|
1
|
Wu N, Bayatpour S, Hylemon PB, Aseem SO, Brindley PJ, Zhou H. Gut Microbiome and Bile Acid Interactions: Mechanistic Implications for Cholangiocarcinoma Development, Immune Resistance, and Therapy. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:397-408. [PMID: 39730075 PMCID: PMC11841492 DOI: 10.1016/j.ajpath.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/05/2024] [Accepted: 11/12/2024] [Indexed: 12/29/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis. It indicates a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome. This leads to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review focuses on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. It also evaluates the therapeutic potential of targeting the gut microbiome and bile acid-mediated signaling pathways for the therapy and prophylaxis of CCA.
Collapse
Affiliation(s)
- Nan Wu
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia
| | - Sareh Bayatpour
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia
| | - Phillip B Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Sayed O Aseem
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia; Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia
| | - Paul J Brindley
- Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia.
| |
Collapse
|
|
2
|
Ramos-Martínez A, Múñez E, Del-Campo R, Nieto-Fernández A, Gonzalez-Haba M, Calderón- Parra J. Fecal microbiota transplantation as a preventive treatment for recurrent acute cholangitis. IDCases 2024; 37:e02025. [PMID: 39071049 PMCID: PMC11280021 DOI: 10.1016/j.idcr.2024.e02025] [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: 01/31/2024] [Revised: 06/16/2024] [Accepted: 07/02/2024] [Indexed: 07/30/2024] Open
Abstract
Background Recurrent acute cholangitis (RAC) is a relatively uncommon entity that presents significant management difficulties. We present the case of a patient with RAC in whom the number of episodes was reduced after a novel therapeutic procedure. Case report A 93-year-old male who in June 2019 was admitted for chills without fever, shivering, epigastric abdominal pain and moderate jaundice. Both abdominal ultrasound and CT scan showed intrahepatic and extrahepatic duct dilatation up to the papilla with no evidence of mass at that level. Endoscopic retrograde cholangiopancreatography (ERCP) was performed and abundant biliary sludge was removed. E. coli was identified as the cause of several of the episodes. Some isolates were shown to produce extended spectrum beta-lactamase (ESBL). Papillotomy was performed and plastic prosthesis and later a metallic prosthesis were implanted. Several months later a surgical bypass of the biliary tract was performed due to persistent episodes of cholangitis. When the chronic suppressive antibiotic treatment subsequently instituted to prevent new episodes of cholangitis failed, it was decided to perform a fecal microbiota transplant from a healthy donor and to suspend the chronic suppressive treatment. Since then, she has not presented new episodes of RAC for more than 10 months of clinical follow-up. BLEE-producing E. coli in the gastrointestinal tract could not be eradicated. Comment Chronic colonization of the biliary tract by certain enterobacteria such as E. coli has been identified as a relevant pathogenic factor in cases of RAC. FMT may be a promising tool to improve the clinical course of patients with RAC.
Collapse
Affiliation(s)
- Antonio Ramos-Martínez
- Infectious Disease Unit, Hospital Universitario Puerta de Hierro, Instituto Investigación Sanitaria Puerta de Hierro – Segovia de Arana (IDIPHIM), Majadahonda, Spain
| | - Elena Múñez
- Infectious Disease Unit, Hospital Universitario Puerta de Hierro, Instituto Investigación Sanitaria Puerta de Hierro – Segovia de Arana (IDIPHIM), Majadahonda, Spain
| | - Rosa Del-Campo
- Department of Microbiology, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | - Mariano Gonzalez-Haba
- Departement of Gastroenterology, Hospital Universitario Puerta de Hierro, Majadahonda, Spain
| | - Jorge Calderón- Parra
- Infectious Disease Unit, Hospital Universitario Puerta de Hierro, Majadahonda, Spain
| |
Collapse
|
|
3
|
Sohal A, Kowdley KV. Novel preclinical developments of the primary sclerosing cholangitis treatment landscape. Expert Opin Investig Drugs 2024; 33:335-345. [PMID: 38480008 DOI: 10.1080/13543784.2024.2330738] [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: 07/10/2023] [Accepted: 03/11/2024] [Indexed: 03/19/2024]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with inflammation, fibrosis, and destruction of intra- and extrahepatic bile ducts. Despite substantial recent advances in our understanding of PSC, the only proven treatment of PSC is liver transplantation. There is an urgent unmet need to find medical therapies for this disorder. AREAS COVERED Multiple drugs are currently under evaluation as therapeutic options for this disease. This article summarizes the literature on the various novel therapeutic options that have been investigated and are currently under development for the treatment of PSC. EXPERT OPINION In the next decade, more than one drug will likely be approved for the treatment of the disease, and we will be looking at combination therapies for the optimal management of the disease.
Collapse
Affiliation(s)
- Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, USA
| | - Kris V Kowdley
- Department of Hepatology, Liver Institute Northwest, Seattle, USA
- Elson S. Floyd College of Medicine, Washington State University, Spokane, USA
| |
Collapse
|
|
4
|
Maccauro V, Fianchi F, Gasbarrini A, Ponziani FR. Gut Microbiota in Primary Sclerosing Cholangitis: From Prognostic Role to Therapeutic Implications. Dig Dis 2024; 42:369-379. [PMID: 38527453 DOI: 10.1159/000538493] [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] [Received: 12/29/2023] [Accepted: 03/04/2024] [Indexed: 03/27/2024]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of unknown etiology characterized by biliary inflammation and periductal fibrosis. The gut microbiota plays a crucial role in the pathogenesis of PSC by regulating bile acid metabolism, inflammation, and immune response. On the other hand, liver disease progression affects the composition of the gut microbiota, fostering these mechanisms in a mutual detrimental way. SUMMARY Recent evidences described a specific pro-inflammatory microbial signature in PSC patients, with an overall reduced bacterial diversity and the loss of beneficial metabolites such as short-chain fatty acids. As effective therapies for PSC are still lacking, targeting the gut microbiota offers a new perspective in the management of this disease. To date, antibiotics, fecal microbiota transplantation, and probiotics are the most studied gut microbiota-targeted intervention in PSC, but new potential strategies such as vaccines and bacteriophages represent possible future therapeutic horizons. KEY MESSAGES In this review, we focus on the role of the gut microbiota in PSC, considering its pathogenetic and prognostic role and the therapeutic implications.
Collapse
Affiliation(s)
- Valeria Maccauro
- Liver Diseases Unit, CEMAD Centro Malattie dell'Apparato Digerente, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Francesca Fianchi
- Liver Diseases Unit, CEMAD Centro Malattie dell'Apparato Digerente, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Liver Diseases Unit, CEMAD Centro Malattie dell'Apparato Digerente, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Romana Ponziani
- Liver Diseases Unit, CEMAD Centro Malattie dell'Apparato Digerente, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy,
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy,
| |
Collapse
|
|
5
|
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
| |
Collapse
|
|
6
|
Kim DY, Lee SY, Lee JY, Whon TW, Lee JY, Jeon CO, Bae JW. Gut microbiome therapy: fecal microbiota transplantation vs live biotherapeutic products. Gut Microbes 2024; 16:2412376. [PMID: 39377231 PMCID: PMC11469438 DOI: 10.1080/19490976.2024.2412376] [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] [Received: 12/01/2023] [Revised: 08/28/2024] [Accepted: 09/30/2024] [Indexed: 10/09/2024] Open
Abstract
The human intestine hosts a complex ecosystem of various microorganisms, collectively known as the gut microbiome, which significantly impacts human health. Disruptions in the gut microbiome are linked to various disorders, including gastrointestinal diseases, such as Clostridioides difficile infection and inflammatory bowel disease, as well as metabolic, neurological, oncologic conditions. Fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs) have emerged as prospective therapeutic procedures to restore microbial and metabolic balance in the gut. This review assesses the latest advancements, challenges, and therapeutic efficacy of FMT and LBPs, highlighting the need for standardization, safety, and long-term evaluation to optimize their clinical application.
Collapse
Affiliation(s)
- Do-Yeon Kim
- Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Seoul, Korea
| | - So-Yeon Lee
- Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Seoul, Korea
| | - Jae-Yun Lee
- Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Seoul, Korea
| | - Tae Woong Whon
- Microbiology and Functionality Research Group, World Institute of Kimchi, Gwangju, Korea
| | - June-Young Lee
- Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Seoul, Korea
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Korea
| | - Che Ok Jeon
- Department of Life Science, Chung-Ang University, Seoul, Korea
| | - Jin-Woo Bae
- Department of Life and Nanopharmaceutical Sciences and Department of Biology, Kyung Hee University, Seoul, Korea
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Korea
| |
Collapse
|
|
7
|
Abstract
Autoimmune liver diseases (AILD) are a group of immune-mediated liver inflammatory diseases with three major forms including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Interaction of both genetic and environmental factors leads to the breakdown of self-tolerance, hence resulting in hyper-responsive of autoantibodies and aggressive autoreactive immune cells. Genetic studies have identified dozens of risk loci associated with initiation and development of AILD. However, the role of exogenous factors remains unclear. Recently, both infectious and inflammatory diseases have been associated with microbiota, which colonizes multiple mucosal surfaces and participates in human physiological process and function in immune system, particularly influencing liver, and biliary system via gut-liver axis. Emerging evidence on the role of gut microbiota has expanded our knowledge of AILD in both pathogenesis and potential therapeutic targets, along with putative diagnosis biomarkers. Herein we review the relationship between host and gut microbiota, discuss their potential roles in disease onset and progression, and summarize the compositional and functional alterations of the microbiota in AILD. We also highlighted the microbiota-based therapeutics such as antibiotics and fecal microbiota transplantation (FMT).
Collapse
Affiliation(s)
- Qiwei Qian
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wei He
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruqi Tang
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiong Ma
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China -
| |
Collapse
|
|
8
|
Research Progress of Fecal Microbiota Transplantation in Liver Diseases. J Clin Med 2023; 12:jcm12041683. [PMID: 36836218 PMCID: PMC9960958 DOI: 10.3390/jcm12041683] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/06/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
A growing body of evidence suggested that gut microbiota is associated with liver diseases through the gut-liver axis. The imbalance of gut microbiota could be correlated with the occurrence, development, and prognosis of a series of liver diseases, including alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), viral hepatitis, cirrhosis, primary sclerosing cholangitis (PSC), and hepatocellular carcinoma (HCC). Fecal microbiota transplantation (FMT) seems to be a method to normalize the patient's gut microbiota. This method has been traced back to the 4th century. In recent decade, FMT has been highly regarded in several clinical trials. As a novel approach to reconstruct the intestinal microecological balance, FMT has been used to treat the chronic liver diseases. Therefore, in this review, the role of FMT in the treatment of liver diseases was summarized. In addition, the relationship between gut and liver was explored through the gut-liver axis, and the definition, objectives, advantages, and procedures of FMT were described. Finally, the clinical value of FMT therapy in liver transplant (LT) recipients was briefly discussed.
Collapse
|
|
9
|
Kasztelan-Szczerbinska B, Rycyk-Bojarzynska A, Szczerbinska A, Cichoz-Lach H. Selected Aspects of the Intricate Background of Immune-Related Cholangiopathies-A Critical Overview. Nutrients 2023; 15:760. [PMID: 36771465 PMCID: PMC9921714 DOI: 10.3390/nu15030760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are rare immune-related cholangiopathies with still poorly explained pathogenesis. Although triggers of chronic inflammation with subsequent fibrosis that affect cholangiocytes leading to obliteration of bile ducts and conversion to liver cirrhosis are unclear, both disorders are regarded to be multifactorial. Different factors can contribute to the development of hepatocellular injury in the course of progressive cholestasis, including (1) body accumulation of bile acids and their toxicity, (2) decreased food intake and nutrient absorption, (3) gut microbiota transformation, and (4) reorganized host metabolism. Growing evidence suggests that intestinal microbiome composition not only can be altered by liver dysfunction, but in turn, it actively impacts hepatic conditions. In this review, we highlight the role of key factors such as the gut-liver axis, intestinal barrier integrity, bile acid synthesis and circulation, and microbiome composition, which seem to be strongly related to PBC and PSC outcome. Emerging treatments and future therapeutic strategies are also presented.
Collapse
Affiliation(s)
- Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Anna Rycyk-Bojarzynska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | | | - Halina Cichoz-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| |
Collapse
|
|
10
|
Li ZJ, Gou HZ, Zhang YL, Song XJ, Zhang L. Role of intestinal flora in primary sclerosing cholangitis and its potential therapeutic value. World J Gastroenterol 2022; 28:6213-6229. [PMID: 36504550 PMCID: PMC9730442 DOI: 10.3748/wjg.v28.i44.6213] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/31/2022] [Accepted: 11/10/2022] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an autoimmune disease characterized by chronic cholestasis, a persistent inflammation of the bile ducts that leads to sclerotic occlusion and cholestasis. Gut microbes, consisting of microorganisms colonized in the human gut, play an important role in nutrient intake, metabolic homeostasis, immune regulation, and immune regulation; however, their presence might aid PSC development. Studies have found that gut-liver axis interactions also play an important role in the pathogenesis of PSC. Patients with PSC have considerably reduced intestinal flora diversity and increased abundance of potentially pathogenic bacteria. Dysbiosis of the intestinal flora leads to increased intestinal permeability, homing of intestinal lymphocytes, entry of bacteria and their associated metabolites, such as bile acids, into the liver, stimulation of hepatic immune activation, and promotion of PSC. Currently, PSC effective treatment is lacking. However, a number of studies have recently investigated the targeted modulation of gut microbes for the treatment of various liver diseases (alcoholic liver disease, metabolic fatty liver, cirrhosis, and autoimmune liver disease). In addition, antibiotics, fecal microbiota transplantation, and probiotics have been reported as successful PSC therapies as well as for the treatment of gut dysbiosis, suggesting their effectiveness for PSC treatment. Therefore, this review briefly summarizes the role of intestinal flora in PSC with the aim of providing new insights into PSC treatment.
Collapse
Affiliation(s)
- Zhen-Jiao Li
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Hong-Zhong Gou
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yu-Lin Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jing Song
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| |
Collapse
|
|
11
|
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: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [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.
Collapse
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
| |
Collapse
|
|
12
|
Gallo C, Howardson BO, Cristoferi L, Carbone M, Gershwin ME, Invernizzi P. An Update on Novel Pharmacological Agents for Primary Sclerosing Cholangitis. Expert Opin Ther Targets 2022; 26:69-77. [PMID: 35040733 DOI: 10.1080/14728222.2022.2030707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease with heterogeneous phenotypes that may lead to liver transplantation and/or end-stage liver disease. Its multifactorial etiopathogenesis remains uncertain, but gut-liver axis and bile composition and excretion are widely demonstrated to influence the immune-mediated fibrogenic reactive cascade. AREAS COVERED : Different experimental therapeutic options are under investigation, mainly aiming at modulating bile acids excretion, limiting inflammatory-cascade reactions, and changing intestinal microbiota composition; none of them yet demonstrated to prolong transplant free survival. This review provides a comprehensive description of the experimental drugs recently tested and/or currently under investigation. A bibliographical search was performed in Pubmed, MEDLINE, EMBASE, OVID and clinicaltrial.gov until July 2021. EXPERT OPINION : The heterogeneity and poor prevalence of PSC, its uncertain pathophysiology, and the lack of surrogate endpoints are the major challenges in drug discovery. Strategies that synergistically target microbiota, bile acids, and liver fibrosis are needed. In parallel, we must enhance biomarker discovery to develop surrogate endpoints, as biochemical markers' fluctuations over the time hamper their effectiveness. Magnetic resonance cholangiopancreatography tools that accurately measure bile duct changes represent a potential, novel marker for disease monitoring. A collaboration between academia, research consortia, patient's associations and industry is required.
Collapse
Affiliation(s)
- Camilla Gallo
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Bright Oworae Howardson
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - M Eric Gershwin
- Division of Rheumatology and Clinical Immunology, University of California at Davis School of Medicine, Davis California 95616 USA
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| |
Collapse
|
|
13
|
Current Status and Future Therapeutic Options for Fecal Microbiota Transplantation. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58010084. [PMID: 35056392 PMCID: PMC8780626 DOI: 10.3390/medicina58010084] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/23/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022]
Abstract
The intestinal microbiota plays an important role in maintaining human health, and its alteration is now associated with the development of various gastrointestinal (ulcerative colitis, irritable bowel syndrome, constipation, etc.) and extraintestinal diseases, such as cancer, metabolic syndrome, neuropsychiatric diseases. In this context, it is not surprising that gut microbiota modification methods may constitute a therapy whose potential has not yet been fully investigated. In this regard, the most interesting method is thought to be fecal microbiota transplantation, which consists of the simultaneous replacement of the intestinal microbiota of a sick recipient with fecal material from a healthy donor. This review summarizes the most interesting findings on the application of fecal microbiota transplantation in gastrointestinal and extraintestinal pathologies.
Collapse
|
|
14
|
Fecal Microbiota Transplantation in Patients with HBV Infection or Other Chronic Liver Diseases: Update on Current Knowledge and Future Perspectives. J Clin Med 2021; 10:jcm10122605. [PMID: 34204748 PMCID: PMC8231596 DOI: 10.3390/jcm10122605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/12/2022] Open
Abstract
Liver disease and gut dysbiosis are strictly associated, and the pathophysiology of this bidirectional relationship has recently been the subject of several investigations. Growing evidence highlights the link between gut microbiota composition, impairment of the gut-liver axis, and the development or progression of liver disease. Therefore, the modulation of gut microbiota to maintain homeostasis of the gut-liver axis could represent a potential instrument to halt liver damage, modify the course of liver disease, and improve clinical outcomes. Among all the methods available to achieve this purpose, fecal microbiota transplantation (FMT) is one of the most promising, being able to directly reshape the recipient’s gut microbial communities. In this review, we report the main characteristics of gut dysbiosis and its pathogenetic consequences in cirrhotic patients, discussing the emerging data on the application of FMT for liver disease in different clinical settings.
Collapse
|
|
15
|
Li Y, Xue H, Fang S, Wang G, Wang Y, Wang T, Shi R, Wu J, Ma Y. Time-series metabolomics insights into the progressive characteristics of 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestatic liver fibrosis in mice. J Pharm Biomed Anal 2021; 198:113986. [PMID: 33690095 DOI: 10.1016/j.jpba.2021.113986] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 01/01/2023]
Abstract
Cholestasis is characterized by obstruction of bile flow and can lead to serious liver injury. With sustained damage, cholestasis can progress to cholestatic liver fibrosis (CLF), and cirrhosis. Non-invasive, predictive, and reliable metabolites based on the early and progressive stages of CLF are urgently needed. Based on the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced CLF mouse model, serum metabolic profiling via a time-series strategy with ultra-performance liquid chromatography-LTQ-Orbitrap-based metabolomics, combined with histological progression, was used to find CLF-specific metabolites, and explore their dynamic changes in progressive stages of CLF. Compared to those in the control group, DDC-induced groups showed a substantial elevation in cholestatic liver injury and fibrosis indices. Next, 21 differential serum metabolites were selected and identified between the normal (control) and DDC groups, and 12 of them were greatly altered over time. Among these, taurocholic acid, tauromuricholic acid, LysoPE (20:2), sulfoglycolithocholic acid, and taurohyodeoxycholic acid were associated with the progression of the hepatocyte injury index, alanine aminotransferase. More importantly, docosahexaenoic acid, arachidonic acid, proline, leucine, and linoleic acid were associated with the progression of liver fibrosis index, liver hydroxyproline. Moreover, the differential metabolites that were related to hepatocyte injury and liver fibrosis were further validated in DDC-induced mice at weeks 4 and 8. Overall, this work provides data on differential metabolites for the progressive pathology of CLF.
Collapse
Affiliation(s)
- Yuanyuan Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Haoyu Xue
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Su Fang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Guofeng Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Yahang Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Tianming Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Rong Shi
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Jiasheng Wu
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
| | - Yueming Ma
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China; Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| |
Collapse
|
|
16
|
Ye ZN, Xia HHX, Zhang R, Li L, Wu LH, Liu XJ, Xie WR, He XX. The Efficacy of Washed Microbiota Transplantation on Helicobacter pylori Eradication: A Pilot Study. Gastroenterol Res Pract 2020; 2020:8825189. [PMID: 33133183 PMCID: PMC7593733 DOI: 10.1155/2020/8825189] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/27/2020] [Accepted: 10/09/2020] [Indexed: 02/07/2023] Open
Abstract
AIM The fecal microbiota transplantation by washed preparation was recently coined as washed microbiota transplantation (WMT). This pilot study is aimed at exploring the feasibility and efficacy of WMT on Helicobacter pylori eradication. METHODS Consecutive patients who had been treated with WMT for various indications and who were positive for H. pylori infection before WMT treatment but had never received eradication therapy for H. pylori infection were invited to take a follow-up 13C-urea breath test. The associations of demographic, clinical factors, and laboratory indicators for gastric function and intestinal barrier function with the therapeutic effect were determined. RESULTS A total of 32 eligible patients were included, and the overall H. pylori eradication rate was 40.6% (13/32). Patients with H. pylori eradication had a higher pepsinogen ratio (PGR) than those without (13.00 ± 6.97vs.8.31 ± 3.733; P = 0.02). Female patients had a higher, albeit not statistically significant, eradication rate than male patients (53.85% vs. 31.58%; P = 0.208). Compared with lower gastrointestinal tract delivery route, middle gastrointestinal tract delivery route seems to be a more suitable way for the treatment of H. pylori infection (58.33% vs 16.67%; P = 0.152). There was no significant difference in other demographic and clinical factors between patients with and without H. pylori eradication. CONCLUSION H. pylori infection is eradicated in a proportion of patients who have received WMT. An increased pre-WMT PGR appears to be associated with the therapeutic effect. Further studies are required to confirm the efficacy of WMT, especially in combination with currently recommended regimens in randomized controlled trials.
Collapse
Affiliation(s)
- Zhi-Ning Ye
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
| | - Harry Hua-Xiang Xia
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
| | - Ran Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
| | - Lan Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
| | - Li-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
| | - Xu-Juan Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
| | - Wen-Rui Xie
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
| | - Xing-Xiang He
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
- Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
| |
Collapse
|
|
17
|
Antushevich H. Fecal microbiota transplantation in disease therapy. Clin Chim Acta 2020; 503:90-98. [DOI: 10.1016/j.cca.2019.12.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/13/2019] [Accepted: 12/13/2019] [Indexed: 12/17/2022]
|
|
18
|
Philips CA, Augustine P, Yerol PK, Ramesh GN, Ahamed R, Rajesh S, George T, Kumbar S. Modulating the Intestinal Microbiota: Therapeutic Opportunities in Liver Disease. J Clin Transl Hepatol 2020; 8:87-99. [PMID: 32274349 PMCID: PMC7132020 DOI: 10.14218/jcth.2019.00035] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/11/2019] [Accepted: 10/27/2019] [Indexed: 12/11/2022] Open
Abstract
Gut microbiota has been demonstrated to have a significant impact on the initiation, progression and development of complications associated with multiple liver diseases. Notably, nonalcoholic fatty liver diseases, including nonalcoholic steatohepatitis and cirrhosis, severe alcoholic hepatitis, primary sclerosing cholangitis and hepatic encephalopathy, have strong links to dysbiosis - or a pathobiological change in the microbiota. In this review, we provide clear and concise discussions on the human gut microbiota, methods of identifying gut microbiota and its functionality, liver diseases that are affected by the gut microbiota, including novel associations under research, and provide current evidence on the modulation of gut microbiota and its effects on specific liver disease conditions.
Collapse
Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit, Monarch Liver Lab and Division of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Philip Augustine
- The Liver Unit, Monarch Liver Lab and Division of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Praveen Kumar Yerol
- Department of Gastroenterology, State Government Medical College, Thrissur, Kerala, India
| | | | - Rizwan Ahamed
- The Liver Unit, Monarch Liver Lab and Division of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Sasidharan Rajesh
- The Liver Unit, Monarch Liver Lab and Division of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Tom George
- The Liver Unit, Monarch Liver Lab and Division of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Sandeep Kumbar
- The Liver Unit, Monarch Liver Lab and Division of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| |
Collapse
|
|
19
|
Lechner S, Yee M, Limketkai BN, Pham EA. Fecal Microbiota Transplantation for Chronic Liver Diseases: Current Understanding and Future Direction. Dig Dis Sci 2020; 65:897-905. [PMID: 32020359 DOI: 10.1007/s10620-020-06100-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Chronic liver disease is a major cause of morbidity and mortality worldwide. Even though effective treatments are now available for most chronic viral hepatitis, treatment options for other causes of chronic liver disease remain inadequate. Recent research has revealed a previously unappreciated role that the human intestinal microbiome plays in mediating the development and progression of chronic liver diseases. The recent remarkable success of fecal microbiota transplantation (FMT) in treating Clostridioides difficile demonstrates that the intestinal microbiota can be manipulated to obtain favorable therapeutic benefits and that FMT may become an important component of a total therapeutic approach to effectively treat hepatic disorders.
Collapse
Affiliation(s)
- Sarah Lechner
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Matthew Yee
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Berkeley N Limketkai
- Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA, USA
| | - Edward A Pham
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
| |
Collapse
|
|
20
|
Fecal Microbiota Transplantation for Primary Sclerosing Cholangitis-A Beautiful but Incomplete Story. Am J Gastroenterol 2019; 114:1353-1354. [PMID: 31205136 DOI: 10.14309/ajg.0000000000000294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|
|
21
|
Fecal Microbiota Transplantation in Patients With Primary Sclerosing Cholangitis: The Next Steps in This Promising Story. Am J Gastroenterol 2019; 114:1354-1355. [PMID: 31306151 DOI: 10.14309/ajg.0000000000000317] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|