo Clinic, Phoenix, AZ
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Xia D, Wang S, Liu A, Li L, Zhou P, Xu S. CCL25 Inhibition Alleviates Sepsis-Induced Acute Lung Injury and Inflammation. Infect Drug Resist 2022; 15:3309-3321. [PMID: 35782530 PMCID: PMC9241997 DOI: 10.2147/idr.s352544] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 05/20/2022] [Indexed: 12/03/2022] Open
Abstract
Purpose Acute lung injury (ALI) is a common clinical syndrome with high mortality. The chemokine ligand 25 (CCL25) is involved in inflammation, leukocyte trafficking and immunoregulation. However, the role and mechanism of CCL25 in ALI are not fully understood yet. The aim of this study was to explore the relationship between acute lung injury and CCL25. Patients and Methods In this study, we first examined chemokine expression in sepsis patients and found that serum CCL25 expression levels were relatively high in sepsis patients compared to healthy individuals. Based on this, we designed in vitro and in vivo experiments to verify the validity of the theory. In vitro, we used lipopolysaccharide-stimulated human pulmonary microvascular endothelial cells (HPMECs). In vivo, we established male C57BL/6 mice cecal ligation puncture (CLP) model of sepsis. Results In vitro, we used lipopolysaccharide-stimulated human pulmonary microvascular endothelial cells (HPMECs) and found significantly higher expression of CCL25 by enzyme-linked immunosorbent assay. Inhibition of CCL25 resulted in a significant decrease in the expression of inflammatory cytokines in HPMECs. In addition, we found that CCL25 promoted increased endothelial permeability by reducing the expression of tight junction proteins and was associated with activation of the P38 MAPK pathway by measuring the transepithelial electrical resistance and fluorescence intensity of fluorescein isothiocyanate. Results from luciferase assays and chromatin immunoprecipitation assays showed that inhibition of NF-κB activity in HPMECs decreased CCL25 expression, but addition of recombinant CCL25 increased cell permeability and inflammatory cytokine expression. In vivo, we established male C57BL/6 mice cecal ligation puncture (CLP) model of sepsis. We found that inhibition of CCL25 significantly reduced inflammatory cytokine expression in a CLP-induced sepsis model, thereby alleviating lung tissue damage in mice. Conclusion Our study suggests that CCL25 contributed to the development of ALI by modulating the functions of microvascular endothelial cells.
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Affiliation(s)
- Demeng Xia
- Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, People’s Republic of China
| | - Sheng Wang
- Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China
| | - Anwei Liu
- Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, People’s Republic of China
- Department of Critical Care Medicine, Hospital of Southern Theatre Command of PLA, Guangzhou, People’s Republic of China
| | - Lei Li
- Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China
| | - Panyu Zhou
- Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China
| | - Shuogui Xu
- Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China
- Correspondence: Shuogui Xu; Panyu Zhou, Department of Emergency, Changhai Hospital, Naval Medical University, Xiangyin Road, Shanghai, 200433, People’s Republic of China, Tel +8613176535161; +8619821317892, Email ;
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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Challenges and opportunities in achieving effective regulatory T cell therapy in autoimmune liver disease. Semin Immunopathol 2022; 44:461-474. [PMID: 35641679 PMCID: PMC9256571 DOI: 10.1007/s00281-022-00940-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/15/2022] [Indexed: 12/29/2022]
Abstract
Autoimmune liver diseases (AILD) include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These immune-mediated liver diseases involve a break down in peripheral self-tolerance with largely unknown aetiology. Regulatory T cells (Treg) are crucial in maintaining immunological tolerance. Hence, Treg immunotherapy is an attractive therapeutic option in AILD. Currently, AILD do not have a curative treatment option and patients take life-long immunosuppression or bile acids to control hepatic or biliary inflammation. Clinical investigations using good manufacturing practice (GMP) Treg in autoimmune liver disease have thus far demonstrated that Treg therapy is safe and that Treg migrate to inflamed liver tissue. For Treg immunotherapy to achieve efficacy in AILD, Treg must be retained within the liver and maintain their suppressive phenotype to dampen ongoing immune responses to hepatocytes and biliary epithelium. Therefore, therapeutic Treg subsets should be selected for tissue residency markers and maximal functionality. Optimisation of dosing regime and understanding longevity of Treg in vivo are critical to successful Treg therapy. It is also essential to consider combination therapy options to complement infused Treg, for instance low-dose interleukin-2 (IL-2) to support pre-existing and infused Treg survival and suppressive function. Understanding the hepatic microenvironment in both early- and late-stage AILD presents significant opportunity to better tailor Treg therapy in different patient groups. Modification of a hostile microenvironment to a more favourable one either prior to or during Treg therapy could enhance the efficacy and longevity of infused GMP-Treg. Applying recent technology to discovery of autoantigen responses in AILD, T cell receptor (TCR) sequencing and use of chimeric antigen receptor (CAR) technology represents the next frontier for disease-specific CAR-Treg therapies. Consideration of all these aspects in future trials and discovery research would position GMP Treg immunotherapy as a viable personalised-medicine treatment option for effective control of autoimmune liver diseases.
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Banerjee S, Nara R, Chakraborty S, Chowdhury D, Haldar S. Integrin Regulated Autoimmune Disorders: Understanding the Role of Mechanical Force in Autoimmunity. Front Cell Dev Biol 2022; 10:852878. [PMID: 35372360 PMCID: PMC8971850 DOI: 10.3389/fcell.2022.852878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/08/2022] [Indexed: 11/13/2022] Open
Abstract
The pathophysiology of autoimmune disorders is multifactorial, where immune cell migration, adhesion, and lymphocyte activation play crucial roles in its progression. These immune processes are majorly regulated by adhesion molecules at cell–extracellular matrix (ECM) and cell–cell junctions. Integrin, a transmembrane focal adhesion protein, plays an indispensable role in these immune cell mechanisms. Notably, integrin is regulated by mechanical force and exhibit bidirectional force transmission from both the ECM and cytosol, regulating the immune processes. Recently, integrin mechanosensitivity has been reported in different immune cell processes; however, the underlying mechanics of these integrin-mediated mechanical processes in autoimmunity still remains elusive. In this review, we have discussed how integrin-mediated mechanotransduction could be a linchpin factor in the causation and progression of autoimmune disorders. We have provided an insight into how tissue stiffness exhibits a positive correlation with the autoimmune diseases’ prevalence. This provides a plausible connection between mechanical load and autoimmunity. Overall, gaining insight into the role of mechanical force in diverse immune cell processes and their dysregulation during autoimmune disorders will open a new horizon to understand this physiological anomaly.
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Graham JJ, Mukherjee S, Yuksel M, Sanabria Mateos R, Si T, Huang Z, Huang X, Arbuq H, Patel V, McPhail MJ, Zen Y, Heaton ND, Longhi MS, Heneghan MA, Liberal R, Vergani D, Mieli-Vergani G, Ma Y, Hayee B. Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis. Hepatology 2022; 75:518-530. [PMID: 34633679 PMCID: PMC8844147 DOI: 10.1002/hep.32193] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine "the gut homing theory" in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases. APPROACH AND RESULTS Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4β7, αEβ7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. β7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with β7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver. CONCLUSIONS These findings refute the widely accepted "gut homing" hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD.
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Affiliation(s)
- Jonathon J Graham
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Sujit Mukherjee
- Section of Hepatology, Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College London
| | - Muhammad Yuksel
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Rebeca Sanabria Mateos
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Tengfei Si
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Zenlin Huang
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Xiahong Huang
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Hadil Arbuq
- Liver Histopathology Laboratory, Institute of Liver Studies, King’s College London, London
| | - Vishal Patel
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Mark J McPhail
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Yoh Zen
- Liver Histopathology Laboratory, Institute of Liver Studies, King’s College London, London
| | - Nigel D Heaton
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Maria Serena Longhi
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Michael A Heneghan
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Rodrigo Liberal
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Diego Vergani
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, Mowat Labs, King’s College London Faculty of Life Sciences & Medicine at King’s College Hospital, London, UK
| | - Yun Ma
- Institute of Liver Studies, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
| | - Bu’Hussain Hayee
- Department of Gastroenterology, King’s College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom
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Li Y, Li N, Liu J, Wang T, Dong R, Ge D, Peng G. Gegen Qinlian Decoction Alleviates Experimental Colitis and Concurrent Lung Inflammation by Inhibiting the Recruitment of Inflammatory Myeloid Cells and Restoring Microbial Balance. J Inflamm Res 2022; 15:1273-1291. [PMID: 35237061 PMCID: PMC8884713 DOI: 10.2147/jir.s352706] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 02/04/2022] [Indexed: 12/12/2022] Open
Abstract
Objective Ulcerative colitis (UC) as one of the intractable diseases in gastroenterology seriously threatens human health. Respiratory pathology is a representative extraintestinal manifestation of UC affecting the quality of life of patients. Gegen Qinlian Decoction (GQD) is a classical traditional Chinese medicine prescription for UC or acute lung injury. This study was aimed to reveal the therapeutic effect of GQD on UC and its pulmonary complications and uncover its molecular mechanism mediated by myeloid cells and microbiota. Methods Mice with DSS-induced colitis were orally administrated with GQD. Overall vital signs were assessed by body weight loss and disease activity index (DAI). Pulmonary general signs were evaluated by pulmonary pathology and lung function. The mechanism of GQD relieving UC was characterized by detecting myeloid cells (neutrophils, macrophages, inflammatory monocytes, and resident monocytes) in colonic and lung tissues, related inflammatory cytokines, as well as the microbiota in bronchoalveolar lavage fluid (BALF) and feces. Results GQD significantly reduced weight loss, DAI scores, and lung injury but improved the lung function of colitis mice. The DSS-induced colonic and concurrent pulmonary inflammation were also alleviated by GQD, as indicated by the down-regulated expressions of inflammatory cytokines (TNF-α, IL-1β, IL-6, CCR2, and CCL2) and the suppressed recruitment of neutrophils and inflammatory monocytes. Meanwhile, GQD greatly improved intestinal microbiota imbalance by enriching Ruminococcaceae UCG-013 while decreasing Parabacteroides, [Eubacterium]_fissicatena_group, and Akkermansia in the feces of colitis mice. Expectantly, GQD also restored lung microbiota imbalance by clearing excessive Coprococcus 2 and Ochrobactrum in the BALF of colitis mice. Finally, significant correlations appeared between GQD-mediated specific bacteria and inflammatory cytokines or immune cells. Conclusion GQD could alleviate UC by decreasing excessive inflammatory myeloid cells and cytokines, and reshaping the microbiota between the colon and lung, which contributes to clarifying the mechanism by which GQD ameliorates colitis-associated pulmonary inflammation.
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Affiliation(s)
- Yalan Li
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Na Li
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Jiajing Liu
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Tieshan Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Ruijuan Dong
- Experimental Teaching Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Dongyu Ge
- Experimental Teaching Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Guiying Peng
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
- Correspondence: Guiying Peng, Email
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Wang Y, Liu Y. Gut-liver-axis: Barrier function of liver sinusoidal endothelial cell. J Gastroenterol Hepatol 2021; 36:2706-2714. [PMID: 33811372 DOI: 10.1111/jgh.15512] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/02/2021] [Accepted: 03/27/2021] [Indexed: 12/15/2022]
Abstract
Liver diseases are associated with the leaky gut via the gut-liver-axis. Previous studies have paid much attention to the effect of gut barrier damage. Notably, clinical observations and basic research reveal that the gut barrier damage seldom leads to liver injury independently but aggravates pre-existing liver diseases such as non-alcoholic fatty liver disease and drug-induced liver injury. These evidences suggest that there is a hepatic barrier in the gut-liver-axis, protecting the liver against gut-derived pathogenic factors. However, it has never been investigated which type of liver cell plays the role of hepatic barrier. Under physiological conditions, liver sinusoidal endothelial cell (LSEC) can take up and eliminate virus, bacteriophage, microbial products, and metabolic wastes. LSEC also keeps the homeostasis of liver immune environment via tolerance-inducing and anti-inflammatory functions. In contrast, under pathological conditions, the clearance function of LSEC is impaired, and LSEC turns into a pro-inflammatory pattern. Given its anatomical position and physiological functions, LSEC is proposed as the hepatic barrier in the gut-liver-axis. In this review, we aim to further understand the role of LSEC as the hepatic barrier. Future studies are warranted to seek effective treatments to improve LSEC health, which appears to be a promising approach to prevent gut-derived liver injury.
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Affiliation(s)
- Yang Wang
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China.,Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
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Bourgonje AR, Hu S, Spekhorst LM, Zhernakova DV, Vich Vila A, Li Y, Voskuil MD, van Berkel LA, Bley Folly B, Charrout M, Mahfouz A, Reinders MJT, van Heck JIP, Joosten LAB, Visschedijk MC, van Dullemen HM, Faber KN, Samsom JN, Festen EAM, Dijkstra G, Weersma RK. The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease. J Crohns Colitis 2021; 16:414-429. [PMID: 34491321 PMCID: PMC8919819 DOI: 10.1093/ecco-jcc/jjab157] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND AIMS Protein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD. METHODS A total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn's disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci [pQTL] analysis). Intestinal mucosal RNA sequencing and faecal metagenomic data were used for complementary analyses. RESULTS Thirty-two proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins were independent of active inflammation; 69 proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 [FUT2] gene [rs602662] and two independent cis-pQTLs of C-C motif chemokine 25 [CCL25] affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression [e]QTL-variant [rs3745387] of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of faecal butyrate-producing bacteria. CONCLUSIONS This study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD, and identifies disease-associated pathways that may help to improve disease management in the future.
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Affiliation(s)
| | | | | | - Daria V Zhernakova
- Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands,Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St Petersburg, Russia
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Yanni Li
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Lisette A van Berkel
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Brenda Bley Folly
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Mohammed Charrout
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Ahmed Mahfouz
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands,Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Marcel J T Reinders
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Julia I P van Heck
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Hendrik M van Dullemen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Janneke N Samsom
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Corresponding author: Prof. Rinse K. Weersma, MD, PhD, Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 361 26 20; fax: +31 50 361 93 06;
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Bozward AG, Ronca V, Osei-Bordom D, Oo YH. Gut-Liver Immune Traffic: Deciphering Immune-Pathogenesis to Underpin Translational Therapy. Front Immunol 2021; 12:711217. [PMID: 34512631 PMCID: PMC8425300 DOI: 10.3389/fimmu.2021.711217] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies.
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Affiliation(s)
- Amber G. Bozward
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
| | - Daniel Osei-Bordom
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Queen Elizabeth Hospital, University Hospital of Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
- Queen Elizabeth Hospital, University Hospital of Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
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Wu X, Sun M, Yang Z, Lu C, Wang Q, Wang H, Deng C, Liu Y, Yang Y. The Roles of CCR9/CCL25 in Inflammation and Inflammation-Associated Diseases. Front Cell Dev Biol 2021; 9:686548. [PMID: 34490243 PMCID: PMC8416662 DOI: 10.3389/fcell.2021.686548] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/23/2021] [Indexed: 12/15/2022] Open
Abstract
Chemokine is a structure-related protein with a relatively small molecular weight, which can target cells to chemotaxis and promote inflammatory response. Inflammation plays an important role in aging. C-C chemokine receptor 9 (CCR9) and its ligand C-C chemokine ligand 25 (CCL25) are involved in the regulating the occurrence and development of various diseases, which has become a research hotspot. Early research analysis of CCR9-deficient mouse models also confirmed various physiological functions of this chemokine in inflammatory responses. Moreover, CCR9/CCL25 has been shown to play an important role in a variety of inflammation-related diseases, such as cardiovascular disease (CVD), rheumatoid arthritis, hepatitis, inflammatory bowel disease, asthma, etc. Therefore, the purpose of this review gives an overview of the recent advances in understanding the roles of CCR9/CCL25 in inflammation and inflammation-associated diseases, which will contribute to the design of future experimental studies on the potential of CCR9/CCL25 and advance the research of CCR9/CCL25 as pharmacological inflammatory targets.
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Affiliation(s)
- Xue Wu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
| | - Meng Sun
- Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhi Yang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
| | - Chenxi Lu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
| | - Qiang Wang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
| | - Haiying Wang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yonglin Liu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
| | - Yang Yang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
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Poch T, Krause J, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E, Gagliani N, Schramm C. Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4 + T cells in primary sclerosing cholangitis. J Hepatol 2021; 75:414-423. [PMID: 33774059 PMCID: PMC8310924 DOI: 10.1016/j.jhep.2021.03.016] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 02/16/2021] [Accepted: 03/17/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver. METHODS Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs. RESULTS We identified a population of intrahepatic naive-like CD4+ T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (TH17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards TH17 cells. CONCLUSION We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4+ T cells in PSC harbour the propensity to develop into TH17 cells. LAY SUMMARY The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4+ T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.
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Affiliation(s)
- Tobias Poch
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Jenny Krause
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Christian Casar
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Timur Liwinski
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Immunology Department, Weizmann Institute of Science, Rehovot 7610001 Israel
| | - Laura Glau
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Max Kaufmann
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Annika E Ahrenstorf
- Virus Immunology Department, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20246 Germany
| | - Leonard U Hess
- Virus Immunology Department, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20246 Germany
| | - Annerose E Ziegler
- Virus Immunology Department, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20246 Germany
| | - Glòria Martrus
- Virus Immunology Department, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20246 Germany
| | - Sebastian Lunemann
- Virus Immunology Department, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20246 Germany
| | - Marcial Sebode
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Jun Li
- Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Dorothee Schwinge
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Christian F Krebs
- III. Department of Medicine, Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105 Germany
| | - Manuel A Friese
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Karl J Oldhafer
- Department of General and Abdominal Surgery, Asklepios Hospital Barmbek, Semmelweis University of Medicine Hamburg, Germany
| | - Lutz Fischer
- Department for Visceral Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Marcus Altfeld
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Virus Immunology Department, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20246 Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Eva Tolosa
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany
| | - Nicola Gagliani
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, Stockholm 17177 Sweden.
| | - Christoph Schramm
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany.
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47
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Wang Y, Liu Y. Neutrophil-Induced Liver Injury and Interactions Between Neutrophils and Liver Sinusoidal Endothelial Cells. Inflammation 2021; 44:1246-1262. [PMID: 33649876 DOI: 10.1007/s10753-021-01442-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 01/29/2021] [Accepted: 02/19/2021] [Indexed: 12/12/2022]
Abstract
Neutrophils are the most abundant type of leukocytes with diverse functions in immune defense including production of reactive oxygen species, bacteriocidal proteins, neutrophil extracellular traps, and pro-inflammatory mediators. However, aberrant accumulation of neutrophils in host tissues and excessive release of bacteriocidal compounds can lead to unexpected injury to host organs. Neutrophil-mediated liver injury has been reported in various types of liver diseases including liver ischemia/reperfusion injury, nonalcoholic fatty liver disease, endotoxin-induced liver injury, alcoholic liver disease, and drug-induced liver injury. Yet the mechanisms of neutrophil-induced hepatotoxicity in different liver diseases are complicated. Current knowledge of these mechanisms are summarized in this review. In addition, a substantial body of evidence has emerged showing that liver sinusoidal endothelial cells (LSECs) participate in several key steps of neutrophil-mediated liver injury including neutrophil recruitment, adhesion, transmigration, and activation. This review also highlights the current understanding of the interactions between LSECs and neutrophils in liver injury. The future challenge is to explore new targets for selectively interfering neutrophil-induced liver injury without impairing host defense function against microbial infection. Further understanding the role of LSECs in neutrophil-induced hepatotoxicity would aid in developing more selective therapeutic approaches for liver disease.
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Affiliation(s)
- Yang Wang
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China.
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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48
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Neyazi M, Bharadwaj SS, Bullers S, Varenyiova Z, Travis S, Arancibia-Cárcamo CV, Powrie F, Geremia A. Overexpression of Cancer-Associated Stem Cell Gene OLFM4 in the Colonic Epithelium of Patients With Primary Sclerosing Cholangitis. Inflamm Bowel Dis 2021; 27:1316-1327. [PMID: 33570127 PMCID: PMC8314119 DOI: 10.1093/ibd/izab025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND To examine immune-epithelial interactions and their impact on epithelial transformation in primary sclerosing cholangitis-associated ulcerative colitis (PSC-UC) using patient-derived colonic epithelial organoid cultures (EpOCs). METHODS The EpOCs were originated from colonic biopsies from patients with PSC-UC (n = 12), patients with UC (n = 14), and control patients (n = 10) and stimulated with cytokines previously associated with intestinal inflammation (interferon (IFN) γ and interleukin (IL)-22). Markers of cytokine downstream pathways, stemness, and pluripotency were analyzed by real-time quantitative polymerase chain reaction and immunofluorescence. The OLFM4 expression in situ was assessed by RNAscope and immunohistochemistry. RESULTS A distinct expression of stem cell-associated genes was observed in EpOCs derived from patients with PSC-UC, with lower expression of the classical stem-cell marker LGR5 and overexpression of OLFM4, previously associated with pluripotency and early stages of neoplastic transformation in the gastrointestinal and biliary tracts. High levels of OLFM4 were also found ex vivo in colonic biopsies from patients with PSC-UC. In addition, IFNγ stimulation resulted in the downregulation of LGR5 in EpOCs, whereas higher expression of OLFM4 was observed after IL-22 stimulation. Interestingly, expression of the IL-22 receptor, IL22RA1, was induced by IFNγ, suggesting that a complex interplay between these cytokines may contribute to carcinogenesis in PSC-UC. CONCLUSIONS Higher expression of OLFM4, a cancer stemness gene induced by IL-22, is present in PSC-UC, suggesting that IL-22 responses may result in alterations of the intestinal stem-cell niche in these patients.
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Affiliation(s)
- Mastura Neyazi
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Sraddha S Bharadwaj
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Samuel Bullers
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK
| | - Zofia Varenyiova
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Oxford IBD Cohort Study Investigators
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Simon Travis
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Carolina V Arancibia-Cárcamo
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK
| | - Alessandra Geremia
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
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49
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Zimmer CL, von Seth E, Buggert M, Strauss O, Hertwig L, Nguyen S, Wong AYW, Zotter C, Berglin L, Michaëlsson J, Hansson MR, Arnelo U, Sparrelid E, Ellis ECS, Söderholm JD, Keita ÅV, Holm K, Özenci V, Hov JR, Mold JE, Cornillet M, Ponzetta A, Bergquist A, Björkström NK. A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells. Sci Transl Med 2021; 13:13/599/eabb3107. [PMID: 34162753 DOI: 10.1126/scitranslmed.abb3107] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 03/13/2021] [Accepted: 05/17/2021] [Indexed: 12/14/2022]
Abstract
The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103+CD69+ effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.
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Affiliation(s)
- Christine L Zimmer
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Erik von Seth
- Division of Upper GI Diseases, Karolinska University Hospital, 14157 Stockholm, Sweden.,Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14157 Stockholm, Sweden
| | - Marcus Buggert
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Otto Strauss
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Laura Hertwig
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Son Nguyen
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA.,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alicia Y W Wong
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Chiara Zotter
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Lena Berglin
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Jakob Michaëlsson
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Marcus Reuterwall Hansson
- Division of Surgery, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Urban Arnelo
- Division of Surgery, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, 14152 Stockholm, Sweden.,Department of Surgical and Perioperative sciences, Surgery, Umeå University, 90187 Umeå, Sweden
| | - Ernesto Sparrelid
- Division of Surgery, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Ewa C S Ellis
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14186 Stockholm, Sweden
| | - Johan D Söderholm
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden.,Department of Surgery, Linköping University Hospital, 58185 Linköping, Sweden
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden
| | - Kristian Holm
- Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.,Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, 0424 Oslo, Norway
| | - Volkan Özenci
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Johannes R Hov
- Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.,Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, 0424 Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, 0424 Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital, 0424 Oslo, Norway
| | - Jeff E Mold
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Martin Cornillet
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Andrea Ponzetta
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden
| | - Annika Bergquist
- Division of Upper GI Diseases, Karolinska University Hospital, 14157 Stockholm, Sweden.,Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14157 Stockholm, Sweden
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 14152 Stockholm, Sweden.
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50
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The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies. Int J Mol Sci 2021; 22:ijms22136975. [PMID: 34203536 PMCID: PMC8268159 DOI: 10.3390/ijms22136975] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.
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