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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.
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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
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Wang L, Cao ZM, Zhang LL, Li JM, Lv WL. The Role of Gut Microbiota in Some Liver Diseases: From an Immunological Perspective. Front Immunol 2022; 13:923599. [PMID: 35911738 PMCID: PMC9326173 DOI: 10.3389/fimmu.2022.923599] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota is a microecosystem composed of various microorganisms. It plays an important role in human metabolism, and its metabolites affect different tissues and organs. Intestinal flora maintains the intestinal mucosal barrier and interacts with the immune system. The liver is closely linked to the intestine by the gut-liver axis. As the first organ that comes into contact with blood from the intestine, the liver will be deeply influenced by the gut microbiota and its metabolites, and the intestinal leakage and the imbalance of the flora are the trigger of the pathological reaction of the liver. In this paper, we discuss the role of gut microbiota and its metabolites in the pathogenesis and development of autoimmune liver diseases((including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), metabolic liver disease such as non-alcoholic fatty liver disease, cirrhosisits and its complications, and liver cancer from the perspective of immune mechanism. And the recent progress in the treatment of these diseases was reviewed from the perspective of gut microbiota.
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Affiliation(s)
- Li Wang
- *Correspondence: Li Wang, ; Zheng-Min Cao, ; Juan-mei Li, ; Wen-liang Lv,
| | - Zheng-Min Cao
- *Correspondence: Li Wang, ; Zheng-Min Cao, ; Juan-mei Li, ; Wen-liang Lv,
| | | | - Juan-mei Li
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wen-liang Lv
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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3
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Di Giorgio A, Tulone A, Nicastro E, Norsa L, Sonzogni A, D'Antiga L. Use of oral vancomycin in children with autoimmune liver disease: A single centre experience. World J Hepatol 2021; 13:2113-2127. [PMID: 35070012 PMCID: PMC8727203 DOI: 10.4254/wjh.v13.i12.2113] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/07/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Previous reports showed some beneficial effect of oral vancomycin treatment (OVT) in children with primary sclerosing cholangitis; conversely, the experience in patients with other autoimmune liver diseases (AILD), including autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), is scant.
AIM To assess the response to immunosuppressive treatment (IS) and to OVT in children diagnosed with AILD.
METHODS Retrospective study of children diagnosed with AIH (normal biliary tree at cholangiography) and ASC (abnormal biliary tree at cholangiography) in the last 10 years. All underwent standard immunosuppressive therapy (IS), but non-responders received also OVT. Biochemical remission [normal aspartate aminotransferase (AST)] and immunological remission (normal IgG and negative autoantibodies) rates and Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index were assessed and compared during the follow up.
RESULTS 75 children were included [69% female, median age 10.5 years (5.6-13.4 years), AIH = 54, ASC= 21]. Sixty-three patients (84%, AIH = 52, ASC = 11) were treated with standard IS and 61 achieved biochemical remission, whereas 12 not responding to IS [16%, F = 75%, median age 13.5 years, (12.2-15.7), 10 with ASC] required OVT and 8 achieved biochemical remission. Overall OVT increased the biochemical remission rate of the whole group of AILD patients from 81% (61/75) to 92% (69/75). Median values of AST, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) decreased significantly after OVT start (P < 0.05). Complete normalization of livers enzymes (AST, ALT and GGT) was observed in 6/12 patients (50%). Decrease in SCOPE index score was reported in 5/12 patients (42%). At last follow up (median of 4.4 years, range 0.6-13.8 years) all 75 patients are alive, 6 (8%, 1 with ASC) successfully discontinued medications, 1 (with ASC) required liver transplantation.
CONCLUSION Children with AIH and ASC respond well to IS treatment. OVT may represent a valuable treatment option to achieve biochemical remission in patients not responding to standard IS. These promising preliminary results suggest that a prospective study is indicated to define the efficacy of OVT in AILD.
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Affiliation(s)
- Angelo Di Giorgio
- Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII , Bergamo 24127, Italy
| | - Anna Tulone
- Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII , Bergamo 24127, Italy
| | - Emanuele Nicastro
- Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII , Bergamo 24127, Italy
| | - Lorenzo Norsa
- Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII , Bergamo 24127, Italy
| | - Aurelio Sonzogni
- Liver Pathology, Hospital Papa Giovanni XXIII, Bergamo 24127, Italy
| | - Lorenzo D'Antiga
- Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII , Bergamo 24127, Italy
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Peruhova M, Peshevska-Sekulovska M, Velikova T. Interactions between human microbiome, liver diseases, and immunosuppression after liver transplant. World J Immunol 2021; 11:11-16. [DOI: 10.5411/wji.v11.i2.11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/16/2021] [Accepted: 10/15/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | | | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Clinical Immunology, University Hospital Lozenetz, Sofia 1407, Bulgaria
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Successful response of primary sclerosing cholangitis and associated ulcerative colitis to oral vancomycin may depend on brand and personalized dose: report in an adolescent. Clin J Gastroenterol 2020; 14:684-689. [PMID: 33231850 DOI: 10.1007/s12328-020-01296-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 11/05/2020] [Indexed: 01/16/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.
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6
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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.
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7
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Abstract
The etiology of primary sclerosing cholangitis (PSC) is unknown. I present a case which may be indicative of a causal link between Bartonella infection and PSC. The patient presented with complaints of abdominal pain and bloody diarrhea. A colonoscopy demonstrated chronic inflammation and changes consistent with ulcerative colitis. Routine laboratory studies revealed elevated liver function tests (LFTs); ultrasound and magnetic resonance imaging (MRI) confirmed the diagnosis of PSC. Bartonella serology was positive. It is established that Bartonella infection is associated with both gastrointestinal inflammation and autoimmunity; indeed, there is an animal model for Bartonella-induced PSC. Bartonella is susceptible to treatment with vancomycin and there are case reports and small series that demonstrate that PSC responds to treatment with oral vancomycin. Because of this, it is postulated that at least some cases of PSC may be associated with Bartonella infection. The patient in this report was treated with oral vancomycin and, since then, has been in remission for both colitis and PSC. Since vancomycin is not systemically absorbed, the premise is that he suffered from Bartonella colitis and an autoimmune reaction to Bartonella causing PSC. This premise warrants further study.
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8
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Fung BM, Lindor KD, Tabibian JH. Cancer risk in primary sclerosing cholangitis: Epidemiology, prevention, and surveillance strategies. World J Gastroenterol 2019; 25:659-671. [PMID: 30783370 PMCID: PMC6378537 DOI: 10.3748/wjg.v25.i6.659] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/10/2019] [Accepted: 01/14/2019] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intra- and/or extrahepatic biliary ducts. While its features and disease course can be variable, most patients with PSC have concurrent inflammatory bowel disease and will eventually develop liver cirrhosis and end-stage liver disease, with liver transplantation representing the only potentially curative option. Importantly, PSC is associated with a significantly increased risk of malignancy compared to the general population, mainly cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, and colorectal cancer, with nearly 50% of deaths in patients with PSC being due to cancer. Therefore, robust surveillance strategies are needed, though uncertainty remains regarding how to best do so. In this review, we discuss the epidemiology, prevention, and surveillance of cancers in patients with PSC. Where evidence is limited, we present pragmatic approaches based on currently available data and expert opinion.
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Affiliation(s)
- Brian M Fung
- UCLA-Olive View Internal Medicine Residency Program, Olive View-UCLA Medical Center, Sylmar, CA 91342, United States
| | - Keith D Lindor
- Office of the University Provost, Arizona State University, Phoenix, AZ 85004, United States
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA 91342, United States
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Virani S, Akers A, Stephenson K, Smith S, Kennedy L, Alpini G, Francis H. Comprehensive Review of Molecular Mechanisms during Cholestatic Liver Injury and Cholangiocarcinoma. JOURNAL OF LIVER 2018; 7:231. [PMID: 30613437 PMCID: PMC6319937 DOI: 10.4172/2167-0889.1000231] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cholestatic liver injury is characterized by damage induced on the biliary tree and cholangiocytes, the cells lining the biliary tree, thus they are termed "cholangiopathies". Cholangiopathies include diseases such as Primary Biliary Cholangitis, Primary Sclerosing Cholangitis, Biliary Atresia and Cholangiocarcinoma. These pathologies lack viable therapies and most patients are diagnosed during late stage disease progression (with the exception of Biliary Atresia, which is found shortly after birth). The lack of therapies for these diseases has put a significant burden on the need for liver transplantation as this is the only indicative "cure" for cholangiopathies. The molecular mechanisms for cholangiopathies have been extensively studied; however, and unfortunately, the lack of effective biomarkers and therapeutics remains. In this review article we highlight the latest studies to investigate the molecular mechanisms regulating cholangiopathies and the potential therapeutics that might be discovered.
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Affiliation(s)
- Shohaib Virani
- Department of Medical Physiology, College of Medicine Texas A&M Health Science Center, Temple, Texas, USA
| | - Austin Akers
- Department of Internal Medicine, Baylor Scott & White Health, Texas, USA
| | - Kristen Stephenson
- Department of Internal Medicine, Baylor Scott & White Health, Texas, USA
| | - Steven Smith
- Department of Internal Medicine, Baylor Scott & White Health, Texas, USA
| | - Lindsey Kennedy
- Department of Medical Physiology, College of Medicine Texas A&M Health Science Center, Temple, Texas, USA
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Texas, USA
- Department of Medical Physiology, College of Medicine Texas A&M Health Science Center, Temple, Texas, USA
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Texas, USA
- Department of Medical Physiology, College of Medicine Texas A&M Health Science Center, Temple, Texas, USA
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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.
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Affiliation(s)
- Priscila Santiago
- Department of Medicine, University of Miami/Jackson Memorial Hospital
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11
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Abstract
PURPOSE OF REVIEW Review the current knowledge about recurrent primary sclerosing cholangitis (rPSC) after transplant in children. RECENT FINDINGS Recurrent PSC is a significant complication that afflicts 16% of children after liver transplantation for primary sclerosing cholangitis (PSC) at a median onset of 38 months post-transplant. Possible risk factors include younger age at PSC diagnosis or transplant, the presence of overlap syndrome or IBD, and post-transplant induction with thymoglobulin. rPSC impairs the patient's quality of life and can be detrimental to the graft. Preventive options and therapeutic measures are limited. Ursodeoxycholic acid is widely used, but its effect on long-term outcome is unknown. Vancomycin can improve the biochemical profile of rPSC, but it remains unknown whether it halts the disease progression. Pediatric liver transplant for primary sclerosis cholangitis can be complicated by recurrence of the disease, which portends poor outcomes. Although few risk factors have been implicated, larger studies with longer follow-ups are needed to characterize cardinal risk factors for rPSC, as well as evaluate possible preventative and therapeutic options.
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Affiliation(s)
- Nisreen Soufi
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Southern California, Los Angeles, CA, USA
| | - Fateh Bazerbachi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Mark Deneau
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, UT, 84113, USA.
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12
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Tabibian JH, Ali AH, Lindor KD. Primary Sclerosing Cholangitis, Part 1: Epidemiology, Etiopathogenesis, Clinical Features, and Treatment. Gastroenterol Hepatol (N Y) 2018; 14:293-304. [PMID: 29991937 PMCID: PMC6034608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic cholangiopathy that can progress to cirrhosis, end-stage liver disease, hepatobiliary cancer, and/or colorectal cancer. The course of PSC is often complicated by portal hypertension, symptoms of cholestasis, and recurrent bacterial cholangitis, among other conditions, with a consequent decrease in survival (median, approximately 20 years) and quality of life. The etiopathogenesis of PSC remains poorly understood, and, as such, pharmacotherapy has yet to be definitively established. Despite its rarity, PSC is the fifth leading indication for liver transplantation (LT) in the United States. Although the only intervention known to extend survival of patients with PSC, LT is costly and invasive, and recurrent PSC affects approximately 30% of LT recipients. Over the past several years, owing in part to progress in the understanding of PSC, novel pharmacotherapeutics have been developed, some of which are currently in the PSC clinical trial pipeline. Here, in the first of a 2-part series, we provide a review and update of the epidemiology, etiopathogenesis, clinical features, and treatment of PSC. The second part of the series will focus on cancer risk, prevention, and surveillance of PSC.
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Affiliation(s)
- James H Tabibian
- Dr Tabibian is an associate professor in the Geffen School of Medicine at UCLA in Los Angeles, California and director of endoscopy in the Department of Medicine at Olive View-UCLA Medical Center in Sylmar, California. Dr Ali is a research fellow in the Division of Gastroenterology and Hepatology at Mayo Clinic in Phoenix, Arizona. Dr Lindor is a professor of medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic and senior advisor to the provost at Arizona State University in Phoenix, Arizona
| | - Ahmad H Ali
- Dr Tabibian is an associate professor in the Geffen School of Medicine at UCLA in Los Angeles, California and director of endoscopy in the Department of Medicine at Olive View-UCLA Medical Center in Sylmar, California. Dr Ali is a research fellow in the Division of Gastroenterology and Hepatology at Mayo Clinic in Phoenix, Arizona. Dr Lindor is a professor of medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic and senior advisor to the provost at Arizona State University in Phoenix, Arizona
| | - Keith D Lindor
- Dr Tabibian is an associate professor in the Geffen School of Medicine at UCLA in Los Angeles, California and director of endoscopy in the Department of Medicine at Olive View-UCLA Medical Center in Sylmar, California. Dr Ali is a research fellow in the Division of Gastroenterology and Hepatology at Mayo Clinic in Phoenix, Arizona. Dr Lindor is a professor of medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic and senior advisor to the provost at Arizona State University in Phoenix, Arizona
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Choi AY, Jalikis F, Westerhoff M, Boukhar S, Pulcini E, Damman C, Yu L. Searching for Bacterial Biofilm in Recurrent Cholangitis in Primary Sclerosing Cholangitis: A Case Presentation and Introduction of an Unexplored Disease Mechanism. J Clin Transl Hepatol 2018; 6:114-118. [PMID: 29577038 PMCID: PMC5863007 DOI: 10.14218/jcth.2017.00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 11/09/2017] [Accepted: 11/11/2017] [Indexed: 12/04/2022] Open
Abstract
Inflammation and fibrosis of the bile ducts are the defining pathological characteristics of primary sclerosing cholangitis (PSC). A previously unexplored mechanism for recurrent cholangitis, one of PSC's most common presentations, is bacterial colonization of the biliary epithelium in the form of biofilm, which may confer resistance to antibiotics and host phagocytic machinery. The aim of the current study was to assess whether bacteria could be seen on the liver explant and whether they organized in the form of biofilm. An explanted PSC liver from a 60-year-old male who suffered from recurrent cholangitis was formalin-fixed, paraffin-embedded and Gram stained. The specimens were observed under light microscopy. Neither bacteria nor biofilm were detected. We did not detect bacteria or biofilm in the liver explant of a single PSC patient with recurrent cholangitis using standard light microscopy. We suspect this may be in part due to techniques related to tissue preservation and microscopy.
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Affiliation(s)
- Alyssa Y. Choi
- Department of Internal Medicine, University of Washington, Seattle, Washington, USA
| | - Florencia Jalikis
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Maria Westerhoff
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Sarag Boukhar
- Department of Pathology, University of Iowa, Iowa City, Iowa, USA
| | - Elinor Pulcini
- Center for Biofilm Engineering, Montana State University, Bozeman, Montana, USA
| | - Chris Damman
- Division of Gastroenterology, University of Washington, Seattle, Washington, USA
| | - Lei Yu
- Division of Gastroenterology, University of Washington, Seattle, Washington, USA
- *Correspondence to: Lei Yu, Division of Gastroenterology, University of Washington, 1959 NE Pacific Street, Box 356175, Seattle, WA 98195-6175, USA. Tel: +1-206-598-2212, Fax: +1-206-598-3884, E-mail:
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Fecal microbiota transplantation and its potential therapeutic uses in gastrointestinal disorders. North Clin Istanb 2018; 5:79-88. [PMID: 29607440 PMCID: PMC5864716 DOI: 10.14744/nci.2017.10692] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 11/09/2017] [Indexed: 02/08/2023] Open
Abstract
Typical human gut flora has been well characterized in previous studies and has been noted to have significant differences when compared with the typical microbiome of various disease states involving the gastrointestinal tract. Such diseases include Clostridium difficile colitis, inflammatory bowel disease, functional bowel syndromes, and various states of liver disease. A growing number of studies have investigated the use of a fecal microbiota transplant as a potential therapy for these disease states.
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15
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Hey P, Lokan J, Johnson P, Gow P. Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation. BMJ Case Rep 2017; 2017:bcr-2017-221165. [PMID: 28951512 PMCID: PMC5747763 DOI: 10.1136/bcr-2017-221165] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease.
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Affiliation(s)
- Penelope Hey
- Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia
| | - Julie Lokan
- Department of Pathology, Austin Health, Heidelberg, Victoria, Australia
| | - Paul Johnson
- Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia
| | - Paul Gow
- Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia
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Bajer L, Kverka M, Kostovcik M, Macinga P, Dvorak J, Stehlikova Z, Brezina J, Wohl P, Spicak J, Drastich P. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J Gastroenterol 2017; 23:4548-4558. [PMID: 28740343 PMCID: PMC5504370 DOI: 10.3748/wjg.v23.i25.4548] [Citation(s) in RCA: 243] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 04/10/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To characterize the gut bacterial microbiota of patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC).
METHODS Stool samples were collected and relevant clinical data obtained from 106 study participants, 43 PSC patients with (n = 32) or without (n = 11) concomitant inflammatory bowel disease, 32 UC patients, and 31 healthy controls. The V3 and V4 regions of the 16S ribosomal RNA gene were sequenced on Illumina MiSeq platform to cover low taxonomic levels. Data were further processed in QIIME employing MaAsLin and LEfSe tools for analysis of the output data.
RESULTS Microbial profiles in both PSC and UC were characterized by low bacterial diversity and significant change in global microbial composition. Rothia, Enterococcus, Streptococcus, Veillonella, and three other genera were markedly overrepresented in PSC regardless of concomitant inflammatory bowel disease (IBD). Rothia, Veillonella and Streptococcus were tracked to the species level to identify Rothia mucilaginosa, Streptococcus infantus, S. alactolyticus, and S. equi along with Veillonella parvula and V. dispar. PSC was further characterized by decreased abundance of Adlercreutzia equolifaciens and Prevotella copri. Decrease in genus Phascolarctobacterium was linked to presence of colonic inflammation regardless of IBD phenotype. Akkermansia muciniphila, Butyricicoccus pullicaecorum and Clostridium colinum were decreased in UC along with genus Roseburia. Low levels of serum albumin were significantly correlated with enrichment of order Actinomycetales.
CONCLUSION PSC is associated with specific gut microbes independently of concomitant IBD and several bacterial taxa clearly distinguish IBD phenotypes (PSC-IBD and UC).
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Abstract
The trillions of microorganisms inhabiting human mucosal surfaces participate intricately in local homeostatic processes as well as development and function of the host immune system. These microorganisms, collectively referred to as the "microbiome," play a vital role in modulating the balance between clearance of pathogenic organisms and tolerance of commensal cells, including but not limited to human allografts. Advances in immunology, gnotobiotics, and culture-independent molecular techniques have provided growing insights into the complex relationship between the microbiome and the host, how it is modified by variables such as immunosuppressive and antimicrobial drugs, and its potential impact on posttransplantation outcomes. Here, we provide an overview of fundamental principles, recent discoveries, and clinical implications of this promising field of research.
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Buness C, Lindor KD, Miloh T. Oral Vancomycin Therapy in a Child with Primary Sclerosing Cholangitis and Severe Ulcerative Colitis. Pediatr Gastroenterol Hepatol Nutr 2016; 19:210-213. [PMID: 27738604 PMCID: PMC5061664 DOI: 10.5223/pghn.2016.19.3.210] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 01/21/2016] [Accepted: 02/05/2016] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC), a rare progressive liver disease characterized by cholestasis and bile duct fibrosis, has no accepted, effective therapy known to delay or arrest its progression. We report a 15 year old female patient diagnosed with PSC and moderate chronic active ulcerative colitis (UC) who achieved normalization of her liver enzymes and bile ducts, and resolution of her UC symptoms with colonic mucosal healing, after treatment with a single drug therapy of the antibiotic oral vancomycin. We postulate that the oral vancomycin may be acting both as an antibiotic by altering the intestinal microbiome and as an immunomodulator. Oral vancomycin may be a promising treatment for PSC that needs to be further studied in randomized trials.
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Affiliation(s)
- Cynthia Buness
- National Patient Advocate Foundation, Paradise Valley, Phoenix, AZ, USA
| | - Keith D Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA.; Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Tamir Miloh
- Department of Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Houston, TX, USA
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Torres J, Bao X, Goel A, Colombel JF, Pekow J, Jabri B, Williams K, Castillo A, Odin J, Meckel K, Fasihuddin F, Peter I, Itzkowitz S, Hu J. The features of mucosa-associated microbiota in primary sclerosing cholangitis. Aliment Pharmacol Ther 2016; 43:790-801. [PMID: 26857969 PMCID: PMC5177987 DOI: 10.1111/apt.13552] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 11/12/2015] [Accepted: 01/18/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Little is known about the role of the microbiome in primary sclerosing cholangitis. AIM To explore the mucosa-associated microbiota in primary sclerosing cholangitis (PSC) patients across different locations in the gut, and to compare it with inflammatory bowel disease (IBD)-only patients and healthy controls. METHODS Biopsies from the terminal ileum, right colon, and left colon were collected from patients and healthy controls undergoing colonoscopy. Microbiota profiling using bacterial 16S rRNA sequencing was performed on all biopsies. RESULTS Forty-four patients were recruited: 20 with PSC (19 with PSC-IBD and one with PSC-only), 15 with IBD-only and nine healthy controls. The overall microbiome profile was similar throughout different locations in the gut. No differences in the global microbiome profile were found. However, we observed significant PSC-associated enrichment in Barnesiellaceae at the family level, and in Blautia and an unidentified Barnesiellaceae at the genus level. At the operational taxa unit level, most shifts in PSC were observed in Clostridiales and Bacteroidales orders, with approximately 86% of shifts occurring within the former order. CONCLUSIONS The overall microbiota profile was similar across multiple locations in the gut from the same individual regardless of disease status. In this study, the mucosa associated-microbiota of patients with primary sclerosing cholangitis was characterised by enrichment of Blautia and Barnesiellaceae and by major shifts in operational taxa units within Clostridiales order.
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Affiliation(s)
- Joana Torres
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Xiuliang Bao
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Aparna Goel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Joel Pekow
- Section of Gastroenterology, Hepatology, and Nutrition University of Chicago, Chicago, Illinois, USA
| | - Bana Jabri
- Section of Gastroenterology, Hepatology, and Nutrition University of Chicago, Chicago, Illinois, USA
| | - Kelli Williams
- Section of Gastroenterology, Hepatology, and Nutrition University of Chicago, Chicago, Illinois, USA
| | - Anabella Castillo
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Joseph Odin
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Katherine Meckel
- Section of Gastroenterology, Hepatology, and Nutrition University of Chicago, Chicago, Illinois, USA
| | - Farah Fasihuddin
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Steven Itzkowitz
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Jianzhong Hu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
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Tabibian JH, O’hara SP, Lindor KD. Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies. Scand J Gastroenterol 2014; 49:901-8. [PMID: 24990660 PMCID: PMC4210190 DOI: 10.3109/00365521.2014.913189] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis. PSC generally progresses to liver cirrhosis, is a major risk factor for hepatobiliary and colonic neoplasia, and confers a median survival to death or liver transplantation of only 12 years. Although it is well recognized that approximately 75% of patients with PSC also have inflammatory bowel disease (IBD), the significance of this association remains elusive. Accumulating evidence now suggests a potentially important role for the intestinal microbiota, and enterohepatic circulation of molecules derived therefrom, as a putative mechanistic link between PSC and IBD and a central pathobiological driver of PSC. In this concise review, we provide a summary of and perspectives regarding the relevant basic, translational, and clinical data, which, taken together, encourage further investigation of the role of the microbiota and microbial metabolites in the etiopathogenesis of PSC and as a potential target for novel pharmacotherapies.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Center for Clinical and Translational Sciences, Mayo Graduate School, Rochester, MN, USA
| | - Steven P. O’hara
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Keith D. Lindor
- Executive Vice Provost & Dean, College of Health Solutions, Arizona State University, Phoenix, AZ, USA
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21
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Tabibian JH, Talwalkar JA, Lindor KD. Role of the microbiota and antibiotics in primary sclerosing cholangitis. BIOMED RESEARCH INTERNATIONAL 2013; 2013:389537. [PMID: 24232746 PMCID: PMC3819830 DOI: 10.1155/2013/389537] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 09/05/2013] [Indexed: 12/18/2022]
Abstract
Primary sclerosing cholangitis (PSC) is an idiopathic, progressive, cholestatic liver disease with considerable morbidity and mortality and no established pharmacotherapy. In addition to the long-recognized association between PSC and inflammatory bowel disease, several lines of preclinical and clinical evidence implicate the microbiota in the etiopathogenesis of PSC. Here we provide a concise review of these data which, taken together, support further investigation of the role of the microbiota and antibiotics in PSC as potential avenues toward elucidating safe and effective pharmacotherapy for patients afflicted by this illness.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Sreet SW, Rochester, MN 55905, USA
| | - Jayant A. Talwalkar
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Sreet SW, Rochester, MN 55905, USA
| | - Keith D. Lindor
- Executive Vice Provost & Dean, College of Health Solutions, Arizona State University, 550 North 3rd Street, Phoenix, AZ 85004, USA
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