|
1
|
Sadri M, Shafaghat Z, Roozbehani M, Hoseinzadeh A, Mohammadi F, Arab FL, Minaeian S, Fard SR, Faraji F. Effects of Probiotics on Liver Diseases: Current In Vitro and In Vivo Studies. Probiotics Antimicrob Proteins 2025; 17:1688-1710. [PMID: 39739162 DOI: 10.1007/s12602-024-10431-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2024] [Indexed: 01/02/2025]
Abstract
Various types of liver or hepatic diseases cause the death of about 2 million people worldwide every year, of which 1 million die from the complications of cirrhosis and another million from hepatocellular carcinoma and viral hepatitis. Currently, the second most common solid organ transplant is the liver, and the current rate represents less than 10% of global transplant requests. Hence, finding new approaches to treat and prevent liver diseases is essential. In liver diseases, the interaction between the liver, gut, and immune system is crucial, and probiotics positively affect the human microbiota. Probiotics are a non-toxic and biosafe alternative to synthetic chemical compounds. Health promotion by lowering cholesterol levels, stimulating host immunity, the natural gut microbiota, and other functions are some of the activities of probiotics, and their metabolites, including bacteriocins, can exert antimicrobial effects against a broad range of pathogenic bacteria. The present review discusses the available data on the results of preclinical and clinical studies on the effects of probiotic administration on different types of liver diseases.
Collapse
Affiliation(s)
- Maryam Sadri
- Department of Immunology, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Shafaghat
- Department of Immunology, Iran University of Medical Sciences, Tehran, Iran
| | - Mona Roozbehani
- Vaccine Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Akram Hoseinzadeh
- Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Mohammadi
- Department of Immunology, School of Medicine, Mashhad University of Medicine Sciences, Mashhad, Iran
| | - Fahimeh Lavi Arab
- Department of Immunology, School of Medicine, Mashhad University of Medicine Sciences, Mashhad, Iran
| | - Sara Minaeian
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran
| | - Soheil Rahmani Fard
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran
| | - Fatemeh Faraji
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran.
| |
Collapse
|
|
2
|
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
|
|
3
|
Al-Shakhshir S, Quraishi MN, Mullish B, Patel A, Vince A, Rowe A, Homer V, Jackson N, Gyimah D, Shabir S, Manzoor S, Cooney R, Alrubaiy L, Quince C, van Schaik W, Hares M, Beggs AD, Efstathiou E, Rimmer P, Weston C, Iqbal T, Trivedi PJ. FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO): study protocol for a randomised, multicentre, phase IIa, placebo-controlled trial. BMJ Open 2025; 15:e095392. [PMID: 39762111 PMCID: PMC11749870 DOI: 10.1136/bmjopen-2024-095392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 12/10/2024] [Indexed: 01/23/2025] Open
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD). The strong association between gut and liver inflammation has driven several pathogenic hypotheses to which the intestinal microbiome is proposed to contribute. Pilot studies of faecal microbiota transplantation (FMT) in PSC and IBD are demonstrated to be safe and associated with increased gut bacterial diversity. However, the longevity of such changes and the impact on markers of disease activity and disease progression have not been studied. The aim of this clinical trial is to determine the effects of repeated FMT as a treatment for PSC-IBD. METHODS AND ANALYSIS FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO) is a phase IIa randomised placebo-controlled trial to assess the efficacy and safety of repeated colonic administration of FMT in patients with non-cirrhotic PSC-IBD. Fifty-eight patients will be recruited from six sites across England and randomised in a 1:1 ratio between active FMT or FMT placebo arms. FMT will be manufactured by the University of Birmingham Microbiome Treatment Centre, using stool collected from rigorously screened healthy donors. A total of 8 weekly treatments will be delivered; the first through colonoscopic administration (week 1) and the remaining seven via once-weekly enema (up to week 8). Participants will then be followed on a 12-weekly basis until week 48 from the first treatment visit. The primary efficacy outcome will be to determine the effect of FMT on serum alkaline phosphatase values over time (end of study at 48 weeks). Key secondary outcomes will be to evaluate the impact of FMT on other liver biochemical parameters, PSC risk scores, circulating and imaging markers of liver fibrosis, health-related quality of life measures, IBD activity and the incidence of PSC-related clinical events. Key translational objectives will be to identify mucosal metagenomic, metatranscriptomic, metabolomic and immunological pathways associated with the administration of FMT. ETHICS AND DISSEMINATION The protocol was approved by the South Central-Hampshire B Research Ethics Committee (REC 23/SC/0147). Participants will be required to provide written informed consent. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER The trial was registered at ClinicalTrials.gov on 23 February 2024 (NCT06286709). Weblink: Study Details | FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis | ClinicalTrials.gov.
Collapse
Affiliation(s)
- Sarah Al-Shakhshir
- National Institute of Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC) Center for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, England, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Mohammed Nabil Quraishi
- University of Birmingham Institute of Cancer and Genomic Sciences, Birmingham, Birmingham, UK
| | - Benjamin Mullish
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London Faculty of Medicine, London, UK
- Department of Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Arzoo Patel
- National Institute of Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC) Center for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, England, UK
| | - Alexandra Vince
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Anna Rowe
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Victoria Homer
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Nicola Jackson
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Derick Gyimah
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Sahida Shabir
- University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
| | - Susan Manzoor
- University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
| | - Rachel Cooney
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Laith Alrubaiy
- Gastroenterology, St Mark's Hospital and Academic Institute, London, UK
| | - Christopher Quince
- Food, Microbiome and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, UK
- Digital Biology, Earlham Institute, Norwich, Norfolk, UK
| | - Willem van Schaik
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, England, UK
| | - Miriam Hares
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, England, UK
| | - Andrew D Beggs
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- University of Birmingham Institute of Cancer and Genomic Sciences, Birmingham, Birmingham, UK
| | - Elena Efstathiou
- University of Birmingham Institute of Cancer and Genomic Sciences, Birmingham, Birmingham, UK
| | - Peter Rimmer
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Chris Weston
- National Institute of Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC) Center for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, England, UK
| | - Tariq Iqbal
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- University of Birmingham Institute of Cancer and Genomic Sciences, Birmingham, Birmingham, UK
- University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
| | - Palak J Trivedi
- National Institute of Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC) Center for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, England, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| |
Collapse
|
|
4
|
Schneider KM, Kummen M, Trivedi PJ, Hov JR. Role of microbiome in autoimmune liver diseases. Hepatology 2024; 80:965-987. [PMID: 37369002 PMCID: PMC11407779 DOI: 10.1097/hep.0000000000000506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/25/2023] [Indexed: 06/29/2023]
Abstract
The microbiome plays a crucial role in integrating environmental influences into host physiology, potentially linking it to autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. All autoimmune liver diseases are associated with reduced diversity of the gut microbiome and altered abundance of certain bacteria. However, the relationship between the microbiome and liver diseases is bidirectional and varies over the course of the disease. This makes it challenging to dissect whether such changes in the microbiome are initiating or driving factors in autoimmune liver diseases, secondary consequences of disease and/or pharmacological intervention, or alterations that modify the clinical course that patients experience. Potential mechanisms include the presence of pathobionts, disease-modifying microbial metabolites, and more nonspecific reduced gut barrier function, and it is highly likely that the effect of these change during the progression of the disease. Recurrent disease after liver transplantation is a major clinical challenge and a common denominator in these conditions, which could also represent a window to disease mechanisms of the gut-liver axis. Herein, we propose future research priorities, which should involve clinical trials, extensive molecular phenotyping at high resolution, and experimental studies in model systems. Overall, autoimmune liver diseases are characterized by an altered microbiome, and interventions targeting these changes hold promise for improving clinical care based on the emerging field of microbiota medicine.
Collapse
Affiliation(s)
| | - Martin Kummen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Palak J. Trivedi
- National Institute for Health and Care Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, UK
| | - Johannes R. Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| |
Collapse
|
|
5
|
Zhao J, Yue P, Mi N, Li M, Fu W, Zhang X, Gao L, Bai M, Tian L, Jiang N, Lu Y, Ma H, Dong C, Zhang Y, Zhang H, Zhang J, Ren Y, Suzuki A, Wong PF, Tanaka K, Rerknimitr R, Junger HH, Cheung TT, Melloul E, Demartines N, Leung JW, Yao J, Yuan J, Lin Y, Schlitt HJ, Meng W. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications. MEDICAL REVIEW (2021) 2024; 4:326-365. [PMID: 39135601 PMCID: PMC11317084 DOI: 10.1515/mr-2024-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/06/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.
Collapse
Affiliation(s)
- Jinyu Zhao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Matu Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xianzhuo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long Gao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Mingzhen Bai
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liang Tian
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningzu Jiang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Lu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jinduo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Azumi Suzuki
- Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
| | - Peng F. Wong
- Department of Vascular Surgery, The James Cook University Hospital, Middlesbrough, UK
| | - Kiyohito Tanaka
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn, Bangkok, Thailand
- Excellence Center for Gastrointestinal Endoscopy, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Henrik H. Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Tan T. Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Joseph W. Leung
- Division of Gastroenterology and Hepatology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, USA
| | - Jia Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| |
Collapse
|
|
6
|
Parthasarathy G, Malhi H, Bajaj JS. Therapeutic manipulation of the microbiome in liver disease. Hepatology 2024:01515467-990000000-00932. [PMID: 38922826 DOI: 10.1097/hep.0000000000000987] [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: 05/24/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted-from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.
Collapse
Affiliation(s)
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
| |
Collapse
|
|
7
|
Chang G, Sun J, Li J, Li T. Effect of Probiotics on Portal Hypertension (PH) with Cirrhosis: A Systematic Review and Meta-Analysis. Clin Res Hepatol Gastroenterol 2024; 48:102361. [PMID: 38701917 DOI: 10.1016/j.clinre.2024.102361] [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: 03/08/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/05/2024]
Abstract
INTRODUCTION There are many options for the reduction of portal hypertension (pH) in cirrhotic patients, but all the current ones have side effects. Probiotics are a new approach for ameliorating the hyperdynamic circulation of cirrhotic patients. The aim of this study is to measure the effect of probiotics on pH in cirrhosis for the first time. METHODS A search was conducted across four electronic databases (PubMed, Scopus, Web of Science, Cochrane) for English-language records evaluating probiotic effects on pH in cirrhotic patients. Quality assessment used the Cochrane Collaboration's tool, employing a random-effects model in statistical analysis with Stata software version 1. RESULTS A search yielded 1,251 articles, which were narrowed down to 5 through screening. These studies, involving 158 participants across Canada, India, Spain, and Russia, focused on probiotic interventions in cirrhotic patients. Meta-analysis of two RCTs (66 participants) indicated a significant decrease in hepatic venous pressure gradient (HVPG) (SMD: -0.60 [-1.09, -0.12]). In single-arm analysis, four studies (58 participants) showed a substantial reduction in HVPG with probiotic use compared to the control (SMD: -2.55 [-3.42, -1.68]). CONCLUSION In summary, it showcased a notable reduction in HVPG compared to the control group, indicating a potential advantage of probiotics in decreasing pH in cirrhotic patients. Further research with larger samples and robust designs is warranted.
Collapse
Affiliation(s)
- Gang Chang
- Department of Minimally invasive intervention, Shandong Provincial Third Hospital, Shandong University, No.11 Wuyingshan Middle Road, Tianqiao District, Jinan, Shandong 250031, PR China.
| | - Jie Sun
- Department of Gastrointestinal surgery, Shandong Provincial Third Hospital, Shandong University, No.11 Wuyingshan Middle Road, Tianqiao District, Jinan, Shandong 250031, PR China
| | - Jianhua Li
- Department of Gastroenterology, Shandong Provincial Third Hospital, Shandong University, No.11 Wuyingshan Middle Road, Tianqiao District, Jinan, Shandong 250031, PR China
| | - Tao Li
- Department of Hepatic, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, PR China
| |
Collapse
|
|
8
|
Pham HN, Pham L, Sato K. Navigating the liver landscape: upcoming pharmacotherapies for primary sclerosing cholangitis. Expert Opin Pharmacother 2024; 25:895-906. [PMID: 38813599 DOI: 10.1080/14656566.2024.2362263] [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: 04/07/2024] [Accepted: 05/28/2024] [Indexed: 05/31/2024]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a bile duct disorder characterized by ductular reaction, hepatic inflammation, and liver fibrosis. The pathogenesis of PSC is still undefined, and treatment options for patients are limited. Previous clinical trials evaluated drug candidates targeting various cellular functions and pathways, such as bile acid signaling and absorption, gut bacteria and permeability, and lipid metabolisms. However, most of phase III clinical trials for PSC were disappointing, except vancomycin therapy, and there are still no established medications for PSC with efficacy and safety confirmed by phase IV clinical trials. AREAS COVERED This review summarizes the currently ongoing or completed clinical studies for PSC, which are phase II or further, and discusses therapeutic targets and strategies, limitations, and future directions and possibilities of PSC treatments. A literature search was conducted in PubMed and ClinicalTrials.gov utilizing the combination of the searched term 'primary sclerosing cholangitis' with other keywords, such as 'clinical trials,' 'antibiotics,' or drug names. Clinical trials at phase II or further were included for consideration. EXPERT OPINION Only vancomycin demonstrated promising therapeutic effects in the phase III clinical trial. Other drug candidates showed futility or inconsistent results, and the search for novel PSC treatments is still ongoing.
Collapse
Affiliation(s)
- Hoang Nam Pham
- Department of Life Sciences, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University - Central Texas, Killeen, TX, USA
| | - Keisaku Sato
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| |
Collapse
|
|
9
|
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
|
|
10
|
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
|
|
11
|
Ichikawa M, Okada H, Nakamoto N, Taniki N, Chu PS, Kanai T. The gut-liver axis in hepatobiliary diseases. Inflamm Regen 2024; 44:2. [PMID: 38191517 PMCID: PMC10773109 DOI: 10.1186/s41232-023-00315-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 12/17/2023] [Indexed: 01/10/2024] Open
Abstract
Recent advances in the analysis of intestinal bacteria have led to reports of variations in intestinal bacterial levels among hepatobiliary diseases. The mechanisms behind the changes in intestinal bacteria in various hepatobiliary diseases include the abnormal composition of intestinal bacteria, weakening of the intestinal barrier, and bacterial translocation outside the intestinal tract, along with their metabolites, but many aspects remain unresolved. Further research employing clinical studies and animal models is expected to clarify the direct relationship between intestinal bacteria and hepatobiliary diseases and to validate the utility of intestinal bacteria as a diagnostic biomarker and potential therapeutic target. This review summarizes the involvement of the microbiota in the pathogenesis of hepatobiliary diseases via the gut-liver axis.
Collapse
Affiliation(s)
- Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Haruka Okada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan.
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan.
| |
Collapse
|
|
12
|
Abaturov A, Babуch V. Drug regulation of microRNA. CHILD`S HEALTH 2024; 18:572-583. [DOI: 10.22141/2224-0551.18.8.2023.1657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The scientific review provides the mechanisms of drug regulation of microRNA in the human body. To write the article, information was searched using Scopus, Web of Science, MEDLINE, PubMed, Google Scholar, Embase, Global Health, The Cochrane Library databases. To restore the reduced functional activity of microRNAs, replacement therapy is used, with modified synthetic analogs of endogenous microRNAs, and drugs that enhance the production of the body’s own microRNAs. The authors state that numerous studies have confirmed the effectiveness of miRNA replacement therapy. It is known that there are several groups of drugs among miRNA inhibitors: anti-miRNA oligonucleotides, miRNA traps, miRNA mimics that prevent miRNA binding; peptide nucleic acids, small-molecule inhibitors. The authors suggest that the expression of drug-metabolizing enzymes is controlled by nuclear receptors and transcription factors, epigenetic regulation such as DNA methylation and histone acetylation, and post-translational modification. It is emphasized that ursodeoxycholic acid modulates the expression of some miRNAs. It is known that probiotic bacteria can modulate the expression level of miRNA genes. The use of probiotics is accompanied by a change in the expression of numerous genes of the body involved in the regulation of the inflammatory response, allergic reactions, metabolism and other biological processes. Thus, modern science is intensively studying the potential of using drugs that restore miRNA content or inhibit miRNA activity for the therapy of miRNA-dependent conditions. The results of scientific research confirmed the therapeutic effect of ursodeoxycholic acid and probiotic preparations due to the effect on the activity of miRNA generation in hepatobiliary diseases. Therefore, the introduction into clinical practice of drugs than can modulate the content and expression of specific miRNAs will certainly open new perspectives in the treatment of patients with hepatobiliary diseases.
Collapse
|
|
13
|
Özdirik B, Schnabl B. Microbial Players in Primary Sclerosing Cholangitis: Current Evidence and Concepts. Cell Mol Gastroenterol Hepatol 2023; 17:423-438. [PMID: 38109970 PMCID: PMC10837305 DOI: 10.1016/j.jcmgh.2023.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with progressive biliary inflammation, destruction of the biliary tract, and fibrosis, resulting in liver cirrhosis and end-stage liver disease. To date, liver transplantation is the only definitive treatment option for PSC. The precise etiology of PSC remains elusive, but it is widely accepted to involve a complex interplay between genetic predisposition, immunologic dysfunction, and environmental influence. In recent years, the gut-liver axis has emerged as a crucial pathway contributing to the pathogenesis of PSC, with particular focus on the role of gut microbiota. However, the role of the fungal microbiome or mycobiome has been overlooked for years, resulting in a lack of comprehensive studies on its involvement in PSC. In this review, we clarify the present clinical and mechanistic data and concepts concerning the gut bacterial and fungal microbiota in the context of PSC. This review sheds light on the role of specific microbes and elucidates the dynamics of bacterial and fungal populations. Moreover, we discuss the latest insights into microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism.
Collapse
Affiliation(s)
- Burcin Özdirik
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California.
| |
Collapse
|
|
14
|
Fu Y, Li J, Zhu Y, Chen C, Liu J, Gu S, Zheng Y, Li Y. Causal effects of gut microbiome on autoimmune liver disease: a two-sample Mendelian randomization study. BMC Med Genomics 2023; 16:232. [PMID: 37789337 PMCID: PMC10548566 DOI: 10.1186/s12920-023-01670-0] [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: 06/04/2023] [Accepted: 09/21/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND Epidemiological studies have indicated a potential link between the gut microbiome and autoimmune liver disease (AILD) such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The relationship between the gut microbiome and autoimmune liver disease is still uncertain due to confounding variables. In our study, we aim to shed light on this relationship by employing a two-sample Mendelian randomization approach. METHODS We conducted a two-sample Mendelian randomization (MR) study using the R package "TwoSampleMR". The exposure data consisted of genetic variants associated with 194 bacterial traits obtained from the MiBioGen consortium. Summary statistics for AILD were obtained from the GWAS Catalog website. Furthermore, a series of sensitivity analyses were performed to validate the initial MR results. RESULTS There were two, four and three bacteria traits associated with an increased risk of AIH. PBC, and PSC respectively. In contrast, there were five, two and five bacteria traits associated with a decreased risk for AIH, PBC and PSC. Notably, the genus_Clostridium_innocuum_group showed a negative association with AIH (OR = 0.67, 95% CI: 0.49-0.93), and the genus_Actinomyces was found to be genetically associated with a decreased risk of PSC (OR = 0.62, 95% CI: 0.42-0.90). CONCLUSIONS Our study identified the causal impact of specific bacterial features on the risk of AILD subtypes. Particularly, the genus_Clostridium_innocuum_group and the genus_Actinomyces demonstrated significant protective effects against AIH and PSC respectively. These findings provide further support for the potential use of targeted probiotics in the management of AILD.
Collapse
Affiliation(s)
- Yugang Fu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Zhijiang Middle Road 274#, Shanghai, Jing'an District, China
- Municipal Medical College of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Jiacheng Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Zhijiang Middle Road 274#, Shanghai, Jing'an District, China
- Municipal Medical College of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Yingying Zhu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Zhijiang Middle Road 274#, Shanghai, Jing'an District, China
- Municipal Medical College of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Chong Chen
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Zhijiang Middle Road 274#, Shanghai, Jing'an District, China
- Municipal Medical College of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Jing Liu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Zhijiang Middle Road 274#, Shanghai, Jing'an District, China
- Municipal Medical College of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Simin Gu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Zhijiang Middle Road 274#, Shanghai, Jing'an District, China
- Municipal Medical College of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Yiyuan Zheng
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Zhijiang Middle Road 274#, Shanghai, Jing'an District, China
| | - Yong Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Zhijiang Middle Road 274#, Shanghai, Jing'an District, China.
| |
Collapse
|
|
15
|
Kim YS, Hurley EH, Park Y, Ko S. Treatment of primary sclerosing cholangitis combined with inflammatory bowel disease. Intest Res 2023; 21:420-432. [PMID: 37519211 PMCID: PMC10626010 DOI: 10.5217/ir.2023.00039] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/28/2023] [Accepted: 04/29/2023] [Indexed: 08/01/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a progressive cholestatic, inflammatory, and fibrotic disease that is strongly associated with inflammatory bowel disease (IBD). PSC-IBD represents a unique disease entity and patients with this disease have an increased risk of malignancy development, such as colorectal cancer and cholangiocarcinoma. The pathogenesis of PSC-IBD involves genetic and environmental factors such as gut dysbiosis and bile acids alteration. However, despite the advancement of disease characteristics, no effective medical therapy has proven to have a significant impact on the prognosis of PSC. The treatment options for patients with PSC-IBD do not differ from those for patients with PSC alone. Potential candidate drugs have been developed based on the pathogenesis of PSC-IBD, such as those that target modulation of bile acids, inflammation, fibrosis, and gut dysbiosis. In this review, we summarize the current medical treatments for PSC-IBD and the status of new emerging therapeutic agents.
Collapse
Affiliation(s)
- You Sun Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Edward H. Hurley
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yoojeong Park
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| |
Collapse
|
|
16
|
Shalaby N, Samocha-Bonet D, Kaakoush NO, Danta M. The Role of the Gastrointestinal Microbiome in Liver Disease. Pathogens 2023; 12:1087. [PMID: 37764895 PMCID: PMC10536540 DOI: 10.3390/pathogens12091087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.
Collapse
Affiliation(s)
- Nicholas Shalaby
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
| | - Dorit Samocha-Bonet
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
- Clinical Insulin Resistance Group, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Nadeem O. Kaakoush
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW 2033, Australia
| | - Mark Danta
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
- Department of Gastroenterology and Hepatology, St Vincent’s Hospital, Darlinghurst, NSW 2010, Australia
| |
Collapse
|
|
17
|
Shah YR, Nombera-Aznaran N, Guevara-Lazo D, Calderon-Martinez E, Tiwari A, Kanumilli S, Shah P, Pinnam BSM, Ali H, Dahiya DS. Liver transplant in primary sclerosing cholangitis: Current trends and future directions. World J Hepatol 2023; 15:939-953. [PMID: 37701917 PMCID: PMC10494561 DOI: 10.4254/wjh.v15.i8.939] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/23/2023] [Accepted: 08/11/2023] [Indexed: 08/22/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic and progressive immune-mediated cholangiopathy causing biliary tree inflammation and scarring, leading to liver cirrhosis and end-stage liver disease. Diagnosis of PSC is challenging due to its nonspecific symptoms and overlap with other liver diseases. Despite the rising incidence of PSC, there is no proven medical therapy that can alter the natural history of the disease. While liver transplantation (LT) is the most effective approach for managing advanced liver disease caused by PSC, post-transplantation recurrence of PSC remains a challenge. Therefore, ongoing research aims to develop better therapies for PSC, and continued efforts are necessary to improve outcomes for patients with PSC. This article provides an overview of PSC's pathogenesis, clinical presentation, and management options, including LT trends and future aspects. It also highlights the need for improved therapeutic options and ethical considerations in providing equitable access to LT for patients with PSC. Additionally, the impact of liver transplant on the quality of life and psychological outcomes of patients with PSC is discussed. Ongoing research into PSC's pathogenesis and post-transplant recurrence is crucial for improved understanding of the disease and more effective treatment options.
Collapse
Affiliation(s)
- Yash R Shah
- Department of Internal Medicine, Trinity Health Oakland, Pontiac, MI 48341, United States
| | | | - David Guevara-Lazo
- Faculty of Medicine, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
| | - Ernesto Calderon-Martinez
- Department of Internal Medicine, Universidad Nacional Autonoma de Mexico, Ciudad De Mexico 04510, Mexico
| | - Angad Tiwari
- Department of Internal Medicine, Maharani Laxmi Bai Medical College, Jhansi 284001, India
| | | | - Purva Shah
- Department of Postgraduate Education, Harvard Medical School, Boston, MA 02115, United States
| | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger Hospital of Cook County, Chicago, IL 60612, United States
| | - Hassam Ali
- Department of Internal Medicine, East Carolina University/Brody School of Medicine, Greenville, NC 27858, United States
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology and Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, United States.
| |
Collapse
|
|
18
|
Awoniyi M, Wang J, Ngo B, Meadows V, Tam J, Viswanathan A, Lai Y, Montgomery S, Farmer M, Kummen M, Thingholm L, Schramm C, Bang C, Franke A, Lu K, Zhou H, Bajaj JS, Hylemon PB, Ting J, Popov YV, Hov JR, Francis HL, Sartor RB. Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC. Gut 2023; 72:671-685. [PMID: 35705368 PMCID: PMC9751228 DOI: 10.1136/gutjnl-2021-326500] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 05/16/2022] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. GOAL define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient (mdr2-/- ) mice and microbial profiles in PSC patient cohorts. DESIGN We measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients. RESULTS GF mdr2-/- mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients' clinical severity by Mayo risk scores. CONCLUSIONS We identified novel functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.
Collapse
Affiliation(s)
- Muyiwa Awoniyi
- Division of Gastroenterology and Hepatology, University of North Carolina System, Chapel Hill, North Carolina, USA
- Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Jeremy Wang
- Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA
- Department of Genetics, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Billy Ngo
- Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Vik Meadows
- Department of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jason Tam
- Department of Microbiology and Immunology, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Amba Viswanathan
- Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Yunjia Lai
- Department of Environmental Sciences and Engineering, Gillings School of Global School of Public Health, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Stephanie Montgomery
- Department of Pathology, Division of Comparative Medicine, and Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Morgan Farmer
- Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA
| | - Martin Kummen
- Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Louise Thingholm
- Institute of Clinical Molecular Biology, Zentrums für Molekulare Biowissenschaften, Kiel, Schleswig-Holstein, Germany
| | | | - Corinna Bang
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Kun Lu
- Department of Environmental Sciences and Engineering, Gillings School of Global School of Public Health, University of North Carolina System, Chapel Hill, North Carolina, USA
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Department of Research, McGuire Veterans Affairs Medical Cente, Richmond, Virginia, USA
- Virginia Commonwealth University Medical Center, Richmond, Virginia, USA
| | - Jasmohan S Bajaj
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Department of Research, McGuire Veterans Affairs Medical Cente, Richmond, Virginia, USA
- Virginia Commonwealth University Medical Center, Richmond, Virginia, USA
| | - Phillip B Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Department of Research, McGuire Veterans Affairs Medical Cente, Richmond, Virginia, USA
- Virginia Commonwealth University Medical Center, Richmond, Virginia, USA
| | - Jenny Ting
- Department of Microbiology and Immunology, University of North Carolina System, Chapel Hill, North Carolina, USA
- UNC Lineberger Comprehensive Cancer Center, Center for Translational Immunology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yury V Popov
- Department of Gastroenterology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, USA
| | - Johannes Roksund Hov
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Heather L Francis
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Ryan Balfour Sartor
- Division of Gastroenterology and Hepatology, University of North Carolina System, Chapel Hill, North Carolina, USA
- Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology, University of North Carolina System, Chapel Hill, North Carolina, USA
| |
Collapse
|
|
19
|
Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023; 20:135-154. [PMID: 36352157 DOI: 10.1038/s41575-022-00690-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut-liver axis owing to the close association between liver disease and colonic inflammation. It is well established that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut-liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut-liver axis.
Collapse
Affiliation(s)
- Johannes R Hov
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| |
Collapse
|
|
20
|
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
|
|
21
|
Yu L, Liu Y, Wang S, Zhang Q, Zhao J, Zhang H, Narbad A, Tian F, Zhai Q, Chen W. Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies. Gut Microbes 2023; 15:2181930. [PMID: 36864554 PMCID: PMC9988349 DOI: 10.1080/19490976.2023.2181930] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/09/2023] [Indexed: 03/04/2023] Open
Abstract
Cholestasis is a condition characterized by the abnormal production or excretion of bile, and it can be induced by a variety of causes, the factors of which are extremely complex. Although great progress has been made in understanding cholestasis pathogenesis, the specific mechanisms remain unclear. Therefore, it is important to understand and distinguish cholestasis from different etiologies, which will also provide indispensable theoretical support for the development of corresponding therapeutic drugs. At present, the treatment of cholestasis mainly involves several bile acids (BAs) and their derivatives, most of which are in the clinical stage of development. Multiple lines of evidence indicate that ecological disorders of the gut microbiota are strongly related to the occurrence of cholestasis, in which BAs also play a pivotal role. Recent studies indicate that probiotics seem to have certain effects on cholestasis, but further confirmation from clinical trials is required. This paper reviews the etiology of and therapeutic strategies for cholestasis; summarizes the similarities and differences in inducement, symptoms, and mechanisms of related diseases; and provides information about the latest pharmacological therapies currently available and those under research for cholestasis. We also reviewed the highly intertwined relationship between gut microbiota-BA-cholestasis, revealing the potential role and possible mechanism of probiotics in the treatment of cholestasis.
Collapse
Affiliation(s)
- Leilei Yu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
| | - Yaru Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Shunhe Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Qingsong Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
| | - Arjan Narbad
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
- Gut Health and Microbiome Institute Strategic Programme, Quadram Institute Bioscience, Norwich, UK
| | - Fengwei Tian
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- International Joint Research Laboratory for Probiotics, Jiangnan University, Wuxi, Jiangsu, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
| |
Collapse
|
|
22
|
Bogatic D, Bryant RV, Lynch KD, Costello SP. Systematic review: microbial manipulation as therapy for primary sclerosing cholangitis. Aliment Pharmacol Ther 2023; 57:23-36. [PMID: 36324251 PMCID: PMC10092549 DOI: 10.1111/apt.17251] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/06/2022] [Accepted: 10/01/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a progressive liver disease with poor prognosis and no effective therapies to prevent progression. An aetiopathological link between PSC and gastrointestinal microbial dysbiosis has been suggested. AIM To evaluate all potential medical therapies which may exert their effect in PSC by modulation of the gut-liver axis. METHODS We conducted a comprehensive scoping review of PubMed and Cochrane Library, including all articles evaluating an intervention aimed at manipulating the gastrointestinal microbiome in PSC. RESULTS A wide range of therapies proposed altering the gastrointestinal microbiome for the treatment of PSC. In particular, these considered antibiotics including vancomycin, metronidazole, rifaximin, minocycline and azithromycin. However, few therapies have been investigated in randomised, placebo-controlled trials. Vancomycin has been the most widely studied antibiotic, with improvement in alkaline phosphatase reported in two randomised controlled trials, but with no data on disease progression. Unlike antibiotics, strategies such as faecal microbiota transplantation and dietary therapy can improve microbial diversity. However, since these have only been tested in small numbers of patients, robust efficacy data are currently lacking. CONCLUSIONS The gut-liver axis is increasingly considered a potential target for the treatment of PSC. However, no therapies have been demonstrated to improve transplant-free survival. Innovative and well-designed clinical trials of microbiome-targeted therapies with long-term follow-up are required for this orphan disease.
Collapse
Affiliation(s)
- Damjana Bogatic
- Department of GastroenterologyThe Queen Elizabeth HospitalWoodvilleSouth AustraliaAustralia
- Faculty of Health SciencesSchool of MedicineUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Robert V. Bryant
- Department of GastroenterologyThe Queen Elizabeth HospitalWoodvilleSouth AustraliaAustralia
- Faculty of Health SciencesSchool of MedicineUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Kate D. Lynch
- Faculty of Health SciencesSchool of MedicineUniversity of AdelaideAdelaideSouth AustraliaAustralia
- IBD ServiceDepartment of Gastroenterology and HepatologyRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Samuel P. Costello
- Department of GastroenterologyThe Queen Elizabeth HospitalWoodvilleSouth AustraliaAustralia
- Faculty of Health SciencesSchool of MedicineUniversity of AdelaideAdelaideSouth AustraliaAustralia
| |
Collapse
|
|
23
|
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
|
|
24
|
Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
Collapse
|
|
25
|
Intestinal homeostasis in autoimmune liver diseases. Chin Med J (Engl) 2022; 135:1642-1652. [PMID: 36193976 PMCID: PMC9509077 DOI: 10.1097/cm9.0000000000002291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
ABSTRACT Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system. Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease (AILD). Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis. Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD. Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation. Additionally, the gut and liver are continuously exposed to microbial metabolic products, mediating variable effects on liver immune pathologies. Importantly, microbiota-specific or associated immune responses, either hepatic or systemic, are abnormal in AILD. Comprehensive knowledge about host-microbiota interactions, included but not limited to this review, facilitates novel clinical practice from a microbiome-based perspective. However, many challenges and controversies remain in the microbiota field of AILD, and there is an urgent need for future investigations.
Collapse
|
|
26
|
Cheng Z, Yang L, Chu H. The Gut Microbiota: A Novel Player in Autoimmune Hepatitis. Front Cell Infect Microbiol 2022; 12:947382. [PMID: 35899041 PMCID: PMC9310656 DOI: 10.3389/fcimb.2022.947382] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/20/2022] [Indexed: 11/25/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease distributed globally in all ethnicities with increasing prevalence. If left untreated, the disease will lead to cirrhosis, liver failure, or death. The intestinal microbiota is a complex ecosystem located in the human intestine, which extensively affects the human physiological and pathological processes. With more and more in-depth understandings of intestinal microbiota, a substantial body of studies have verified that the intestinal microbiota plays a crucial role in a variety of digestive system diseases, including alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). However, only a few studies have paid attention to evaluate the relationship between AIH and the intestinal microbiota. While AIH pathogenesis is not fully elucidated yet, some studies have indicated that intestinal microbiota putatively made significant contributions to the occurrence and the development of AIH by triggering several specific signaling pathways, altering the metabolism of intestinal microbiota, as well as modulating the immune response in the intestine and liver. By collecting the latest related literatures, this review summarized the increasing trend of the aerobic bacteria abundance in both AIH patients and AIH mice models. Moreover, the combination of specific bacteria species was found distinct to AIH patients, which could be a promising tool for diagnosing AIH. In addition, there were alterations of luminal metabolites and immune responses, including decreased short-chain fatty acids (SCFAs), increased pathogen associated molecular patterns (PAMPs), imbalanced regulatory T (Treg)/Th17 cells, follicular regulatory T (TFR)/follicular helper T (TFH) cells, and activated natural killer T (NKT) cells. These alterations participate in the onset and the progression of AIH via multiple mechanisms. Therefore, some therapeutic methods based on restoration of intestinal microbiota composition, including probiotics and fecal microbiota transplantation (FMT), as well as targeted intestinal microbiota-associated signaling pathways, confer novel insights into the treatment for AIH patients.
Collapse
Affiliation(s)
| | - Ling Yang
- *Correspondence: Huikuan Chu, ; Ling Yang, ;
| | - Huikuan Chu
- *Correspondence: Huikuan Chu, ; Ling Yang, ;
| |
Collapse
|
|
27
|
Abstract
Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.
Collapse
Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Claudia Daniela Fuchs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
28
|
New agents for immunosuppression. Best Pract Res Clin Gastroenterol 2021; 54-55:101763. [PMID: 34874846 DOI: 10.1016/j.bpg.2021.101763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/16/2021] [Accepted: 08/30/2021] [Indexed: 01/31/2023]
Abstract
The human abdomen harbors organs that the host's immune system can attack easily. This immunological storm front leads to diseases like Crohn's Disease, Ulcerative Colitis or Autoimmune Hepatitis. Serious symptoms like pain, diarrhea, fatigue, or malnutrition accompany these diseases. Moreover, many patients have an increased risk for developing special kind of malignancies and some autoimmune disease can show a high mortality. The key to treat them consists of a deep understanding of their pathophysiology. In vitro and especially in vivo basic research laid the foundation for our increasing knowledge about it during the past years. This enabled the development of new therapeutic approaches that interact directly with cytokines or immune cells instead of building the treatment on a total immunosuppression. Different kind of antibodies, kinase inhibitors, and regulatory T cells build the base for these approaches. This review shows new therapeutical approaches in gastrointestinal autoimmune diseases in context to their pathophysiological basis.
Collapse
|
|
29
|
Zheng Y, Ran Y, Zhang H, Wang B, Zhou L. The Microbiome in Autoimmune Liver Diseases: Metagenomic and Metabolomic Changes. Front Physiol 2021; 12:715852. [PMID: 34690796 PMCID: PMC8531204 DOI: 10.3389/fphys.2021.715852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Recent studies have identified the critical role of microbiota in the pathophysiology of autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Metagenomic studies reveal significant decrease of gut bacterial diversity in AILDs. Although profiles of metagenomic vary widely, Veillonella is commonly enriched in AIH, PBC, and PSC. Apart from gut microbiome, the oral and bile microbiome seem to be associated with these diseases as well. The functional analysis of metagenomics suggests that metabolic pathways changed in the gut microbiome of the patients. Microbial metabolites, including short-chain fatty acids (SCFAs) and microbial bile acid metabolites, have been shown to modulate innate immunity, adaptive immunity, and inflammation. Taken together, the evidence of host–microbiome interactions and in-depth mechanistic studies needs further accumulation, which will offer more possibilities to clarify the mechanisms of AILDs and provide potential molecular targets for the prevention and treatment in the future.
Collapse
Affiliation(s)
- Yanping Zheng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Ying Ran
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongxia Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.,Department of Gastroenterology and Hepatology, Hotan People's Hospital, Xinjiang, China
| |
Collapse
|
|
30
|
Maslennikov R, Ivashkin V, Efremova I, Poluektova E, Shirokova E. Probiotics in hepatology: An update. World J Hepatol 2021; 13:1154-1166. [PMID: 34630882 PMCID: PMC8473492 DOI: 10.4254/wjh.v13.i9.1154] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/04/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
The gut-liver axis plays an important role in the pathogenesis of various liver diseases. Probiotics are living bacteria that may be used to correct disorders of this axis. Notable progress has been made in the study of probiotic drugs for the treatment of various liver diseases in the last decade. It has been proven that probiotics are useful for hepatic encephalopathy, but their effects on other symptoms and syndromes of cirrhosis are poorly studied. Their effectiveness in the treatment of metabolic associated fatty liver disease has been shown both in experimental models and in clinical trials, but their effect on the prognosis of this disease has not been described. The beneficial effects of probiotics in alcoholic liver disease have been shown in many experimental studies, but there are very few clinical trials to support these findings. The effects of probiotics on the course of other liver diseases are either poorly studied (such as primary sclerosing cholangitis, chronic hepatitis B and C, and autoimmune hepatitis) or not studied at all (such as primary biliary cholangitis, hepatitis A and E, Wilson's disease, hemochromatosis, storage diseases, and vascular liver diseases). Thus, despite the progress in the study of probiotics in hepatology over the past decade, there are many unexplored and unclear questions surrounding this topic.
Collapse
Affiliation(s)
- Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- Scientific Community for Human Microbiome Research, Moscow 119435, Russia
- Department of Internal Medicine, Consultative and Diagnostic Center of the Moscow City Health Department, Moscow 107564, Russia.
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- Scientific Community for Human Microbiome Research, Moscow 119435, Russia
| | - Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- Scientific Community for Human Microbiome Research, Moscow 119435, Russia
| | - Elena Shirokova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| |
Collapse
|
|
31
|
Liu C, Wang YL, Yang YY, Zhang NP, Niu C, Shen XZ, Wu J. Novel approaches to intervene gut microbiota in the treatment of chronic liver diseases. FASEB J 2021; 35:e21871. [PMID: 34473374 DOI: 10.1096/fj.202100939r] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/05/2021] [Accepted: 08/09/2021] [Indexed: 02/07/2023]
Abstract
Recent investigations of gut microbiota have contributed to understanding of the critical role of microbial community in pathophysiology. Dysbiosis not only causes disturbance directly to the gastrointestinal tract but also affects the liver through gut-liver axis. Various types of dysbiosis have been documented in alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune hepatitis (AIH), primary sclerosing cholangitis, and may be crucial for the initiation, progression, or deterioration to end-stage liver disease. A few microbial species have been identified as the causal factors leading to these chronic illnesses that either do not have clear etiologies or lack effective treatment. Notably, cytolysin-producing Enterococcus faecalis, Klebsiella pneumoniae and Enterococcus gallinarum were defined for ALD, NASH, and AIH, respectively. These groundbreaking discoveries drive a rapid development in innovative therapeutics, such as fecal microbial transplantation and implementation of specific bacteriophages in addition to prebiotics, probiotics, or synbiotics for intervention of dysbiosis. Although most emerging interventions are in preclinical development or early clinical trials, a better delineation of specific dysbiosis in these disorders at metabolic, immunogenic, or molecular levels in establishing particular causal effects aids in modulating or correcting the microbial community which is the part of daily life for human being.
Collapse
Affiliation(s)
- Chang Liu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Yu-Li Wang
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Yong-Yu Yang
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Ning-Ping Zhang
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| | - Chen Niu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Xi-Zhong Shen
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| | - Jian Wu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.,Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| |
Collapse
|
|
32
|
Yan S, Yin XM. Gut microbiome in liver pathophysiology and cholestatic liver disease. LIVER RESEARCH 2021; 5:151-163. [PMID: 35355516 PMCID: PMC8963136 DOI: 10.1016/j.livres.2021.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
An increasing amount of evidence has shown critical roles of gut microbiome in host pathophysiology. The gut and the liver are anatomically and physiologically connected. Given the critical role of gut-liver axis in the homeostasis of the liver, gut microbiome interplays with a diverse spectrum of hepatic changes, including steatosis, inflammation, fibrosis, cholestasis, and tumorigenesis. In clinic, cholestasis manifests with fatigue, pruritus, and jaundice, caused by the impairment in bile formation or flow. Studies have shown that the gut microbiome is altered in cholestatic liver disease. In this review, we will explore the interaction between the gut microbiome and the liver with a focus on the alteration and the role of gut microbiome in cholestatic liver disease. We will also discuss the prospect of exploiting the gut microbiome in the development of novel therapies for cholestatic liver disease.
Collapse
|
|
33
|
Abstract
Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.
Collapse
|
|
34
|
Blesl A, Stadlbauer V. The Gut-Liver Axis in Cholestatic Liver Diseases. Nutrients 2021; 13:nu13031018. [PMID: 33801133 PMCID: PMC8004151 DOI: 10.3390/nu13031018] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
The gut-liver axis describes the physiological interplay between the gut and the liver and has important implications for the maintenance of health. Disruptions of this equilibrium are an important factor in the evolution and progression of many liver diseases. The composition of the gut microbiome, the gut barrier, bacterial translocation, and bile acid metabolism are the key features of this cycle. Chronic cholestatic liver diseases include primary sclerosing cholangitis, the generic term secondary sclerosing cholangitis implying the disease secondary sclerosing cholangitis in critically ill patients and primary biliary cirrhosis. Pathophysiology of these diseases is not fully understood but seems to be multifactorial. Knowledge about the alterations of the gut-liver axis influencing the pathogenesis and the outcome of these diseases has considerably increased. Therefore, this review aims to describe the function of the healthy gut-liver axis and to sum up the pathological changes in these cholestatic liver diseases. The review compromises the actual level of knowledge about the gut microbiome (including the mycobiome and the virome), the gut barrier and the consequences of increased gut permeability, the effects of bacterial translocation, and the influence of bile acid composition and pool size in chronic cholestatic liver diseases. Furthermore, therapeutic implications and future scientific objectives are outlined.
Collapse
Affiliation(s)
- Andreas Blesl
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Correspondence:
| | - Vanessa Stadlbauer
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
| |
Collapse
|
|
35
|
Camilleri M. Human Intestinal Barrier: Effects of Stressors, Diet, Prebiotics, and Probiotics. Clin Transl Gastroenterol 2021; 12:e00308. [PMID: 33492118 PMCID: PMC7838004 DOI: 10.14309/ctg.0000000000000308] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/18/2020] [Indexed: 12/12/2022] Open
Abstract
The objectives of this article are to understand the effects of stressors (nonsteroidal antiinflammatory drug, exercise, and pregnancy) and components in the diet, specifically prebiotics and probiotics, on intestinal barrier function. Stressors generally reduce barrier function, and these effects can be reversed by supplements such as zinc or glutamine that are among the substances that enhance the barrier. Other dietary factors in the diet that improve the barrier are vitamins A and D, tryptophan, cysteine, and fiber; by contrast, ethanol, fructose, and dietary emulsifiers increase permeability. Effects of prebiotics on barrier function are modest; on the other hand, probiotics exert direct and indirect antagonism of pathogens, and there are documented effects of diverse probiotic species, especially combination agents, on barrier function in vitro, in vivo in animal studies, and in human randomized controlled trials conducted in response to stress or disease. Clinical observations of benefits with combination probiotics in inflammatory diseases have simultaneously not appraised effects on intestinal permeability. In summary, probiotics and synbiotics enhance intestinal barrier function in response to stressor or disease states. Future studies should address the changes in barrier function and microbiota concomitant with assessment of clinical outcomes.
Collapse
Affiliation(s)
- Michael Camilleri
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
36
|
Khoshbin K, Camilleri M. Effects of dietary components on intestinal permeability in health and disease. Am J Physiol Gastrointest Liver Physiol 2020; 319:G589-G608. [PMID: 32902315 PMCID: PMC8087346 DOI: 10.1152/ajpgi.00245.2020] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Altered intestinal permeability plays a role in many pathological conditions. Intestinal permeability is a component of the intestinal barrier. This barrier is a dynamic interface between the body and the food and pathogens that enter the gastrointestinal tract. Therefore, dietary components can directly affect this interface, and many metabolites produced by the host enzymes or the gut microbiota can act as signaling molecules or exert direct effects on this barrier. Our aim was to examine the effects of diet components on the intestinal barrier in health and disease states. Herein, we conducted an in-depth PubMed search based on specific key words (diet, permeability, barrier, health, disease, and disorder), as well as cross references from those articles. The normal intestinal barrier consists of multiple components in the lumen, epithelial cell layer and the lamina propria. Diverse methods are available to measure intestinal permeability. We focus predominantly on human in vivo studies, and the literature is reviewed to identify dietary factors that decrease (e.g., emulsifiers, surfactants, and alcohol) or increase (e.g., fiber, short-chain fatty acids, glutamine, and vitamin D) barrier integrity. Effects of these dietary items in disease states, such as metabolic syndrome, liver disease, or colitis are documented as examples of barrier dysfunction in the multifactorial diseases. Effects of diet on intestinal barrier function are associated with precise mechanisms in some instances; further research of those mechanisms has potential to clarify the role of dietary interventions in treating diverse pathologic states.
Collapse
Affiliation(s)
- Katayoun Khoshbin
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
37
|
Dean G, Hanauer S, Levitsky J. The Role of the Intestine in the Pathogenesis of Primary Sclerosing Cholangitis: Evidence and Therapeutic Implications. Hepatology 2020; 72:1127-1138. [PMID: 32394535 DOI: 10.1002/hep.31311] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/26/2020] [Accepted: 04/29/2020] [Indexed: 12/13/2022]
Abstract
The pathogenesis of primary sclerosing cholangitis (PSC), a progressive biliary tract disease without approved medical therapy, is not well understood. The relationship between PSC and inflammatory bowel disease has inspired theories that intestinal factors may contribute to the development and progression of hepatobiliary fibrosis in PSC. There is evidence from both fecal and mucosa-associated microbial studies that patients with PSC harbor an abnormal enteric microbiome. These organisms are thought to produce toxic byproducts that stimulate immune-mediated damage of hepatocytes and the biliary tree. The link between these mechanisms may be related to altered intestinal permeability leading to migration of bacteria or associated toxins to the liver through the portal circulation. In support of these concepts, early trials have demonstrated improved biochemical parameters and symptoms of PSC with oral antibiotics, ostensibly through manipulation of the enteric microbiota. This article reviews the published literature for evidence as well as gaps in knowledge regarding these mechanisms by which intestinal aberrations might drive the development of PSC. We also identify areas of future research that are needed to link and verify these pathways to enhance diagnostic and therapeutic approaches.
Collapse
Affiliation(s)
- Gregory Dean
- Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Stephen Hanauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| |
Collapse
|
|
38
|
Scarpellini E, Fagoonee S, Rinninella E, Rasetti C, Aquila I, Larussa T, Ricci P, Luzza F, Abenavoli L. Gut Microbiota and Liver Interaction through Immune System Cross-Talk: A Comprehensive Review at the Time of the SARS-CoV-2 Pandemic. J Clin Med 2020; 9:2488. [PMID: 32756323 PMCID: PMC7464500 DOI: 10.3390/jcm9082488] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS The gut microbiota is a complex ecosystem containing bacteria, viruses, fungi, yeasts and other single-celled organisms. It is involved in the development and maintenance of both innate and systemic immunity of the body. Emerging evidence has shown its role in liver diseases through the immune system cross-talk. We review herein literature data regarding the triangular interaction between gut microbiota, immune system and liver in health and disease. METHODS We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: gut microbiota, microbiome, gut virome, immunity, gastrointestinal-associated lymphoid tissue (GALT), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH), alcoholic liver disease, liver cirrhosis, hepatocellular carcinoma. RESULTS The gut microbiota consists of microorganisms that educate our systemic immunity through GALT and non-GALT interactions. The latter maintain health but are also involved in the pathophysiology and in the outcome of several liver diseases, particularly those with metabolic, toxic or immune-mediated etiology. In this context, gut virome has an emerging role in liver diseases and needs to be further investigated, especially due to the link reported between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and hepatic dysfunctions. CONCLUSIONS Changes in gut microbiota composition and alterations in the immune system response are involved in the pathogenesis of metabolic and immune-mediated liver diseases.
Collapse
Affiliation(s)
- Emidio Scarpellini
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
- Department of Biomedical Sciences, KU Leuven, Gasthuisberg University Hospital, TARGID, 3000 Leuven, Belgium
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, 10121 Turin, Italy;
| | - Emanuele Rinninella
- Nephrology and Urology Department, Gastroenterology, Endocrinology, Fondazione Policlinico A, Clinical Nutrition Unit, Gemelli IRCCS, 00168 Rome, Italy;
- Institute of Medical Pathology, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Carlo Rasetti
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
| | - Isabella Aquila
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Tiziana Larussa
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Pietrantonio Ricci
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Francesco Luzza
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| |
Collapse
|
|
39
|
Abstract
Primary sclerosing cholangitis (PSC) is a rare, immune-mediated, chronic cholestatic liver disease associated with a unique phenotype of inflammatory bowel disease that frequently manifests as pancolitis with right-sided predominance. Available data suggest a bidirectional interplay of the gut-liver axis with critical roles for the gastrointestinal microbiome and circulating bile acids (BAs) in the pathophysiology of PSC. BAs shape the gut microbiome, whereas gut microbes have the potential to alter BAs, and there are emerging data that alterations of BAs and the microbiome are not simply a consequence but the cause of PSC. Clustering of PSC in families may suggest that PSC occurs in genetically susceptible individuals. After exposure to an environmental trigger (e.g., microbial byproducts or BAs), an aberrant or exaggerated cholangiocyte-induced immune cascade occurs, ultimately leading to bile duct damage and progressive fibrosis. The pathophysiology can be conceptualized as a triad of (1) gut dysbiosis, (2) altered BA metabolism, and (3) immune-mediated biliary injury. Immune activation seems to be central to the disease process, but immunosuppression does not improve clinical outcomes or alter the natural history of PSC. Currently, orthoptic liver transplantation is the only established life-saving treatment, whereas antimicrobial therapy or fecal transplantation is an emerging therapeutic option for PSC. The beneficial effects of these microbiome-based therapies are likely mediated by a shift of the gut microbiome with favorable effects on BA metabolism. In the future, personalized approaches will allow to better target the interdependence between microbiome, immune function, and BA metabolism and potentially cure patients with PSC.
Collapse
|
|
40
|
Abstract
Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.
Collapse
Affiliation(s)
- Martin Wagner
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria
| |
Collapse
|
|
41
|
Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities. J Gastroenterol 2020; 55:588-614. [PMID: 32222826 PMCID: PMC7242240 DOI: 10.1007/s00535-020-01681-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 03/05/2020] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics.
Collapse
|
|
42
|
Anti-Inflammatory Diets and Fatigue. Nutrients 2019; 11:nu11102315. [PMID: 31574939 PMCID: PMC6835556 DOI: 10.3390/nu11102315] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/12/2019] [Accepted: 09/25/2019] [Indexed: 12/12/2022] Open
Abstract
Accumulating data indicates a link between a pro-inflammatory status and occurrence of chronic disease-related fatigue. The questions are whether the observed inflammatory profile can be (a) improved by anti-inflammatory diets, and (b) if this improvement can in turn be translated into a significant fatigue reduction. The aim of this narrative review was to investigate the effect of anti-inflammatory nutrients, foods, and diets on inflammatory markers and fatigue in various patient populations. Next to observational and epidemiological studies, a total of 21 human trials have been evaluated in this work. Current available research is indicative, rather than evident, regarding the effectiveness of individuals’ use of single nutrients with anti-inflammatory and fatigue-reducing effects. In contrast, clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms. Nonetheless, further research is needed to clarify conflicting results in the literature and substantiate the promising results from human trials on fatigue.
Collapse
|
|
43
|
Zhang C, Hussaini T, Yoshida EM. Review of pharmacotherapeutic treatments for primary sclerosing cholangitis. CANADIAN LIVER JOURNAL 2019; 2:58-70. [PMID: 35990218 PMCID: PMC9202752 DOI: 10.3138/canlivj-2018-0016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 08/15/2018] [Indexed: 11/13/2023]
Abstract
BACKGROUND The objective of this review was to evaluate pharmacotherapeutic treatments for primary sclerosing cholangitis (PSC) through a literature search of current published data. A review of the current clinical data for each treatment is discussed. METHODS We conducted a systematic literature search for articles using EMBASE (1980 to April 1, 2018), and MEDLINE (1948 to April 1, 2018) using Ovid, to identify studies investigating various therapies in PSC. Search terms included the following: primary sclerosing cholangitis, cholangitis, sclerosing cholangitis; ursodeoxycholic acid, glucocorticoids, cyclosporine, tacrolimus, methotrexate, azathioprine, 6-mercaptopurine, penicillamine, anti-TNF, antibiotics, and probiotics. We also performed a review of current clinical trials using ClinicalTrials.gov. We considered for review relevant studies published in English, pilot studies, and randomized controlled trials involving human subjects. RESULTS Therapies that have been investigated in the management of PSC include those used in search terms and others that were not included in our search parameters. Analysis of published data involving each therapy was explored and none have shown any sustained, significant benefit in the treatment of PSC. In terms of relevance to patient care and clinical practice, this review evaluates and compares various pharmacotherapeutic treatments for PSC where liver transplantation remains the only definitive treatment. CONCLUSIONS To date, no clinical study of any drug has demonstrated effectiveness in terms of survival benefit or a decreased need for liver transplantation. More clinical studies are needed, and patients need to be adequately informed before any medical therapy for PSC is undertaken.
Collapse
Affiliation(s)
- Chaoran Zhang
- Internal Medicine Residency Training Program, Department of Medicine, University of British Columbia, Vancouver, British Columbia;
| | - Trana Hussaini
- Department of Pharmaceutical Sciences Medicine, Vancouver General Hospital, Vancouver, British Columbia;
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia
| |
Collapse
|
|
44
|
Elshaer AM, El-Kharashi OA, Hamam GG, Nabih ES, Magdy YM, Abd El Samad AA. Involvement of TLR4/ CXCL9/ PREX-2 pathway in the development of hepatocellular carcinoma (HCC) and the promising role of early administration of lactobacillus plantarum in Wistar rats. Tissue Cell 2019; 60:38-47. [PMID: 31582017 DOI: 10.1016/j.tice.2019.07.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 06/30/2019] [Accepted: 07/30/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Improvement of gut microbiota may help in preventing the progression of cirrhosis. We supposed that Lactobacillus Plantarum (L. Plantarum) protects the cirrhotic liver through suppression of TLR4/ CXCL9/ PREX-2. METHODOLOGY Rats were divided into two groups. Group I, lasts for six weeks and Group II lasts for 12 weeks. Each group was subdivided into: naïve, Lactobacillus Plantarum (L. Plantarum), thioacetamide (TAA) and TAA + L. Plantarum. Liver function tests, α fetoprotein (AFP) levels, CXCL9, PREX-2 and TLR4 expression were assessed. Histological studies were performed. RESULTS TAA induced significant deterioration in liver functions and increased AFP. There was periportal cirrhosis, vacuolated hepatocytes, decrease hepatocyte parrafin-1 (hep par-1) expression, increase proliferating cell nuclear antigen (PCNA) positive nuclei and cytokeratin AE1/AE3. The PCR results showed significant increase in TLR4, CXCL9 and PREX-2 expression. Early administration of L. Plantarum significantly decreased the expression of TLR4, CXCL9 and PREX-2 together with improvement in liver function and prevented the pathological changes. CONCLUSIONS The cirrhotic complications induced by TAA are through activation of TLR4/ CXCL9/ PREX-2 pathway and could be prevented by the early administration of L. Plantarum.
Collapse
Affiliation(s)
- Asmaa M Elshaer
- Department of clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Omnyah A El-Kharashi
- Department of clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Ghada Galal Hamam
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Enas S Nabih
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Yosra M Magdy
- Department of clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Abeer A Abd El Samad
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| |
Collapse
|
|
45
|
Kummen M, Hov JR. The gut microbial influence on cholestatic liver disease. Liver Int 2019; 39:1186-1196. [PMID: 31125502 DOI: 10.1111/liv.14153] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/03/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023]
Abstract
Patients with cholestatic liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) have a different gut microbiome composition than healthy controls. In contrast with PBC, PSC has a strong association with inflammatory bowel disease and is the prototypical disease of the gut-liver axis. Still, there are some distinct overlapping microbial features in the microbiome of patients with PSC and PBC suggesting similarities in cholestatic diseases, although the possible pathogenetic involvement of these shared microbial changes is unknown. Herein, we present an overview of the available data and discuss the relevance for potential disease relevant host-microbiota interactions. In general, the microbiome interacts with the host via the immunobiome (interactions between the host immune system and the gut microbiome), the endobiome (where the gut microbiome contributes to host physiology by producing or metabolizing endogenous molecules) and the xenobiome (gut microbial transformation of exogenous compounds, including nutrients and drugs). Experimental and human observational evidence suggest that the presence and functions of gut microbes are relevant for the severity and progression of cholestatic liver disease. Interestingly, the majority of new drugs that are currently being tested in PBC and PSC in clinical trials act on bile acid homeostasis, where the endobiome is important. In the future, it will be paramount to perform longitudinal studies, through which we can identify new intervention targets, biomarkers or treatment-stratifiers. In this way, gut microbiome-based clinical care and therapy may become relevant in cholestatic liver disease within the foreseeable future.
Collapse
Affiliation(s)
- Martin Kummen
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Johannes R Hov
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of transplantation medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| |
Collapse
|
|
46
|
Sato K, Meng F, Fava G, Glaser S, Alpini G. Functional roles of gut bacteria imbalance in cholangiopathies. LIVER RESEARCH 2019; 3:40-45. [DOI: 10.1016/j.livres.2018.11.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
47
|
Arunima A, Das JK, Suar M. Gut Microbes in Liver Diseases. DIETARY INTERVENTIONS IN GASTROINTESTINAL DISEASES 2019:117-131. [DOI: 10.1016/b978-0-12-814468-8.00010-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
48
|
Santiago P, Scheinberg AR, Levy C. Cholestatic liver diseases: new targets, new therapies. Therap Adv Gastroenterol 2018; 11:1756284818787400. [PMID: 30159035 PMCID: PMC6109852 DOI: 10.1177/1756284818787400] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 06/14/2018] [Indexed: 02/04/2023] Open
Abstract
Cholestatic liver diseases result from gradual destruction of bile ducts, accumulation of bile acids and self-perpetuation of the inflammatory process leading to damage to cholangiocytes and hepatocytes. If left untreated, cholestasis will lead to fibrosis, biliary cirrhosis, and ultimately end-stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the two most common chronic cholestatic liver diseases affecting adults, and their etiologies remain puzzling. While treatment with ursodeoxycholic acid (UDCA) has significantly improved outcomes and prolonged transplant-free survival for patients with PBC, treatment options for UDCA nonresponders remain limited. Furthermore, there is no available medical therapy for PSC. With recent advances in molecular biochemistry specifically related to bile acid regulation and understanding of immunologic pathways, novel pharmacologic treatments have emerged. In this review, we discuss the standard of care and emphasize the various emerging treatments for PBC and PSC.
Collapse
Affiliation(s)
- Priscila Santiago
- Department of Medicine, University of Miami/Jackson Memorial Hospital
| | | | | |
Collapse
|
|
49
|
Kalani A, Tabibian JH, Lindor KD. Emerging therapeutic targets for primary sclerosing cholangitis. Expert Opin Orphan Drugs 2018; 6:393-401. [DOI: 10.1080/21678707.2018.1490643] [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: 10/28/2022]
Affiliation(s)
- Amir Kalani
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA Gastroenterology Fellowship Training Program, Los Angeles, CA, USA
| | - James H. Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
| | - Keith D. Lindor
- Professor of Medicine and Senior Advisor to the Provost, College of Health Solutions, Arizona State University, USA
| |
Collapse
|
|
50
|
Glassner K, Quigley EM, Franco L, Victor DW. Autoimmune liver disease and the enteric microbiome. AIMS Microbiol 2018; 4:334-346. [PMID: 31294219 PMCID: PMC6604930 DOI: 10.3934/microbiol.2018.2.334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/08/2018] [Indexed: 12/13/2022] Open
Abstract
The human enteric microbiome is highly complex and has more than 150 times more genes within it than its host. The host and the microbiome have a commensurate relationship that can evolve over time. The typically symbiotic relationship between the two can become pathogenic. The microbiome composition in adults reflects their history of exposure to bacteria and environmental factors during early life, their genetic background, age, interactions with the immune system, geographical location, and, most especially, their diet. Similarly, these factors are thought to contribute to the development of autoimmune disease. It is possible that alterations in the intestinal microbiome could lead to liver disease. There is emerging data for the contribution of the microbiome in development of primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis; liver disorders associated with aberrant immune function in genetically susceptible individuals.
Collapse
Affiliation(s)
- Kerri Glassner
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
| | - Eamonn Mm Quigley
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
| | - Lissa Franco
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
| | - David W Victor
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA.,Sherrie and Alan Conover Center for Liver Disease, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
| |
Collapse
|