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Gil-Gómez A, Muñoz-Hernández R, Martínez F, Jiménez F, Romero-Gómez M. Hepatic encephalopathy: experimental drugs in development and therapeutic potential. Expert Opin Investig Drugs 2024; 33:1219-1230. [PMID: 39588934 DOI: 10.1080/13543784.2024.2434053] [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: 09/19/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
INTRODUCTION Hepatic encephalopathy (HE) presents a complex pathophysiology, creating multiple potential treatment avenues. This review covers current and emerging treatments for HE. AREAS COVERED Standard therapies, including non-absorbable disaccharides and rifaximin, are widely used but show inconsistent efficacy. Alternatives such as polyethylene glycol and L-ornithine L-aspartate have been effective in certain cases. Advancements in understanding HE reveal a growing need for personalized treatments. Novel approaches targeting immune modulation and neuroinflammation are under investigation, though clinical translation is slow. Nutritional interventions and fecal microbiota transplantation show potential but lack robust evidence. Innovative therapies like gene and cell therapies, as well as extracellular vesicles from mesenchymal stem cells, present promising avenues for liver disease treatment, potentially benefiting HE. EXPERT OPINION A key challenge in HE research is the design of randomized clinical trials, which often suffer from small sample sizes, heterogeneity in patient population, and inconsistent blinding. Additionally, the multifactorial nature of HE, together with a high spontaneous response rate, complicates efforts to isolate treatment effects. Despite current limitations, ongoing research and technological advances hold promise for more effective and individualized HE treatments in the future.
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Affiliation(s)
- Antonio Gil-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío Muñoz-Hernández
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Filomeno Martínez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Fernando Jiménez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Manuel Romero-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
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Tafader A, Bajaj JS. Present and future of fecal microbiome transplantation in cirrhosis. Liver Transpl 2024:01445473-990000000-00519. [PMID: 39591377 DOI: 10.1097/lvt.0000000000000542] [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: 09/02/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024]
Abstract
Over the last few decades, there have been tremendous advances in our understanding of the role of the gut microbiome in cirrhosis and the clinical sequelae that follow. Progressive dysbiosis and immune dysregulation occur in patients with cirrhosis. In fact, alterations in the gut microbiome occur long before a diagnosis of cirrhosis is made. Understandably, our attention has recently been diverted toward potential modulators of the gut microbiome and the gut-liver axis as targets for treatment. The goal of this review is to highlight the utility of manipulating the gut microbiome with a focus on fecal microbiome transplantation (FMT) in patients with cirrhosis. In addition, we will provide an overview of disease-specific microbial alterations and the resultant impact this has on cirrhosis-related complications.
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Affiliation(s)
- Asiya Tafader
- Department of Medicine, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
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3
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Wang Y, Li Y, Lv L, Zhu L, Hong L, Wang X, Zhang Y, Wang X, Diao H. Faecal hsa-miR-7704 inhibits the growth and adhesion of Bifidobacterium longum by suppressing ProB and aggravates hepatic encephalopathy. NPJ Biofilms Microbiomes 2024; 10:13. [PMID: 38396001 PMCID: PMC10891095 DOI: 10.1038/s41522-024-00487-8] [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: 07/29/2023] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Both gut microbiome and microRNAs (miRNAs) play a role in the development of hepatic encephalopathy (HE). However, the functional link between the microbiome and host-derived miRNAs in faeces remains poorly understood. In the present study, patients with HE had an altered gut microbiome and faecal miRNAs compared with patients with chronic hepatitis B. Transferring faeces and faecal miRNAs from patients with HE to the recipient mice aggravated thioacetamide-induced HE. Oral gavage of hsa-miR-7704, a host-derived miRNA highly enriched in faeces from patients with HE, aggravated HE in mice in a microbiome-dependent manner. Mechanistically, hsa-miR-7704 inhibited the growth and adhesion of Bifidobacterium longum by suppressing proB. B. longum and its metabolite acetate alleviated HE by inhibiting microglial activation and ammonia production. Our findings reveal the role of miRNA-microbiome axis in HE and suggest that faecal hsa-miR-7704 are potential regulators of HE progression.
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Affiliation(s)
- Yuchong Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yuyu Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Longxian Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Liying Zhu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Liang Hong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xueyao Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, China
| | - Yu Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xin Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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4
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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: 13] [Impact Index Per Article: 13.0] [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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5
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Shah YR, Ali H, Tiwari A, Guevara-Lazo D, Nombera-Aznaran N, Pinnam BSM, Gangwani MK, Gopakumar H, Sohail AH, Kanumilli S, Calderon-Martinez E, Krishnamoorthy G, Thakral N, Dahiya DS. Role of fecal microbiota transplant in management of hepatic encephalopathy: Current trends and future directions. World J Hepatol 2024; 16:17-32. [PMID: 38313244 PMCID: PMC10835490 DOI: 10.4254/wjh.v16.i1.17] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 12/02/2023] [Accepted: 01/03/2024] [Indexed: 01/23/2024] Open
Abstract
Fecal microbiota transplantation (FMT) offers a potential treatment avenue for hepatic encephalopathy (HE) by leveraging beneficial bacterial displacement to restore a balanced gut microbiome. The prevalence of HE varies with liver disease severity and comorbidities. HE pathogenesis involves ammonia toxicity, gut-brain communication disruption, and inflammation. FMT aims to restore gut microbiota balance, addressing these factors. FMT's efficacy has been explored in various conditions, including HE. Studies suggest that FMT can modulate gut microbiota, reduce ammonia levels, and alleviate inflammation. FMT has shown promise in alcohol-associated, hepatitis B and C-associated, and non-alcoholic fatty liver disease. Benefits include improved liver function, cognitive function, and the slowing of disease progression. However, larger, controlled studies are needed to validate its effectiveness in these contexts. Studies have shown cognitive improvements through FMT, with potential benefits in cirrhotic patients. Notably, trials have demonstrated reduced serious adverse events and cognitive enhancements in FMT arms compared to the standard of care. Although evidence is promising, challenges remain: Limited patient numbers, varied dosages, administration routes, and donor profiles. Further large-scale, controlled trials are essential to establish standardized guidelines and ensure FMT's clinical applications and efficacy. While FMT holds potential for HE management, ongoing research is needed to address these challenges, optimize protocols, and expand its availability as a therapeutic option for diverse hepatic conditions.
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Affiliation(s)
- Yash R Shah
- Department of Internal Medicine, Trinity Health Oakland/Wayne State University, Pontiac, MI 48341, United States
| | - Hassam Ali
- Division of Gastroenterology and Hepatology, East Carolina University/Brody School of Medicine, Greenville, NC 27858, United States
| | - Angad Tiwari
- Department of Internal Medicine, Maharani Laxmi Bai Medical College, Jhansi 284001, India
| | - David Guevara-Lazo
- Faculty of Medicine, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
| | | | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger Hospital of Cook County, Chicago, IL 60612, United States
| | - Manesh Kumar Gangwani
- Department of Internal Medicine, The University of Toledo, Toledo, OH 43606, United States
| | - Harishankar Gopakumar
- Department of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, United States
| | - Amir H Sohail
- Department of Surgery, University of New Mexico, Albuquerque, NM 87106, United States
| | | | - Ernesto Calderon-Martinez
- Department of Internal Medicine, Universidad Nacional Autonoma de Mexico, Ciudad De Mexico 04510, Mexico
| | - Geetha Krishnamoorthy
- Department of Internal Medicine, Trinity Health Oakland/Wayne State University, Pontiac, MI 48341, United States
| | - Nimish Thakral
- Department of Digestive Diseases and Nutrition, University of Kentucky, Lexington, KY 40536, United States
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology & Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, United States.
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6
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Karna R, Babich M. Fecal microbiota transplant in liver diseases: Current evidence and future directions. Clin Liver Dis (Hoboken) 2024; 23:e0154. [PMID: 38841199 PMCID: PMC11152867 DOI: 10.1097/cld.0000000000000154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 02/02/2024] [Indexed: 06/07/2024] Open
Affiliation(s)
- Rahul Karna
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Michael Babich
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
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7
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Bloom PP, Bajaj JS. The Current and Future State of Microbiome Therapeutics in Liver Disease. Am J Gastroenterol 2024; 119:S36-S41. [PMID: 38153225 DOI: 10.14309/ajg.0000000000002581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/31/2023] [Indexed: 12/29/2023]
Affiliation(s)
| | - Jasmohan S Bajaj
- Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
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Saeidinejad M, Elshabrawi A, Sriphoosanaphan S, Andreola F, Mehta G, Agarwal B, Jalan R. Novel Therapeutic Approaches in Treatment of Acute-on-Chronic Liver Failure. Semin Liver Dis 2023; 43:429-445. [PMID: 38101419 PMCID: PMC10723941 DOI: 10.1055/s-0043-1776773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2023]
Abstract
Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.
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Affiliation(s)
- MohammadMahdi Saeidinejad
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Ahmed Elshabrawi
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Intensive Care Unit, Endemic Hepatology and Gastroenterology Department, Mansoura University, Mansoura, Egypt
| | - Supachaya Sriphoosanaphan
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok
| | - Fausto Andreola
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Gautam Mehta
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Banwari Agarwal
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Intensive Care Unit, Royal Free Hospital, London, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Hepatology Department, Royal Free Hospital, London, United Kingdom
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
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9
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Boicean A, Birlutiu V, Ichim C, Brusnic O, Onișor DM. Fecal Microbiota Transplantation in Liver Cirrhosis. Biomedicines 2023; 11:2930. [PMID: 38001930 PMCID: PMC10668969 DOI: 10.3390/biomedicines11112930] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
The human gastrointestinal tract houses a diverse array of probiotic and pathogenic bacteria and any alterations in this microbial composition can exert a significant influence on an individual's well-being. It is well-established that imbalances in the gut microbiota play a pivotal role in the development of liver diseases. In light of this, a new adjuvant therapy for liver diseases could be regulating the intestinal microbiota. Through fecal microbiota transplantation, patients whose microbiomes are compromised are treated with stool from healthy donors in an attempt to restore a normal microbiome and alleviate their symptoms. A review of cross-sectional studies and case reports suggests that fecal microbiota transplants may offer effective treatment for chronic liver diseases. Adding to the potential of this emerging therapy, recent research has indicated that fecal microbiota transplantation holds promise as a therapeutic approach specifically for liver cirrhosis. By introducing a diverse range of beneficial microorganisms into the gut, this innovative treatment aims to address the microbial imbalances often observed in cirrhotic patients. While further validation is still required, these preliminary findings highlight the potential impact of fecal microbiota transplantation as a novel and targeted method for managing liver cirrhosis. We aimed to summarize the current state of understanding regarding this procedure, as a new therapeutic method for liver cirrhosis, as well as to explain its clinical application and future potential.
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Affiliation(s)
- Adrian Boicean
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania; (A.B.); (V.B.)
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Victoria Birlutiu
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania; (A.B.); (V.B.)
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Cristian Ichim
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania; (A.B.); (V.B.)
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Olga Brusnic
- Department of Gastroenterology, University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Târgu Mures, Romania
| | - Danusia Maria Onișor
- Department of Gastroenterology, University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Târgu Mures, Romania
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10
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Kibble H, Shawcross DL. The microbiome in portal hypertension. Clin Liver Dis (Hoboken) 2023; 22:70-74. [PMID: 37663552 PMCID: PMC10473356 DOI: 10.1097/cld.0000000000000051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 04/10/2023] [Indexed: 09/05/2023] Open
Affiliation(s)
- Henry Kibble
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King’s College London, London, UK
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
| | - Debbie L. Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King’s College London, London, UK
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
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11
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Zhu R, Liu L, Zhang G, Dong J, Ren Z, Li Z. The pathogenesis of gut microbiota in hepatic encephalopathy by the gut-liver-brain axis. Biosci Rep 2023; 43:BSR20222524. [PMID: 37279097 PMCID: PMC10272964 DOI: 10.1042/bsr20222524] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 05/05/2023] [Accepted: 05/31/2023] [Indexed: 06/08/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological disease occurring in patients with hepatic insufficiency and/or portal-systemic blood shunting based on cirrhosis. The pathogenesis is not completely clear till now, but it is believed that hyperammonemia is the core of HE. Hyperammonemia caused by increased sources of ammonia and decreased metabolism further causes mental problems through the gut-liver-brain axis. The vagal pathway also plays a bidirectional role in the axis. Intestinal microorganisms play an important role in the pathogenesis of HE through the gut-liver-brain axis. With the progression of cirrhosis to HE, intestinal microbial composition changes gradually. It shows the decrease of potential beneficial taxa and the overgrowth of potential pathogenic taxa. Changes in gut microbiota may lead to a variety of effects, such as reduced production of short-chain fatty acids (SCFAs), reduced production of bile acids, increased intestinal barrier permeability, and bacterial translocation. The treatment aim of HE is to decrease intestinal ammonia production and intestinal absorption of ammonia. Prebiotics, probiotics, antibiotics, and fecal microbiota transplantation (FMT) can be used to manipulate the gut microbiome to improve hyperammonemia and endotoxemia. Especially the application of FMT, it has become a new treated approach to target microbial composition and function. Therefore, restoring intestinal microbial homeostasis can improve the cognitive impairment of HE, which is a potential treatment method.
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Affiliation(s)
- Ruirui Zhu
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Liwen Liu
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
| | - Guizhen Zhang
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
| | - Jianxia Dong
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zhigang Ren
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
| | - Zhiqin Li
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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12
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Pabst O, Hornef MW, Schaap FG, Cerovic V, Clavel T, Bruns T. Gut-liver axis: barriers and functional circuits. Nat Rev Gastroenterol Hepatol 2023:10.1038/s41575-023-00771-6. [PMID: 37085614 DOI: 10.1038/s41575-023-00771-6] [Citation(s) in RCA: 137] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/23/2023] [Indexed: 04/23/2023]
Abstract
The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut-liver axis. In this Review we discuss the gut-liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches.
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Affiliation(s)
- Oliver Pabst
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany.
| | - Mathias W Hornef
- Institute of Medical Microbiology, RWTH Aachen University, Aachen, Germany
| | - Frank G Schaap
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University, Aachen, Germany
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Vuk Cerovic
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, RWTH Aachen University, Aachen, Germany
| | - Tony Bruns
- Department of Internal Medicine III, RWTH Aachen University, Aachen, Germany
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Nardelli S, Gioia S, Faccioli J, Riggio O, Ridola L. Hepatic encephalopathy - recent advances in treatment and diagnosis. Expert Rev Gastroenterol Hepatol 2023; 17:225-235. [PMID: 36843291 DOI: 10.1080/17474124.2023.2183386] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/28/2023]
Abstract
INTRODUCTION Hepatic encephalopathy (HE) is a peculiar kind of brain dysfunction typical of liver cirrhosis characterized by nonspecific neurological and psychiatric manifestations. HE ranges from minimal hepatic encephalopathy (MHE) to the most severe form characterized by alteration of consciousness or coma (overt HE, OHE). Once the diagnosis of OHE is made, every effort to identify and correct the precipitating cause is essential for the resolution of symptoms. Clinical studies that assessed the prevalence and incidence of any type of HE (MHE and OHE) in patients affected by cirrhosis were included in this review. No language, publication date, or publication status restrictions were imposed. The studies were identified by searching electronic databases (PubMed and SCOPUS). AREAS COVERED The most widely empirical pharmacological approach consists of non-absorbable antibiotics (rifaximin) and non-absorbable disaccharides (lactulose, lactitol per os and per enemas). Other agents (including branched-chain amino acids, probiotics, other antibiotics, or intravenous L-ornithine L-aspartate) are available, but the evidence supporting their efficacy remains under debate. EXPERT OPINION Gray areas and future needs remain the therapeutic approach to MHE and issues in the design of therapeutic studies for HE which have been extensively discussed in this review.
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Affiliation(s)
- Silvia Nardelli
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Stefania Gioia
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Jessica Faccioli
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
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Wang Y, Zhang S, Borody TJ, Zhang F. Encyclopedia of fecal microbiota transplantation: a review of effectiveness in the treatment of 85 diseases. Chin Med J (Engl) 2022; 135:1927-1939. [PMID: 36103991 PMCID: PMC9746749 DOI: 10.1097/cm9.0000000000002339] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Indexed: 01/06/2023] Open
Abstract
ABSTRACT Fecal microbiota transplantation (FMT) has been used as a core therapy for treating dysbiosis-related diseases by remodeling gut microbiota. The methodology and technology for improving FMT are stepping forward, mainly including washed microbiota transplantation (WMT), colonic transendoscopic enteral tubing (TET) for microbiota delivery, and purified Firmicutes spores from fecal matter. To improve the understanding of the clinical applications of FMT, we performed a systematic literature review on FMT published from 2011 to 2021. Here, we provided an overview of the reported clinical benefits of FMT, the methodology of processing FMT, the strategy of using FMT, and the regulations on FMT from a global perspective. A total of 782 studies were included for the final analysis. The present review profiled the effectiveness from all clinical FMT uses in 85 specific diseases as eight categories, including infections, gut diseases, microbiota-gut-liver axis, microbiota-gut-brain axis, metabolic diseases, oncology, hematological diseases, and other diseases. Although many further controlled trials will be needed, the dramatic increasing reports have shown the promising future of FMT for dysbiosis-related diseases in the gut or beyond the gut.
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Affiliation(s)
- Yun Wang
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
- Key Lab of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Sheng Zhang
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
- Key Lab of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | | | - Faming Zhang
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
- Key Lab of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, Jiangsu 210011, China
- National Clinical Research Center for Digestive Diseases, Xi’an, Shaanxi 710032, China
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15
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Fecal Microbiota Transplantation in Decompensated Cirrhosis: A Systematic Review on Safety and Efficacy. Antibiotics (Basel) 2022; 11:antibiotics11070838. [PMID: 35884093 PMCID: PMC9311594 DOI: 10.3390/antibiotics11070838] [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: 05/30/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 11/17/2022] Open
Abstract
Background and Aims: Due to increasing knowledge of the “gut–liver axis”, there has been growing interest regarding the use of fecal microbiota transplant in the management of chronic liver disease. There are limited data available and current guidelines are mostly based on expert opinions. We aim to perform the first systematic review investigating safety and efficacy of fecal microbiota transplant particularly among high-risk decompensated cirrhosis patient populations. Methods: Literature search was performed using variations of the keywords “fecal microbiota transplant” and “cirrhosis” on PubMed/Medline from inception to 3 October 2021. The resulting 116 articles were independently screened by two authors. In total, 5 qualifying studies, including 2 randomized control trials and 3 retrospective case series, were found to meet established eligibility criteria and have adequate quality of evidence to be included in this review. Results: Of the total 58 qualifying patients, there were 2 deaths post fecal microbiota transplant, 1 of which could not rule out being related (1.7%). Among the remaining 56 participants, 8 serious adverse events were reported, of which 2 could not rule out being related (3.6%). The success rate of fecal microbiota transplantation in treating recurrent Clostridioides difficile infection among patients with decompensated cirrhosis was 77.8%. The success rate when used as investigational treatment for hepatic encephalopathy was 86.7%, with multiple studies reporting clinically significant improvement in encephalopathy testing scores. Conclusions: We found a marginally higher rate of deaths and serious adverse events from fecal microbiota transplant in our patient population compared with the average immunocompetent population, where it was previously found to have 0 deaths and SAE rate of 2.83%. The efficacy when used for recurrent C.difficile infection was 77.8% and 87% in the decompensated cirrhotic and general populations, respectively. Studies on efficacy in novel treatment of hepatic encephalopathy have been promising. This study concludes that fecal microbiota transplant use in decompensated cirrhosis patients should be used with caution and preferably be limited to research purposes until better data are available.
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16
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Bajaj JS, Ng SC, Schnabl B. Promises of microbiome-based therapies. J Hepatol 2022; 76:1379-1391. [PMID: 35589257 PMCID: PMC9588437 DOI: 10.1016/j.jhep.2021.12.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/15/2021] [Accepted: 12/06/2021] [Indexed: 02/03/2023]
Abstract
Humans harbour large quantities of microbes, including bacteria, fungi, viruses and archaea, in the gut. Patients with liver disease exhibit changes in the intestinal microbiota and gut barrier dysfunction. Preclinical models demonstrate the importance of the gut microbiota in the pathogenesis of various liver diseases. In this review, we discuss how manipulation of the gut microbiota can be used as a novel treatment approach for liver disease. We summarise current data on untargeted approaches, including probiotics and faecal microbiota transplantation, and precision microbiome-centered therapies, including engineered bacteria, postbiotics and phages, for the treatment of liver diseases.
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Affiliation(s)
- Jasmohan S Bajaj
- Department of Medicine, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA.
| | - Siew C Ng
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, Institute of Digestive Disease, The Chinese University of Hong Kong; Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
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17
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Tun KM, Hong AS, Batra K, Naga Y, Ohning G. A Systematic Review of the Efficacy and Safety of Fecal Microbiota Transplantation in the Treatment of Hepatic Encephalopathy and Clostridioides difficile Infection in Patients With Cirrhosis. Cureus 2022; 14:e25537. [PMID: 35800791 PMCID: PMC9246246 DOI: 10.7759/cureus.25537] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2022] [Indexed: 12/17/2022] Open
Abstract
The microbiome of the human gut and liver coexists by influencing the health and disease state of each system. Fecal microbiota transplantation (FMT) has recently emerged as a potential treatment for conditions associated with cirrhosis, such as hepatic encephalopathy and recurrent/refractory Clostridioides difficile infection (rCDI). We have conducted a systematic review of the safety and efficacy of FMT in treating hepatic encephalopathy and rCDI. A literature search was performed using variations of the keywords "fecal microbiota transplant" and "cirrhosis" on PubMed/MEDLINE from inception to October 3, 2021. The resulting 116 articles were independently reviewed by two authors. Eight qualifying studies were included in the systematic review. A total of 127 cirrhotic patients received FMT. Hepatic encephalopathy was evaluated by cognitive tests, such as the Psychometric Hepatic Encephalopathy Score (PHES) and EncephalApp Stroop test. Not only was there an improvement in the cognitive performance in the FMT cohort, but the improvement was also maintained throughout long-term follow-up. In the treatment of rCDI, the FMT success rate is similar between cirrhotic patients and the general population, although more than one dose may be needed in the former. The rate of serious adverse events and adverse events in the cirrhotic cohort was slightly higher than that in the general population but was low overall. We found evidence that supports the therapeutic potential and safety profile of FMT to treat hepatic encephalopathy and rCDI in cirrhotic patients. Further research will be beneficial to better understand the role of FMT in cirrhosis.
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Affiliation(s)
- Kyaw Min Tun
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, Las Vegas, USA
| | - Annie S Hong
- Department of Gastroenterology and Hepatology, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, Las Vegas, USA
| | - Kavita Batra
- Department of Research, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, Las Vegas, USA
| | - Yassin Naga
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, Las Vegas, USA
| | - Gordon Ohning
- Department of Gastroenterology and Hepatology, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, Las Vegas, USA
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18
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Hoilat GJ, Suhail FK, Adhami T, John S. Evidence-based approach to management of hepatic encephalopathy in adults. World J Hepatol 2022; 14:670-681. [PMID: 35646276 PMCID: PMC9099111 DOI: 10.4254/wjh.v14.i4.670] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 08/07/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a reversible syndrome of impaired brain function and represents one of the many complications of portal hypertension and decompensated liver disease. Although ammonia is clearly implicated in the pathogenesis of HE, the pathogenesis of HE is multifactorial with numerous mechanisms that results in functional impairment of neuronal cells. The initial management of HE focuses on supportive care and stabilization which includes providing appropriate nutritional support. Thereafter, focus should be on identifying and treating the precipitating factors. There are many therapeutic agents available for the management of HE, most of which are directed towards lowering the gut nitrogen load and thus the serum ammonia level. This review aims to provide an update on the conventional and emerging treatment options for HE.
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Affiliation(s)
- Gilles Jadd Hoilat
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
| | - Fathima Keshia Suhail
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Talal Adhami
- Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
| | - Savio John
- Department of Gastroenterology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
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19
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Philips CA, Augustine P. Gut Barrier and Microbiota in Cirrhosis. J Clin Exp Hepatol 2022; 12:625-638. [PMID: 35535069 PMCID: PMC9077238 DOI: 10.1016/j.jceh.2021.08.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota and their homeostatic functions are central to the maintenance of the intestinal mucosal barrier. The gut barrier functions as a structural, biological, and immunological barrier, preventing local and systemic invasion and inflammation of pathogenic taxa, resulting in the propagation or causation of organ-specific (liver disease) or systemic diseases (sepsis) in the host. In health, commensal bacteria are involved in regulating pathogenic bacteria, sinister bacterial products, and antigens; and help control and kill pathogenic organisms by secreting antimicrobial metabolites. Gut microbiota also participates in the extraction, synthesis, and absorption of nutrient metabolites, maintains intestinal epithelial integrity and regulates the development, homeostasis, and function of innate and adaptive immune cells. Cirrhosis is associated with local and systemic immune, vascular, and inflammatory changes directly or indirectly linked to perturbations in quality and quantity of intestinal microbiota and intestinal mucosal integrity. Dysbiosis and gut barrier dysfunction are directly involved in the pathogenesis of compensated cirrhosis and the type and severity of complications in decompensated cirrhosis, such as bacterial infections, encephalopathy, extrahepatic organ failure, and progression to acute on chronic liver failure. This paper reviews the normal gut barrier, gut barrier dysfunction, and dysbiosis-associated clinical events in patients with cirrhosis. The role of dietary interventions, antibiotics, prebiotics, probiotics, synbiotics, and healthy donor fecal microbiota transplantation (FMT) to modulate the gut microbiota for improving patient outcomes is further discussed.
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Affiliation(s)
- Cyriac A. Philips
- Department of Translational Hepatology, Monarch Liver Laboratory, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Ernakulam, Kerala, India
| | - Philip Augustine
- Department of Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Ernakulam, Kerala, India
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20
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Suk KT, Koh H. New perspective on fecal microbiota transplantation in liver diseases. J Gastroenterol Hepatol 2022; 37:24-33. [PMID: 34734433 DOI: 10.1111/jgh.15729] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 01/01/2023]
Abstract
Chronic liver disease including non-alcoholic fatty liver disease and alcohol-related liver disease is one of the most common diseases worldwide. The gut-liver axis plays an important role in the pathogenesis of liver disease. Small intestinal bacterial overgrowth, dysbiosis, leaky bowel, bacterial translocation, and imbalanced metabolites are related to the progression of chronic liver disease. Recently, novel therapeutic approaches for microbiota modulation such as personalized diet, probiotics, prebiotics, antibiotics, engineered microbiotas, phage therapy, stomach operation, and fecal microbiota transplantation (FMT) have been proposed with numerous promising results in the effectiveness and clinical application. Although the evidence is still lacking, FMT, a type of fecal bacteriotherapy, has been known as a candidate for the treatment of liver disease. This review article focuses on the most recent advances in our understanding of FMT in chronic liver disease such as non-alcoholic and alcohol-related liver disease.
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Affiliation(s)
- Ki Tae Suk
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Hong Koh
- Department of Pediatrics, Severance Fecal Microbiota Transplantation Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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21
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Gu X, Lu Q, Zhang C, Tang Z, Chu L. Clinical Application and Progress of Fecal Microbiota Transplantation in Liver Diseases: A Review. Semin Liver Dis 2021; 41:495-506. [PMID: 34261137 PMCID: PMC8492191 DOI: 10.1055/s-0041-1732319] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The human gut harbors a dense and highly diverse microbiota of approximately 1,000 bacterial species. The interaction between the host and gut bacteria strongly influences human health. Numerous evidence suggest that intestinal flora imbalance is closely associated with the development and treatment of liver diseases, including acute liver injury and chronic liver diseases (cirrhosis, autoimmune liver disease, and fatty liver). Therefore, regulating the gut microbiota is expected to be a new method for the adjuvant treatment of liver diseases. Fecal microbiota transplantation (FMT) is defined as the transplantation of gut microbiota from healthy donors to sick patients via the upper or lower gastrointestinal route to restore the normal intestinal balance. In this study, we briefly review the current research on the gut microbiota and its link to liver diseases and then summarize the evidence to elucidate the clinical application and development of FMT in liver disease treatment.
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Affiliation(s)
- Xinpei Gu
- Department of Human Anatomy, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Qin Lu
- Department of Prescription Science, School of Basic Medical Sciences, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Chengcheng Zhang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhewei Tang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China,Address for correspondence Liuxi Chu, PhD Institute of Child Development and Education, School of Biological Sciences and Medical Engineering, Southeast UniversityNanjing - 210096China
| | - Liuxi Chu
- Institute of Child Development and Education, School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, China
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22
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Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol 2021; 75 Suppl 1:S67-S81. [PMID: 34039493 PMCID: PMC8973011 DOI: 10.1016/j.jhep.2020.11.013] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
Cirrhosis - the common end-stage of chronic liver disease - is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.
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Affiliation(s)
- Jonel Trebicka
- Translational Hepatology, Internal Medicine I, Goethe University Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
| | - Jane Macnaughtan
- Institute for Liver and Digestive Health, Royal Free Campus, University College London, United Kingdom
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Debbie L Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Denmark Hill Campus, London, United Kingdom
| | - Jasmohan S Bajaj
- Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, VA, USA
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23
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Madsen M, Kimer N, Bendtsen F, Petersen AM. Fecal microbiota transplantation in hepatic encephalopathy: a systematic review. Scand J Gastroenterol 2021; 56:560-569. [PMID: 33840331 DOI: 10.1080/00365521.2021.1899277] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Hepatic encephalopathy (HE) is a reversible neurocognitive dysfunction that ranges in severity from subclinical alterations to coma. Patients with chronic liver disease are predisposed to HE due to metabolic failure and portosystemic shunting of toxins, of which ammonia is believed to be the main toxic chemical. Fecal microbiota transplantation (FMT) may reduce ammonia synthesis by altering the gut microbiota composition to a taxon low in urease, diminish uptake of ammonia by reestablishing the integrity of the intestinal barrier and increase ammonia clearance by improving liver function. In this systematic review, we summarize the insights of the current literature examining FMT as a treatment for HE.PubMed and EMBASE were searched on 08 February 2021 using the MeSH terms 'fecal microbiota transplantation & hepatic encephalopathy' and the abbreviations 'FMT & HE'.Eight studies fulfilled our inclusion criteria, comprising two randomized clinical trials, three case reports and three rodent studies. Thirty-nine patients with HE were treated with FMT. Thirty-nine rodents received FMT in laboratory tests. FMT improved neurocognitive test results in four human studies and two rodent studies. Microbiota originating from donors was found in human recipients one year post-FMT. Readmission of patients was lower after treatment with FMT compared to standard of care.FMT may improve neurocognitive function and reduce serious adverse events in patients with HE, but the studies conducted so far have been small and their long-term follow-up is limited. Large-scale, randomized and controlled trials are needed to validate and help standardize the clinical application of FMT in cases of HE.
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Affiliation(s)
- Mathias Madsen
- Gastro Unit, Medical Division, Hvidovre University Hospital, Copenhagen, Denmark
| | - Nina Kimer
- Gastro Unit, Medical Division, Hvidovre University Hospital, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Hvidovre University Hospital, Copenhagen, Denmark
| | - Andreas Munk Petersen
- Gastro Unit, Medical Division, Hvidovre University Hospital, Copenhagen, Denmark.,Department of Clinical Microbiology, Hvidovre University Hospital, Copenhagen, Denmark
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24
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Hassouneh R, Bajaj JS. Gut Microbiota Modulation and Fecal Transplantation: An Overview on Innovative Strategies for Hepatic Encephalopathy Treatment. J Clin Med 2021; 10:330. [PMID: 33477417 PMCID: PMC7830387 DOI: 10.3390/jcm10020330] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/07/2021] [Accepted: 01/09/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a major complication of cirrhosis, which is associated with gut microbial composition and functional alterations. Current treatments largely focus on gut microbiota using lactulose, rifaximin and other agents. However, despite these treatments, patients with HE have a high rate of readmission, morbidity and cognitive impairment. Fecal microbiota transplant (FMT) involves introduction of a donor microbiota into a recipient and is currently mainly used for recurrent C. difficile infection (rCDI). The role of FMT in cirrhosis and HE is evolving. There have been two randomized clinical trials (RCT) and several case reports/series in cirrhosis. Both RCTs were safety-focused phase 1 trials. One involved pre-FMT antibiotics and FMT enema versus standard of care, while the other involved 15 FMT capsules versus placebo without pre-FMT antibiotics. There was evidence of safety in both trials and the FMT group demonstrated reduction in hospitalizations compared to the non-FMT group. Changes in microbial function centered around short-chain fatty acids, bile acids and brain function showed improvement in the FMT groups. Long-term follow-up demonstrated continued safety and reduction in the antibiotic-resistance gene carriage. However, larger trials of FMT in HE are needed that can refine the dose, duration and route of FMT administration.
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Affiliation(s)
- Ramzi Hassouneh
- Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA;
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University and Central Virginia Veterans Healthcare System, 1201 Broad Rock Blvd, Richmond, VA 23249, USA
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25
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Hartmann P, Schnabl B. New Developments in Microbiome in Alcohol-Associated and Nonalcoholic Fatty Liver Disease. Semin Liver Dis 2021; 41:87-102. [PMID: 33957682 PMCID: PMC8163568 DOI: 10.1055/s-0040-1719174] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are important causes of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of both ALD and NAFLD. Here we describe associated changes in the intestinal microbiota, and we detail randomized clinical trials in ALD and NAFLD which evaluate treatments modulating the intestinal microbiome including fecal microbiota transplantation, probiotics, prebiotics, synbiotics, and antibiotics. Finally, we discuss precision medicine approaches targeting the intestinal microbiome to ameliorate ALD and NAFLD.
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Affiliation(s)
- Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA;,Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA;,Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA.,Corresponding Author: Bernd Schnabl, MD, Department of Medicine, University of California, San Diego, Biomedical Research Facility 2 (BRF2), Room 4A22, 9500 Gilman Drive, MC0063, La Jolla, CA 92093, Phone: +1 858-822-5311, Fax: +1 858-822-5370,
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26
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Fecal microbiota transplantation in hepatic encephalopathy : a review of the current evidence and future perspectives. Acta Gastroenterol Belg 2021; 84:87-90. [PMID: 33639698 DOI: 10.51821/84.1.884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) is a leading cause of hospitalization and morbimortality in advanced cirrhosis with limited therapeutic options available. Given the paramount role of gut microbiota in HE, and the efficacy of fecal microbiota transplantation (FMT) in other diseases, this review intends to summarize the evidence supporting the safety, efficacy and future perspectives of FMT in HE. Current evidence, despite being scarce, points towards FMT being a safe, effective and tolerable procedure in HE. Some unanswered questions remain about the optimal dose, the administration route, the long term effects and the selection of the optimal donor. Future trials, some of which are already underway, will provide us additional evidence and hopefully the necessary answers.
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27
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Bajaj JS, Lauridsen M, Tapper EB, Duarte-Rojo A, Rahimi RS, Tandon P, Shawcross DL, Thabut D, Dhiman RK, Romero-Gomez M, Sharma BC, Montagnese S. Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus. Am J Gastroenterol 2020; 115:989-1002. [PMID: 32618647 DOI: 10.14309/ajg.0000000000000603] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.
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Affiliation(s)
- Jasmohan S Bajaj
- Virginia Commonwealth University, McGuire VA Medical Center, Richmond, Virginia, USA
| | | | | | | | | | | | | | - Dominique Thabut
- Paris Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France
| | - Radha K Dhiman
- Postgraduate Institute of Medical Education & Research, Chandigarh, India
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28
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Bruns T, Stallmach A. Gastrointestinale Mikrobiota bei Leberzirrhose: pathophysiologische Veränderungen und therapeutische Interventionen. DER GASTROENTEROLOGE 2020; 15:194-200. [DOI: 10.1007/s11377-020-00436-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Bajaj JS, Khoruts A. Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. J Hepatol 2020; 72:1003-1027. [PMID: 32004593 DOI: 10.1016/j.jhep.2020.01.017] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/07/2020] [Accepted: 01/20/2020] [Indexed: 02/08/2023]
Abstract
Patients with chronic liver disease and cirrhosis demonstrate a global mucosal immune impairment, which is associated with altered gut microbiota composition and functionality. These changes progress along with the advancing degree of cirrhosis and can be linked with hepatic encephalopathy, infections and even prognostication independent of clinical biomarkers. Along with compositional changes, functional alterations to the microbiota, related to short-chain fatty acids, bioenergetics and bile acid metabolism, are also associated with cirrhosis progression and outcomes. Altering the functional and structural profile of the microbiota is partly achieved by medications used in patients with cirrhosis such as rifaximin, lactulose, proton pump inhibitors and other antibiotics. However, the role of faecal or intestinal microbiota transplantation is increasingly being recognised. Herein, we review the challenges, opportunities and road ahead for the appropriate and safe use of intestinal microbiota transplantation in liver disease.
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Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
| | - Alexander Khoruts
- Division of Gastroenterology Hepatology and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
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DuPont HL, Jiang ZD, DuPont AW, Utay NS. Abnormal Intestinal Microbiome in Medical Disorders and Potential Reversibility by Fecal Microbiota Transplantation. Dig Dis Sci 2020; 65:741-756. [PMID: 32008133 DOI: 10.1007/s10620-020-06102-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Reduction in diversity of the intestinal microbiome (dysbiosis) is being identified in many disease states, and studies are showing important biologic contributions of microbiome to health and disease. Fecal microbiota transplantation (FMT) is being evaluated as a way to reverse dysbiosis in diseases and disorders in an attempt to improve health. The published literature was reviewed to determine the value of FMT in the treatment of medical disorders for which clinical trials have recently been conducted. FMT is effective in treating recurrent C. difficile infection in one or two doses, with many healthy donors providing efficacious fecal-derived products. In inflammatory bowel disease (IBD), FMT may lead to remission in approximately one-third of moderate-to-severe illnesses with one study suggesting that more durable FMT responses may be seen when used once medical remissions have been achieved. Donor products differ in their efficacy in treatment of IBD. Combining donor products has been one way to increase the potential value of FMT in treating chronic disorders. FMT is being explored in a variety of clinical settings affecting different organ systems outside CDI, with positive preliminary signals, in treatment of functional constipation, immunotherapy-induced colitis, neurodegenerative disease, as well as prevention of cancer-related disorders like graft versus host disease and decolonization of patients with recurrent urinary tract infection due to antibiotic-resistant bacteria. Currently, intense research is underway to see how the microbiome products like FMT can be harnessed for health benefits.
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Affiliation(s)
- Herbert L DuPont
- Kelsey Research Foundation, Houston, TX, USA. .,University of Texas School of Public Health, 1200 Pressler St, Houston, TX, 77030, USA. .,University of Texas McGovern Medical School, Houston, USA. .,Baylor College of Medicine, Houston, USA. .,MD Anderson Cancer Center, Houston, USA.
| | - Zhi-Dong Jiang
- University of Texas School of Public Health, 1200 Pressler St, Houston, TX, 77030, USA
| | | | - Netanya S Utay
- Kelsey Research Foundation, Houston, TX, USA.,University of Texas McGovern Medical School, Houston, USA
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Rosenbaum JT. Just another crappy commentary: the future of fecal microbiota transplantation. Expert Rev Clin Immunol 2019; 15:987-989. [PMID: 31414930 DOI: 10.1080/1744666x.2019.1656528] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- James T Rosenbaum
- Departments of Ophthalmology, Medicine, and Cell Biology, Oregon Health & Science University , Portland , OR , USA.,Legacy Devers Eye Institute , Portland , OR , USA
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