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Quraishi MN, Cheesbrough J, Rimmer P, Mullish BH, Sharma N, Efstathiou E, Acharjee A, Gkoutus G, Patel A, Marchesi JR, Camuzeaux S, Chappell K, Valdivia-Garcia MA, Ferguson J, Brookes MJ, Walmsley M, Rossiter AE, van Schaik W, McInnes RS, Cooney R, Trauner M, Beggs AD, Iqbal TH, Trivedi PJ. Open Label Vancomycin in Primary Sclerosing Cholangitis-Inflammatory Bowel Disease: Improved Colonic Disease Activity and Associations With Changes in Host-Microbiome-Metabolomic Signatures. J Crohns Colitis 2025; 19:jjae189. [PMID: 39673746 PMCID: PMC11831226 DOI: 10.1093/ecco-jcc/jjae189] [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: 07/21/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD); NCT05376228. METHODS Fifteen patients with PSC and active colitis (median fecal calprotectin 459 µg/g; median total Mayo score 5) were treated with OV (125 mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and Week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics, and metabolomics) were collected at Weeks 0, 2, 4, and 8. The primary efficacy outcome measure was the induction of clinical remission. RESULTS Oral vancomycin resulted in clinical remission in 12/15 patients and significant reductions in fecal calprotectin. Oral vancomycin was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia, and Escherichia. Oral vancomycin treatment was associated with the downregulation of multiple metatranscriptomic pathways (including short-chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. Oral vancomycin use resulted in the loss of specific fecal SCFAs and secondary BAs, including lithocholic acid derivatives. Colitis activity relapsed following OV withdrawal, with host mucosal and microbial changes trending toward baseline. CONCLUSIONS Four weeks of OV induces remission in PSC-IBD activity, associated with a reduction in gut bacterial diversity and compositional changes relating to BA and SCFA homeostasis.
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Affiliation(s)
- Mohammed Nabil Quraishi
- Department of Gastroenterology, University Hospitals Birmingham, Birmingham, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Gastroenterology, Inflammatory Bowel Disease Center, Sheikh Shakhbout Medical City, Abu Dhabi, UAE
| | - Jonathan Cheesbrough
- Department of Gastroenterology, University Hospitals Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Peter Rimmer
- Department of Gastroenterology, University Hospitals Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Benjamin H Mullish
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
- Department of Gastroenterology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
- Department of Hepatology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Naveen Sharma
- Department of Gastroenterology, University Hospitals Birmingham, Birmingham, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
| | - Elena Efstathiou
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Animesh Acharjee
- Institute of Translational Medicine, University Hospitals Birmingham, Birmingham, UK
- MRC Health Data Research UK (HDR UK), Birmingham, UK
| | - Georgios Gkoutus
- Institute of Translational Medicine, University Hospitals Birmingham, Birmingham, UK
- MRC Health Data Research UK (HDR UK), Birmingham, UK
| | - Arzoo Patel
- Liver Unit, University Hospitals Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Julian R Marchesi
- Department of Gastroenterology, Inflammatory Bowel Disease Center, Sheikh Shakhbout Medical City, Abu Dhabi, UAE
| | | | | | - Maria A Valdivia-Garcia
- Department of Metabolism, Digestion and Reproduction, National Phenome Centre and Imperial Clinical Phenotyping Centre, Section of Bioanalytical Chemistry, IRDB Building, Imperial College London, London, UK
| | - James Ferguson
- Liver Unit, University Hospitals Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Matthew J Brookes
- Department of Gastroenterology, University of Wolverhampton, Wolverhampton, UK
| | | | - Amanda E Rossiter
- Institute of Microbiology and Infection, University of Birmingham, UK
| | - Willem van Schaik
- Institute of Microbiology and Infection, University of Birmingham, UK
| | - Ross S McInnes
- Institute of Microbiology and Infection, University of Birmingham, UK
| | - Rachel Cooney
- Department of Gastroenterology, University Hospitals Birmingham, Birmingham, UK
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andrew D Beggs
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
| | - Tariq H Iqbal
- Department of Gastroenterology, University Hospitals Birmingham, Birmingham, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Institute of Microbiology and Infection, University of Birmingham, UK
| | - Palak J Trivedi
- Liver Unit, University Hospitals Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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Xiao J, Hou Y, Luo X, Zhu Y, Li W, Li B, Zhou L, Chen X, Guo Y, Zhang X, He H, Liu X. Clostridium Scindens Protects Against Vancomycin-Induced Cholestasis and Liver Fibrosis by Activating Intestinal FXR-FGF15/19 Signaling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406445. [PMID: 39680750 PMCID: PMC11791999 DOI: 10.1002/advs.202406445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 11/11/2024] [Indexed: 12/18/2024]
Abstract
Primary sclerosing cholangitis (PSC) is characterized by abnormal bile acid metabolites and altered gut microbiota, with no effective treatments available. Vancomycin, a glycopeptide antibiotic, has emerged as a promising candidate. However, the mechanism by which vancomycin impacts the progression of PSC remains unknown. Mice treated with vancomycin exhibit increased hepatic collagen deposition and injury, due to the inhibition of intestinal FXR-FGF15/19 axis and the elevation of bile acid levels. These effects are associated with the reduction in Clostridia XIVa, especially Clostridium scindens (C. scindens). Gavage of C. scindens alleviates vancomycin-induced bile acid accumulation and liver fibrosis via activating intestinal FXR-FGF15/19 signaling. Similar effects are observed in mice treated with engineered Escherichia coli Nissle 1917 that are capable of expressing bile acid 7α-dehydratas (BaiE) from C. scindens (EcN-BaiE). Activating intestinal FXR-FGF15/19 signaling by fexaramine (Fex) or recombinant protein FGF19 reverse vancomycin-induced liver injury and fibrosis. These results demonstrate that long-term oral vancomycin exacerbates cholestatic liver injury, while C. scindens mitigates this effect by activating the intestinal FXR-FGF15/19 signaling pathway. This underscores the importance of monitoring bile acid levels in PSC patients receiving vancomycin treatment and suggests that C. scindens may serve as a potential therapeutic approach for PSC patients.
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Affiliation(s)
- Jintao Xiao
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Yanliang Hou
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Xingyang Luo
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Yuhao Zhu
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Wenhu Li
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Bingbing Li
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - LinXiang Zhou
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Xia Chen
- Department of Clinical LaboratoryXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Ying Guo
- Department of Clinical PharmacologyXiangya HospitalHunan Key Laboratory of PharmacogeneticsCentral South UniversityChangshaHunan410008China
| | - Xiaomei Zhang
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Haiyue He
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Xiaowei Liu
- Department of GastroenterologyXiangya HospitalCentral South UniversityChangshaHunan410008China
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunan410008China
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van Rheenen PF, Kolho K, Russell RK, Aloi M, Deganello A, Hussey S, Junge N, De Laffolie J, Deneau MR, Fitzpatrick E, Griffiths AM, Hojsak I, Nicastro E, Nita A, Pakarinen M, Ricciuto A, de Ridder L, Sonzogni A, Tenca A, Samyn M, Indolfi G. Primary sclerosing cholangitis in children with inflammatory bowel disease: An ESPGHAN position paper from the Hepatology Committee and the IBD Porto group. J Pediatr Gastroenterol Nutr 2025; 80:374-393. [PMID: 39741383 PMCID: PMC11788976 DOI: 10.1002/jpn3.12378] [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: 04/20/2024] [Revised: 07/31/2024] [Accepted: 08/21/2024] [Indexed: 01/03/2025]
Abstract
OBJECTIVE We aimed to provide an evidence-supported approach to diagnose, monitor, and treat children with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). METHODS The core group formulated seven PICO-structured clinical questions. A systematic literature search from inception to December 2022 was conducted by a medical librarian using MEDLINE and EMBASE. Core messages from the literature were phrased as position statements and then circulated to a sounding board composed of international experts in pediatric gastroenterology and hepatology, histopathology, adult gastroenterology and hepatology, radiology, and surgery. Statements reaching at least 80% agreement were considered as final. The other statements were refined and then subjected to a second online vote or rejection. RESULTS Regular screening for gamma-glutamyltransferase (GGT) is essential for detecting possible biliary disease in children with IBD. MR cholangiopancreatography is the radiological modality of choice for establishing the diagnosis of PSC. Liver biopsy is relevant in the evaluation of small duct PSC or autoimmune hepatitis. Children who do not have known IBD at the time of PSC diagnosis should undergo initial screening with fecal calprotectin for asymptomatic colitis, and then at least once yearly thereafter. Children with a cholestatic liver enzyme profile can be considered for treatment with ursodeoxycholic acid and can continue if there is a meaningful reduction or normalization in GGT. Oral vancomycin may have a beneficial effect on GGT and intestinal inflammation, but judicious use is recommended due to the lack of long-term studies. Children with PSC-IBD combined with convincing features of autoimmune hepatitis may benefit from corticosteroids and antimetabolites. CONCLUSIONS We present state-of-the-art guidance on the diagnostic criteria, follow-up strategies, and therapeutic strategies and point out research gaps in children and adolescents with PSC-IBD.
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Affiliation(s)
- Patrick F. van Rheenen
- Department of Paediatric Gastroenterology, Hepatology, and NutritionUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | | | - Richard K. Russell
- Department of Paediatric Gastroenterology, and NutritionRoyal Hospital for Children and Young PeopleEdinburghUK
| | - Marina Aloi
- Sapienza University of Rome ‐ Umberto I HospitalRomeItaly
| | - Annamaria Deganello
- Department of RadiologyKing's College Hospital, School of Biomedical Engineering and Imaging Sciences, King's College LondonLondonUK
| | - Séamus Hussey
- Children's Health Ireland and University College DublinDublinIreland
| | - Norman Junge
- Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic DiseasesHannover Medical SchoolHannoverGermany
| | - Jan De Laffolie
- General Paediatrics and Neonatology, GastroenterologyJustus Liebig University GiessenGiessenGermany
| | - Mark R. Deneau
- University of Utah and Intermountain Healthcare Primary Children's HospitalSalt Lake CityUtahUSA
| | - Emer Fitzpatrick
- Children's Health Ireland and University College DublinDublinIreland
| | - Anne M. Griffiths
- Faculty of Medicine, IBD Centre, SickKids HospitalUniversity of TorontoTorontoOntarioCanada
| | - Iva Hojsak
- Children's Hospital ZagrebUniversity of Zagreb Medical SchoolZagrebCroatia
| | - Emanuele Nicastro
- Pediatric HepatologyGastroenterology and Transplantation, Hospital Papa Giovanni XXIIIBergamoItaly
| | - Andreia Nita
- Department of Paediatric GastroenterologyGreat Ormond Street HospitalLondonUK
| | - Mikko Pakarinen
- Department of Pediatric SurgeryThe New Children's HospitalUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Amanda Ricciuto
- Faculty of Medicine, IBD Centre, SickKids HospitalUniversity of TorontoTorontoOntarioCanada
| | - Lissy de Ridder
- Department of Paediatric GastroenterologyErasmus University Medical Center Sophia Children's HospitalRotterdamThe Netherlands
| | | | - Andrea Tenca
- Helsinki University and Helsinki University Hospital HUS, Abdominal CenterHelsinkiFinland
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition ServiceKing's College HospitalLondonUK
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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.
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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
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Arbabzada N, Dennett L, Meng G, Peerani F. The Effectiveness of Oral Vancomycin on Inflammatory Bowel Disease in Patients With Primary Sclerosing Cholangitis: A Systematic Review. Inflamm Bowel Dis 2024:izae257. [PMID: 39495039 DOI: 10.1093/ibd/izae257] [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: 06/26/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Approximately 70% of primary sclerosing cholangitis (PSC) patients have inflammatory bowel disease (IBD). The IBD therapies currently used to treat PSC-IBD patients have side effects and can be costly. Oral vancomycin (OV)-a safe, economical, and convenient therapy-has been reported to be a salvage therapy in refractory PSC-IBD patients. This systematic review aims to summarize the current literature regarding the effectiveness and safety of OV to treat IBD in PSC patients. METHODS A systematic literature review of Scopus, Embase, Web of Science, MEDLINE, and CINAHL was performed until March 2024. The Murad scale, Newcastle-Ottawa scale, and Cochrane Collaboration Risk of Bias Tool were used to determine the quality of the case reports and case series, cohort studies, and randomized controlled trial (RCT), respectively. The outcomes sought were response or remission across clinical, biochemical, endoscopic, and histological parameters. RESULTS Of the 1725 published studies, we identified 9 case reports, 7 case series, 3 cohort studies, and 1 RCT. Most studies reported an improvement in clinical IBD symptoms such as diarrhea and hematochezia. Fewer publications provided supporting objective data in the form of fecal calprotectin, endoscopic Mayo scores, and histology. There were no reports of vancomycin-resistant enterococci infections. CONCLUSIONS Oral vancomycin appears safe and effective to treat IBD in a subset of PSC patients. Future studies would benefit from prospective data collection incorporating standardized symptomatic, endoscopic, and histologic indices. Ultimately, a well-powered RCT is needed to better assess the effectiveness, safety, and durability of OV therapy.
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Affiliation(s)
- Naik Arbabzada
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Liz Dennett
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Geoffrey and Robyn Sperber Health Sciences Library, University of Alberta, Edmonton, AB, Canada
| | - Guanmin Meng
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Farhad Peerani
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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Schneider KM, Kummen M, Trivedi PJ, Hov JR. Role of microbiome in autoimmune liver diseases. Hepatology 2024; 80:965-987. [PMID: 37369002 PMCID: PMC11407779 DOI: 10.1097/hep.0000000000000506] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/25/2023] [Indexed: 06/29/2023]
Abstract
The microbiome plays a crucial role in integrating environmental influences into host physiology, potentially linking it to autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. All autoimmune liver diseases are associated with reduced diversity of the gut microbiome and altered abundance of certain bacteria. However, the relationship between the microbiome and liver diseases is bidirectional and varies over the course of the disease. This makes it challenging to dissect whether such changes in the microbiome are initiating or driving factors in autoimmune liver diseases, secondary consequences of disease and/or pharmacological intervention, or alterations that modify the clinical course that patients experience. Potential mechanisms include the presence of pathobionts, disease-modifying microbial metabolites, and more nonspecific reduced gut barrier function, and it is highly likely that the effect of these change during the progression of the disease. Recurrent disease after liver transplantation is a major clinical challenge and a common denominator in these conditions, which could also represent a window to disease mechanisms of the gut-liver axis. Herein, we propose future research priorities, which should involve clinical trials, extensive molecular phenotyping at high resolution, and experimental studies in model systems. Overall, autoimmune liver diseases are characterized by an altered microbiome, and interventions targeting these changes hold promise for improving clinical care based on the emerging field of microbiota medicine.
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Affiliation(s)
| | - Martin Kummen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Palak J. Trivedi
- National Institute for Health and Care Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, UK
| | - Johannes R. Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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Pinnuck B, Lynch KD. Navigating the pharmacotherapeutic management of comorbid inflammatory bowel disease and primary sclerosing cholangitis. Expert Opin Pharmacother 2024; 25:1835-1849. [PMID: 39316754 DOI: 10.1080/14656566.2024.2407022] [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: 06/21/2024] [Revised: 09/04/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is the most specific hepatobiliary extraintestinal manifestation in inflammatory bowel disease (IBD). PSC ultimately has a poor prognosis, with disease progression resulting in liver cirrhosis and subsequent liver failure. While there is current data for the medical management of IBD, the optimal approach for concurrent PSC-IBD is unclear. AREAS COVERED This review focuses on the current literature of pharmacotherapy in the PSC-IBD population including anti-tumor necrosis factor agents, vedolizumab, JAK inhibitors, IL-12/23 inhibitors, and thiopurines. Regarding PSC-IBD, it focuses on effectiveness of IBD therapies on liver biochemistry and IBD activity as well as the advent of clinically relevant liver outcomes and safety. The authors also address the need for further advances in research. EXPERT OPINION The longer-term data for pharmacological management for IBD is well established. In the concomitant PSC-IBD population there is no drug to date that has effectively reduced disease related morbidity and mortality outcomes. There are limitations in the current, mostly retrospective data on IBD drugs in PSC-IBD with respect to samples sizes, heterogenous outcomes, and lack of a high-quality surrogate endpoint in PSC. However, current data for adalimumab offers encouraging results which require further exploration with larger prospective studies.
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Affiliation(s)
- Brigid Pinnuck
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Kate D Lynch
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
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Pérez Martin CY, Alberto Alonso JR, González Chávez J, Díaz Ruiz MP, Suárez González M, Merino Alonso J. Oral vancomycin in a pediatric patient with primary sclerosing cholangitis and inflammatory bowel disease. FARMACIA HOSPITALARIA 2023; 47:297-299. [PMID: 37612183 DOI: 10.1016/j.farma.2023.06.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 08/25/2023] Open
Affiliation(s)
| | | | - Jenifer González Chávez
- Servicio de Farmacia, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, España.
| | - María Pilar Díaz Ruiz
- Servicio de Farmacia, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, España
| | - Marta Suárez González
- Servicio de Farmacia, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, España
| | - Javier Merino Alonso
- Servicio de Farmacia, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, España
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9
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Martin CYP, Alonso JRA, Chávez JG, Ruiz MPD, González MS, Alonso JM. [Translated article] Oral vancomycin in a pediatric patient with primary sclerosing cholangitis and inflammatory bowel disease. FARMACIA HOSPITALARIA 2023; 47:T297-T299. [PMID: 37852822 DOI: 10.1016/j.farma.2023.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 10/20/2023] Open
Affiliation(s)
| | | | - Jenifer González Chávez
- Servicios de Farmacia, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz, Spain.
| | - María Pilar Díaz Ruiz
- Servicios de Farmacia, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz, Spain
| | - Marta Suárez González
- Servicios de Farmacia, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz, Spain
| | - Javier Merino Alonso
- Servicios de Farmacia, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz, Spain
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10
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Di Vincenzo F, Nicoletti A, Negri M, Vitale F, Zileri Dal Verme L, Gasbarrini A, Ponziani FR, Cerrito L. Gut Microbiota and Antibiotic Treatments for the Main Non-Oncologic Hepato-Biliary-Pancreatic Disorders. Antibiotics (Basel) 2023; 12:1068. [PMID: 37370387 DOI: 10.3390/antibiotics12061068] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/10/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
The gut microbiota is a pivotal actor in the maintenance of the balance in the complex interconnections of hepato-biliary-pancreatic system. It has both metabolic and immunologic functions, with an influence on the homeostasis of the whole organism and on the pathogenesis of a wide range of diseases, from non-neoplastic ones to tumorigenesis. The continuous bidirectional metabolic communication between gut and hepato-pancreatic district, through bile ducts and portal vein, leads to a continuous interaction with translocated bacteria and their products. Chronic liver disease and pancreatic disorders can lead to reduced intestinal motility, decreased bile acid synthesis and intestinal immune dysfunction, determining a compositional and functional imbalance in gut microbiota (dysbiosis), with potentially harmful consequences on the host's health. The modulation of the gut microbiota by antibiotics represents a pioneering challenge with striking future therapeutic opportunities, even in non-infectious diseases. In this setting, antibiotics are aimed at harmonizing gut microbial function and, sometimes, composition. A more targeted and specific approach should be the goal to pursue in the future, tailoring the treatment according to the type of microbiota modulation to be achieved and using combined strategies.
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Affiliation(s)
- Federica Di Vincenzo
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Alberto Nicoletti
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Marcantonio Negri
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Federica Vitale
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Lorenzo Zileri Dal Verme
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Lucia Cerrito
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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11
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Shaw DG, Aguirre-Gamboa R, Vieira MC, Gona S, DiNardi N, Wang A, Dumaine A, Gelderloos-Arends J, Earley ZM, Meckel KR, Ciszewski C, Castillo A, Monroe K, Torres J, Shah SC, Colombel JF, Itzkowitz S, Newberry R, Cohen RD, Rubin DT, Quince C, Cobey S, Jonkers IH, Weber CR, Pekow J, Wilson PC, Barreiro LB, Jabri B. Antigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis. Nat Med 2023; 29:1520-1529. [PMID: 37322120 PMCID: PMC10287559 DOI: 10.1038/s41591-023-02372-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 04/26/2023] [Indexed: 06/17/2023]
Abstract
Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single-cell transcriptomics, and T and B cell receptor repertoire analysis of right colon tissue from 65 patients with PSC, 108 patients with IBD and 48 healthy individuals we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia in patients with PSC. This inflammatory signature is characterized by antigen-driven interleukin-17A (IL-17A)+ forkhead box P3 (FOXP3)+ CD4 T cells that express a pathogenic IL-17 signature, as well as an expansion of IgG-secreting plasma cells. These results suggest that the mechanisms that drive the emergence of dysplasia in PSC and IBD are distinct and provide molecular insights that could guide prevention of colorectal cancer in individuals with PSC.
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Affiliation(s)
- Dustin G Shaw
- Committee on Immunology, University of Chicago, Chicago, IL, USA
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Raúl Aguirre-Gamboa
- Department of Medicine, University of Chicago, Chicago, IL, USA
- Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA
| | - Marcos C Vieira
- Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA
| | - Saideep Gona
- Department of Medicine, University of Chicago, Chicago, IL, USA
- Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA
| | - Nicholas DiNardi
- Committee on Immunology, University of Chicago, Chicago, IL, USA
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Anni Wang
- Committee on Immunology, University of Chicago, Chicago, IL, USA
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Anne Dumaine
- Department of Medicine, University of Chicago, Chicago, IL, USA
- Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA
| | - Jody Gelderloos-Arends
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Zachary M Earley
- Committee on Immunology, University of Chicago, Chicago, IL, USA
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | | | - Cezary Ciszewski
- Committee on Immunology, University of Chicago, Chicago, IL, USA
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Anabella Castillo
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kelly Monroe
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Joana Torres
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
- Division of Gastroenterology, Hospital Luz, Lisboa, Portugal
- Faculty of Medicine, Universidade de Lisboa, Lisboa, Portugal
| | - Shailja C Shah
- Division of Gastroenterology, University of California San Diego, San Diego, CA, USA
- Jennifer Moreno VA San Diego Healthcare System, San Diego, CA, USA
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven Itzkowitz
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rodney Newberry
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Russell D Cohen
- University of Chicago Inflammatory Bowel Disease Center, Chicago, IL, USA
| | - David T Rubin
- University of Chicago Inflammatory Bowel Disease Center, Chicago, IL, USA
| | - Christopher Quince
- Organisms and Ecosystems, Earlham Institute, Norwich, NR4 7UZ, UK
- Warwick Medical School, University of Warwick, Coventry, CV4 7HL, UK
- Gut Microbes and Health, Quadram Institute, Norwich, NR4 7UQ, UK
| | - Sarah Cobey
- Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA
| | - Iris H Jonkers
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | | | - Joel Pekow
- University of Chicago Inflammatory Bowel Disease Center, Chicago, IL, USA
| | - Patrick C Wilson
- Committee on Immunology, University of Chicago, Chicago, IL, USA
- Department of Medicine, University of Chicago, Chicago, IL, USA
- Section of Rheumatology, University of Chicago, Chicago, IL, USA
| | - Luis B Barreiro
- Committee on Immunology, University of Chicago, Chicago, IL, USA.
- Department of Medicine, University of Chicago, Chicago, IL, USA.
- Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
| | - Bana Jabri
- Committee on Immunology, University of Chicago, Chicago, IL, USA.
- Department of Medicine, University of Chicago, Chicago, IL, USA.
- Department of Pathology, University of Chicago, Chicago, IL, USA.
- Department of Pediatrics, University of Chicago, Chicago, IL, USA.
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12
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Single Center Experience of Oral Vancomycin Therapy in Young Patients with Primary Sclerosing Cholangitis: A Case Series. LIVERS 2023. [DOI: 10.3390/livers3010009] [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] [Indexed: 03/08/2023] Open
Abstract
There is no single proven therapy that prolongs hepatic transplant-free survival in patients with primary sclerosing cholangitis (PSC). Oral vancomycin (OV) has shown some benefit in small pediatric and adult series. We describe the effect of OV on pediatric onset PSC at our tertiary hospital. This is a single-center, retrospective, descriptive case series involving patients (<21 years at diagnosis) with PSC on OV from 2001 till 2021. The therapy effect was assessed based on symptoms, biochemical labs, imaging and liver biopsy at six and twelve months, and then annually until therapy was discontinued. The inclusion criteria identified 17 patients. Baseline GGT (n = 17) was elevated among 88.2% which then normalized among 53.8% (n = 13) at six months and 55.6% (n = 9) at one year post-OV. Baseline ALT normalized in 58.8% (n = 17) at six months and 42.8% (n = 14) at one year. Imaging findings within one year of OV revealed improved/stable biliary findings among 66.7% (n = 8/12). No adverse events were reported. OV was associated with an improvement in bile duct injury marker (GGT) after at least six months of therapy, with no disease progression on imaging within one year of therapy.
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13
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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: 51] [Impact Index Per Article: 25.5] [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.
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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.
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14
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 141] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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15
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Little R, Kamath BM, Ricciuto A. Liver Disease in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:129-149. [DOI: 10.1007/978-3-031-14744-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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16
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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: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [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.
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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
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17
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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: 13] [Impact Index Per Article: 4.3] [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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18
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Stevens JP, Gupta NA. Recent Insights into Pediatric Primary Sclerosing Cholangitis. Clin Liver Dis 2022; 26:489-519. [PMID: 35868687 DOI: 10.1016/j.cld.2022.03.009] [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] [Indexed: 01/31/2023]
Abstract
This article reviews recent literature on the pathogenesis, presentation, diagnosis, comorbidities, natural history, and management of pediatric primary sclerosing cholangitis (PSC). The authors shed light on the role of genetic and environmental factors in PSC, although recognize the limitations in the understanding of PSC pathogenesis. They reflect on presenting disease phenotypes, including the association with inflammatory bowel disease and frequent histologic presence of autoimmune hepatitis features. The current lack of effective medications is discussed, and disease complications and prognosis are described. Finally, the authors highlight available evidence while acknowledging the paucity of prospective pediatric data.
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Affiliation(s)
- James P Stevens
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 1760 Haygood Drive, Atlanta GA 30322, USA
| | - Nitika A Gupta
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 1760 Haygood Drive, Atlanta GA 30322, USA.
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19
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Abstract
ABSTRACT Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system. Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease (AILD). Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis. Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD. Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation. Additionally, the gut and liver are continuously exposed to microbial metabolic products, mediating variable effects on liver immune pathologies. Importantly, microbiota-specific or associated immune responses, either hepatic or systemic, are abnormal in AILD. Comprehensive knowledge about host-microbiota interactions, included but not limited to this review, facilitates novel clinical practice from a microbiome-based perspective. However, many challenges and controversies remain in the microbiota field of AILD, and there is an urgent need for future investigations.
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20
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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: 38] [Impact Index Per Article: 12.7] [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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21
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The intestinal and biliary microbiome in autoimmune liver disease-current evidence and concepts. Semin Immunopathol 2022; 44:485-507. [PMID: 35536431 PMCID: PMC9088151 DOI: 10.1007/s00281-022-00936-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 04/03/2022] [Indexed: 02/07/2023]
Abstract
Autoimmune liver diseases are a group of immune-mediated liver diseases with three distinct entities, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. The interplay of genetic and environmental factors leads to the breakdown of self-tolerance, resulting in hyper-responsiveness, and auto-aggressive immune activation. Emerging evidence links autoimmune liver diseases with alterations of the commensal microbiome configuration and aberrant immune system activation by microbial signals, mainly via the gut-liver axis. Thus, the microbiome is a new frontier to deepen the pathogenetic understanding, uncover biomarkers, and inspire innovative treatments. Herein, we review the current evidence on the role of the microbiome in autoimmune liver diseases from both clinical and basic research. We highlight recent achievements and also bottlenecks and limitations. Moreover, we give an outlook on future developments and potential for clinical applications.
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Di Giorgio A, Vergani D, Mieli-Vergani G. Cutting edge issues in juvenile sclerosing cholangitis. Dig Liver Dis 2022; 54:417-427. [PMID: 34289942 DOI: 10.1016/j.dld.2021.06.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/08/2021] [Accepted: 06/23/2021] [Indexed: 12/11/2022]
Abstract
Sclerosing cholangitis (SC) is a rare chronic disorder characterised by inflammation and progressive obliterative fibrosis of the intrahepatic and/or extrahepatic bile ducts. Diagnosis is based on cholangiogram showing bile duct dilatation, narrowing and obliteration of the biliary tree, and histologically, on the presence of inflammatory bile duct damage leading to periductal fibrosis. In children the most common SC is associated with strong autoimmune features, overlapping with those of autoimmune hepatitis (AIH); this form is known as autoimmune sclerosing cholangitis, ASC. Conversely, primary SC (PSC), a condition in which the term "primary" indicates that aetiology and pathogenesis are unknown, is rare in paediatrics. Secondary SC (SSC) defines a cholangiopathy associated with an identifiable aetiology such as immunodeficiencies, infections or haematological disorders. ASC and PSC are strongly associated with inflammatory bowel disease (IBD). ASC responds biochemically well to immunosuppressive drugs and ursodeoxycholic acid (UDCA). Primary forms are exclusively managed with oral UDCA, while in the secondary forms the medical treatment depends on the underlying aetiology. Despite treatment, SC often progresses to biliary cirrhosis and end-stage liver disease requiring liver transplantation. The disease can recur after transplant. Better understanding of pathogenic mechanisms and better treatment modalities are needed to improve the prognosis of this invalidating hepatic disorder.
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Affiliation(s)
- Angelo Di Giorgio
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy.
| | - Diego Vergani
- King's College London Faculty of Life Sciences and Medicine, Institute of Liver Studies, Mowat Labs King's College Hospital, London, United Kingdom
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences and Medicine, Institute of Liver Studies, Mowat Labs King's College Hospital, London, United Kingdom; Paediatric Liver, Gastrointestinal, and Nutrition Centre, King's College Hospital, London, United Kingdom
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23
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Binda C, Gibiino G, Coluccio C, Sbrancia M, Dajti E, Sinagra E, Capurso G, Sambri V, Cucchetti A, Ercolani G, Fabbri C. Biliary Diseases from the Microbiome Perspective: How Microorganisms Could Change the Approach to Benign and Malignant Diseases. Microorganisms 2022; 10:312. [PMID: 35208765 PMCID: PMC8877314 DOI: 10.3390/microorganisms10020312] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 11/18/2022] Open
Abstract
Recent evidence regarding microbiota is modifying the cornerstones on pathogenesis and the approaches to several gastrointestinal diseases, including biliary diseases. The burden of biliary diseases, indeed, is progressively increasing, considering that gallstone disease affects up to 20% of the European population. At the same time, neoplasms of the biliary system have an increasing incidence and poor prognosis. Framing the specific state of biliary eubiosis or dysbiosis is made difficult by the use of heterogeneous techniques and the sometimes unwarranted invasive sampling in healthy subjects. The influence of the microbial balance on the health status of the biliary tract could also account for some of the complications surrounding the post-liver-transplant phase. The aim of this extensive narrative review is to summarize the current evidence on this topic, to highlight gaps in the available evidence in order to guide further clinical research in these settings, and, eventually, to provide new tools to treat biliary lithiasis, biliopancreatic cancers, and even cholestatic disease.
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Affiliation(s)
- Cecilia Binda
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Giulia Gibiino
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Chiara Coluccio
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Monica Sbrancia
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Elton Dajti
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
| | - Emanuele Sinagra
- Endoscopy Unit, Fondazione Istituto San Raffaele-G. Giglio, 90015 Cefalù, Italy;
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90100 Palermo, Italy
| | - Gabriele Capurso
- Division of Pancreato-Biliary Endoscopy and EUS, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, 20132 Milano, Italy;
| | - Vittorio Sambri
- Unit of Microbiology, The Great Romagna Hub Laboratory, 47522 Pievesestina, Italy;
- Unit of Microbiology, Department of Pathological Anatomy, Trasfusion Medicine and Laboratory Medicine, University of Bologna, 40125 Bologna, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
- Department of General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Ausl Romagna, 47121 Forlì, Italy
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
- Department of General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Ausl Romagna, 47121 Forlì, Italy
| | - Carlo Fabbri
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
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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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25
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Abbas N, Quraishi MN, Trivedi P. Emerging drugs for the treatment of primary sclerosing cholangitis. Curr Opin Pharmacol 2021; 62:23-35. [PMID: 34894541 DOI: 10.1016/j.coph.2021.11.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/02/2021] [Accepted: 11/07/2021] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare immune-mediated cholestatic disease for which no medical therapy has been shown to slow disease progression. Consequently, liver transplantation is the only lifesaving intervention for patients, and despite being a rare disease, PSC is the lead indication for transplantation across several European countries. The vast majority of patients (>70%) also develop inflammatory bowel disease (IBD) at some point in their lifetime, which imparts added lifetime risks of hepatobiliary malignancy and colorectal cancer. The rare disease nature, variable and often slow rates of disease progression (years rather than months), and lack of robust surrogate biomarkers for early stage yet high risk disease, represent critical challenges in trial design that have long precluded the development of effective medical treatment. However, the horizon for new treatments is encouraging, given innovative clinical trial programmes led by industry, alongside several investigator-initiated studies. Herein, we outline the current platform of interventional trials in PSC, before discussing emerging areas of therapeutic interest.
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Affiliation(s)
- Nadir Abbas
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Mohammad Nabil Quraishi
- Department of Gastroenterology, University Hospital Birmingham NHS Trust, UK; University of Birmingham Microbiome Treatment Centre, University of Birmingham, UK
| | - Palak Trivedi
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK.
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26
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Vancomycin Use in Children and Neonates across Three Decades: A Bibliometric Analysis of the Top-Cited Articles. Pathogens 2021; 10:pathogens10101343. [PMID: 34684291 PMCID: PMC8537673 DOI: 10.3390/pathogens10101343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/17/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022] Open
Abstract
Vancomycin is frequently prescribed in pediatrics, especially in intensive care unit settings, to treat Gram-positive bacterial infections. This work aims to collect the top-cited articles of pediatric and infectious diseases areas to gather the current evidence and gaps of knowledge on the use of vancomycin in these populations. The most relevant journals reported in the "pediatrics" and "infectious diseases" categories of the 2019 edition of Journal Citation Reports were browsed. Articles with more than 30 citations and published over the last three decades were collected. A bibliometric analysis was performed and 115 articles were retrieved. They were published in 21 journals, with a median impact factor of 4.6 (IQR 2.9-5.4). Sixty-eight of them (59.1%) belonged to "infectious diseases" journals. The most relevant topic was "bloodstream/complicated/invasive infections", followed by "antibiotic resistance/MRSA treatment". As for population distribution, 27 articles were on children only and 27 on neonates, most of which were from intensive care unit (ICU) settings. The current literature mainly deals with vancomycin as a treatment for severe infections and antibiotic resistance, especially in neonatal ICU settings. Lately, attention to new dosing strategies in the neonatal and pediatric population has become a sensible topic.
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27
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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: 20] [Impact Index Per Article: 5.0] [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.
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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
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28
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Schneider KM, Candels LS, Hov JR, Myllys M, Hassan R, Schneider CV, Wahlström A, Mohs A, Zühlke S, Liao L, Elfers C, Kilic K, Henricsson M, Molinaro A, Hatting M, Zaza A, Drasdo D, Frissen M, Devlin AS, Gálvez EJC, Strowig T, Karlsen TH, Hengstler JG, Marschall HU, Ghallab A, Trautwein C. Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling. Nat Metab 2021; 3:1228-1241. [PMID: 34552267 DOI: 10.1038/s42255-021-00452-1] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology for which there are no approved therapeutic options. Patients with PSC display changes in gut microbiota and in bile acid (BA) composition; however, the contribution of these alterations to disease pathogenesis remains controversial. Here we identify a role for microbiota-dependent changes in BA synthesis that modulates PSC pathophysiology. In a genetic mouse model of PSC, we show that loss of microbiota-mediated negative feedback control of BA synthesis results in increased hepatic BA concentrations, disruption of bile duct barrier function and, consequently, fatal liver injury. We further show that these changes are dependent on decreased BA signalling to the farnesoid X receptor, which modulates the activity of the rate-limiting enzyme in BA synthesis, CYP7A1. Moreover, patients with advanced stages of PSC show suppressed BA synthesis as measured by serum C4 levels, which is associated with poor disease prognosis. Our preclinical data highlight the microbiota-dependent dynamics of BA metabolism in cholestatic liver disease, which could be important for future therapies targeting BA and gut microbiome interactions, and identify C4 as a potential biomarker to functionally stratify patients with PSC and predict disease outcomes.
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Affiliation(s)
- Kai Markus Schneider
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Johannes R Hov
- Norwegian PSC Research Center, Section of Gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Maiju Myllys
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Reham Hassan
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | | | - Annika Wahlström
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Antje Mohs
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sebastian Zühlke
- Center for Mass Spectrometry (CMS), Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Lijun Liao
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Carsten Elfers
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Konrad Kilic
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Marcus Henricsson
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Antonio Molinaro
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maximilian Hatting
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ayham Zaza
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Dirk Drasdo
- Institute National de Recherche en Informatique et en Automatique (INRIA), Le Chesnay, France
| | - Mick Frissen
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - A Sloan Devlin
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Eric J C Gálvez
- Helmholtz Centre for Infection Research, Braunschweig, Germany and Hannover Medical School, Hannover, Germany
| | - Till Strowig
- Helmholtz Centre for Infection Research, Braunschweig, Germany and Hannover Medical School, Hannover, Germany
| | - Tom H Karlsen
- Norwegian PSC Research Center, Section of Gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
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Czaja AJ. Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease. World J Gastroenterol 2021; 27:3705-3733. [PMID: 34321839 PMCID: PMC8291028 DOI: 10.3748/wjg.v27.i25.3705] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 03/22/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The goals of this review are to describe their biological properties, indicate their involvement in chronic liver disease, and encourage investigations that clarify their actions and therapeutic implications. English abstracts were identified in PubMed by multiple search terms, and bibliographies were developed. MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines. Diverse pro-inflammatory, anti-inflammatory, and immune regulatory cytokines are released; infected cells are eliminated; and memory cells emerge. Circulating MAIT cells are hyper-activated, immune exhausted, dysfunctional, and depleted in chronic liver disease. This phenotype lacks disease-specificity, and it does not predict the biological effects. MAIT cells have presumed protective actions in chronic viral hepatitis, alcoholic hepatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, and decompensated cirrhosis. They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis. Local factors in the hepatic microenvironment (cytokines, bile acids, gut-derived bacterial antigens, and metabolic by-products) may modulate their response in individual diseases. Investigational manipulations of function are warranted to establish an association with disease severity and outcome. In conclusion, MAIT cells constitute a disease-nonspecific, immune response to chronic liver inflammation and infection. Their pathological role has been deduced from their deficiencies during active liver disease, and future investigations must clarify this role, link it to outcome, and explore therapeutic interventions.
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Affiliation(s)
- Albert J Czaja
- Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
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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.
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Björnsson ES, Kalaitzakis E. Recent advances in the treatment of primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol 2021; 15:413-425. [PMID: 33283566 DOI: 10.1080/17474124.2021.1860751] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: PSC is a rare liver disease that leads frequently to cirrhosis and need for liver transplantation. No medical treatment is of proven value. Liver transplantation is the only curative therapy available. There is a big medical need to find medical therapy that can alter the natural history of the disease.Areas covered: The authors highlight advances in PSC, based on recent literature retrieved from PubMed until September 2020 regarding both medical and endoscopic biliary therapy.Future possibilities for treatment of PSC are discussed.Expert opinion: Biliary endoscopy is the cornerstone in the treatment of dominant strictures. Single-user peroral cholangioscopy is an emerging modality. Balloon dilatation therapy is the treatment of choice of dominant strictures. The most promising medical therapies showing efficacy in phase II trials are nor-Ursodeoxycholic acid, obethicolic acid, the non-steroidal FXR agonist Cilofexor and Aldafermin, a synthetic analogue of FGF-19. Antibiotics, particularly vancomycin have shown potential benefits, particularly in children but phase III studies are lacking. In observational studies of effects of biological therapy in patients with IBD/PSC adalimumab was associated with reduction in ALP. Results of liver transplantation are favorable but recurrence can be of clinical relevance particularly in patients transplanted before the age of 40.
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Affiliation(s)
- Einar S Björnsson
- Department of Internal Medicine, Faculty of Medicine, University of Iceland, Division of Gastroenterology and Hepatology, Landspitali University Hospital of Iceland
| | - Evangelos Kalaitzakis
- Department of Internal Medicine, University Hospital Heraklion, Faculty of Medicine, University of Crete, Rethymno, Greece
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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: 42] [Impact Index Per Article: 10.5] [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.
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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
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McCain JD, Chascsa DM, Lindor KD. Assessing and managing symptom burden and quality of life in primary sclerosing cholangitis patients. Expert Opin Orphan Drugs 2021. [DOI: 10.1080/21678707.2021.1898370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Josiah D. McCain
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | - David M. Chascsa
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
- Department of Transplant Center, Mayo Clinic, Phoenix, Arizona, USA
| | - Keith D. Lindor
- Office of University Provost, Arizona State University, Arizona, USA
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Deneau MR, Mack C, Mogul D, Perito ER, Valentino PL, Amir AZ, DiGuglielmo M, Draijer LG, El-Matary W, Furuya KN, Gupta N, Hochberg JT, Horslen S, Jensen MK, Jonas MM, Kerkar N, Koot BG, Laborda TJ, Lee CK, Loomes KM, Martinez M, Miethke A, Miloh T, Mohammad S, Ovchinsky N, Rao G, Ricciuto A, Sathya P, Schwarz KB, Shah U, Singh R, Vitola B, Zizzo A, Guthery SL. Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis. Hepatology 2021; 73:1061-1073. [PMID: 32946600 PMCID: PMC8557636 DOI: 10.1002/hep.31560] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/21/2020] [Accepted: 08/27/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. APPROACH AND RESULTS We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. CONCLUSIONS We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.
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Affiliation(s)
- Mark R. Deneau
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
| | - Cara Mack
- University of Colorado School of Medicine, Aurora, CO
| | | | | | | | - Achiya Z. Amir
- The Dana-Dwek Children’s Hospital, The Tel-Aviv Medical Center, Tel-Aviv University, Tel Aviv, Israel
| | | | | | | | - Katryn N. Furuya
- Mayo Clinic, Rochester, MN
- University of Wisconsin–Madison School of Medicine and Public Health, Madison, WI
| | - Nitika Gupta
- Emory University School of Medicine, Atlanta, GA
| | | | | | - M. Kyle Jensen
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
| | - Maureen M. Jonas
- Boston Children’s Hospital and Harvard Medical School, Boston, MA
| | - Nanda Kerkar
- University of Rochester Medical Center, Rochester, NY
| | - Bart G.P. Koot
- Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Trevor J. Laborda
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
| | - Christine K. Lee
- Boston Children’s Hospital and Harvard Medical School, Boston, MA
| | | | | | | | | | | | - Nadia Ovchinsky
- Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY
| | | | | | - Pushpa Sathya
- Memorial University, St. John’s, Newfoundland and Labrador, Canada
| | - Kathleen B. Schwarz
- Johns Hopkins University, Baltimore, MD
- University of California San Diego, San Diego, CA
| | - Uzma Shah
- Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ruchi Singh
- Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | | | - Andréanne Zizzo
- London Health Sciences Center, Western University, London, Ontario, Canada
| | - Stephen L. Guthery
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
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35
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D. Goldenberg S, Merrick B. The role of faecal microbiota transplantation: looking beyond Clostridioides difficile infection. Ther Adv Infect Dis 2021; 8:2049936120981526. [PMID: 33614028 PMCID: PMC7841662 DOI: 10.1177/2049936120981526] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/16/2020] [Indexed: 12/17/2022] Open
Abstract
Faecal microbiota transplantation (FMT) is the transfer of screened and minimally processed faecal material from a 'healthy' donor to 'diseased' recipient. It has an established role, and is recommended as a therapeutic strategy, in the management of recurrent Clostridioides difficile infection (CDI). Recognition that gut dysbiosis is associated with, and may contribute to, numerous disease states has led to interest in exploiting FMT to 'correct' this microbial imbalance. Conditions for which it is proposed to be beneficial include inflammatory bowel disease, irritable bowel syndrome, liver disease and hepatic encephalopathy, neuropsychiatric conditions such as depression and anxiety, systemic inflammatory states like sepsis, and even coronavirus disease 2019. To understand what role, if any, FMT may play in the management of these conditions, it is important to consider the potential risks and benefits of the therapy. Regardless, there are several barriers to its more widespread adoption, which include incompletely understood mechanism of action (especially outside of CDI), inability to standardise treatment, disagreement on its active ingredients and how it should be regulated, and lack of long-term outcome and safety data. Whilst the transfer of faecal material from one individual to another to treat ailments or improve health has a history dating back thousands of years, there are fewer than 10 randomised controlled trials supporting its use. Moving forward, it will be imperative to gather as much data from FMT donors and recipients over as long a timeframe as possible, and for trials to be conducted with rigorous methodology, including appropriate control groups, in order to best understand the utility of FMT for indications beyond CDI. This review discusses the history of FMT, its appreciable mechanisms of action with reference to CDI, indications for FMT with an emerging evidence base above and beyond CDI, and future perspectives on the field.
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Affiliation(s)
- Simon D. Goldenberg
- Centre for Clinical Infection & Diagnostics Research, King’s College London and Guy’s & St. Thomas’ NHS Foundation Trust, 5th floor, North Wing, St Thomas’ hospital, Westminster Bridge Road, London, SE1 7EH, UK
| | - Blair Merrick
- Centre for Clinical Infection & Diagnostics Research, King’s College London and Guy’s & St. Thomas’ NHS Foundation Trust, London, UK
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Du W, Han W, Dong J. Long-term oral vancomycin for refractory inflammatory bowel diseases without Clostridium difficile infection: Lessons from primary sclerosing cholangitis. Med Hypotheses 2020; 144:110211. [PMID: 33254520 DOI: 10.1016/j.mehy.2020.110211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/09/2020] [Accepted: 08/20/2020] [Indexed: 02/07/2023]
Abstract
Dysbiosis is a prominent feature of inflammatory bowel diseases (IBD). However, the efficacy of using antibiotics aiming at the aberrant gut microflora for IBD treatment are either unsuccessful or not persistent. In contrast, long-term oral vancomycin has been proved effective in controlling both the bile duct and gut inflammation of primary sclerosing cholangitis (PSC), an autoimmune disease against the intra- and extrahepatic bile ducts that holds a high rate of concomitant IBD and shares many common characteristics with IBD, including similar dysbiosis patterns. Two discrepancies of antibiotic usage might explain the dramatically different responses of the two diseases toward this strategy. First, the vast majority of antibiotic formulas for IBD management consist of broad-spectrum antibiotics mainly targeting gram-negative bacteria with some covering anaerobes and gram-positive ones, while vancomycin used for PSC treatment almost exclusively targets gram-positive bacteria. Several lines of clues suggested that gram-positive microorganisms might be responsible for the chronic inflammation observed in IBD and PSC. Second, improvement of liver test in PSC patients is usually observed after a relatively long period of oral vancomycin treatment (more than 12 weeks) and it takes even longer for gut mucosal healing. Moreover, long-term low dose oral vancomycin is required to prevent PSC recurrence. However, most trials of using antibiotics for IBD management is aiming at inducing remission with short treatment course (most less than 2 weeks) without maintenance. We hypothesize that the host antimicrobial response favors the growth of certain gram-positive intestinal bacteria in genetically predisposed individuals which is responsible for the aberrant immunological reaction towards the gut mucosa. Oral vancomycin induces disease remission by suppressing the pathogenic gram-positive microorganisms, but long course is needed since the gut inflammation is usually severe than that concomitant with PSC. Moreover, long-term maintenance is required to prevent the rebound of the pathogens and flare of the intestinal inflammation.
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Affiliation(s)
- Wei Du
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 Shaanxi Province, PR China; Grade 2016, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032 Shaanxi Province, PR China
| | - Weili Han
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 Shaanxi Province, PR China
| | - Jiaqiang Dong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 Shaanxi Province, PR China.
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Fischer RT, Day JC, Wasserkrug H, Faseler M, Kats A, Daniel JF, Slowik V, Andrews W, Hendrickson RJ. Complications of Cryptosporidium infection after pediatric liver transplantation: Diarrhea, rejection, and biliary disease. Pediatr Transplant 2020; 24:e13807. [PMID: 32777150 DOI: 10.1111/petr.13807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/22/2020] [Accepted: 06/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cryptosporidium enteritis can be devastating in the immunocompromised host. In pediatric liver transplant recipients, infection may be complicated by prolonged carriage of the parasite, rejection, and biliary tree damage and fibrosis. Herein, we report on six patients and their long-term outcomes following cryptosporidiosis. METHODS We reviewed all cases of cryptosporidiosis in a pediatric liver transplant population over a 17-year period at a single center. Six patients with infection were identified, and their outcomes were analyzed. RESULTS Infection was associated with significant diarrhea and dehydration in all cases, and led to hospitalization in one-half of patients. Four of the six patients developed biopsy-proven rejection following infection, with three of those patients developing rejection that was recalcitrant to intravenous steroid treatment. Additionally, three patients developed biliary tree abnormalities with similarity to sclerosing cholangitis. In one patient, those biliary changes led to repeated need for biliary drain placement and advancing fibrotic liver allograft changes. CONCLUSIONS Cryptosporidiosis in pediatric liver transplant recipients may lead to significant complications, including recalcitrant episodes of rejection and detrimental biliary tree changes. We advocate for increased awareness of this cause of diarrheal disease and the allograft injuries that may accompany infection.
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Affiliation(s)
- Ryan T Fischer
- Division of Gastroenterology, Children's Mercy Hospital, Kansas City, Missouri, USA
| | - J Christopher Day
- Division of Infectious Disease, Children's Mercy Hospital, Kansas City, Missouri, USA
| | - Heather Wasserkrug
- Division of Gastroenterology, Children's Mercy Hospital, Kansas City, Missouri, USA
| | - Megan Faseler
- Division of Pediatric Surgery, Children's Mercy Hospital, Kansas City, Missouri, USA
| | - Alexander Kats
- Division of Pathology, Children's Mercy Hospital, Kansas City, Missouri, USA
| | - James F Daniel
- Division of Gastroenterology, Children's Mercy Hospital, Kansas City, Missouri, USA
| | - Voytek Slowik
- Division of Gastroenterology, Children's Mercy Hospital, Kansas City, Missouri, USA
| | - Walter Andrews
- Division of Pediatric Surgery, Children's Mercy Hospital, Kansas City, Missouri, USA
| | - Richard J Hendrickson
- Division of Pediatric Surgery, Children's Mercy Hospital, Kansas City, Missouri, USA
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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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39
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Rahman AU, Inayat F, Ali S, Zahid E, Charles R. The role of oral vancomycin in inducing remission for biologic-experienced ulcerative colitis with concomitant primary sclerosing cholangitis and liver transplantation. Clin J Gastroenterol 2020; 14:159-164. [PMID: 33130984 DOI: 10.1007/s12328-020-01272-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 10/12/2020] [Indexed: 02/07/2023]
Abstract
While a minority of patients with ulcerative colitis has primary sclerosing cholangitis (PSC), a significant proportion of patients with PSC have ulcerative colitis. The activity of PSC is usually not commensurate with the degree of concomitant colonic inflammation. Moreover, up to one-third of patients with a history of ulcerative colitis may paradoxically experience worsening of their colonic inflammation despite receiving immunosuppression after liver transplantation for PSC. There is a dearth of data pertaining to the management of ulcerative colitis in this post-transplantation patient population. We hereby delineate the case of a patient with severe refractory ulcerative colitis in the aftermath of liver transplantation due to PSC who eventually responded to oral vancomycin after failure of biologic therapy. Since current data implicate that patients with ulcerative colitis and PSC often present with distinct alterations of their colonic microbiome, oral vancomycin may be conjectured to demonstrate a therapeutic role. In this article, the review of literature suggests that oral vancomycin might indeed be an effective substitute in patients in whom the uptake of biologic agents may be challenging owing to their already immunosuppressed status.
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Affiliation(s)
| | - Faisal Inayat
- Allama Iqbal Medical College, Lahore, Punjab, Pakistan.
| | - Saeed Ali
- University of Iowa Health Care, Iowa City, Iowa, USA
| | - Effa Zahid
- Services Institute of Medical Sciences, Lahore, Punjab, Pakistan
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40
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Ee LC. Liver disease in the older child. J Paediatr Child Health 2020; 56:1702-1707. [PMID: 33197971 DOI: 10.1111/jpc.14708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 09/07/2019] [Accepted: 11/07/2019] [Indexed: 11/30/2022]
Abstract
Liver disease in children tends to present either as: (i) an acute hepatitis with or without jaundice; (ii) incidental finding of abnormal liver function tests; or (iii) from a complication of portal hypertension with either haematemesis and/or incidental splenomegaly. Acute hepatitis may result from acute infection, prescribed or other drugs, ischaemia or vascular causes, autoimmune hepatitis, or idiopathic liver failure. Non-alcoholic fatty liver disease is now the most likely reason for abnormal liver function tests but medications, metabolic disease, cholangiopathy and non-liver causes should be considered. Autoimmune hepatitis and alpha-1-antitrypsin deficiency are the most likely causes of insidious liver disease. An international normalised ratio uncorrected by vitamin K reflects the severity of liver synthetic dysfunction, but not propensity to bleed. Creatine kinase helps to differentiate muscle from liver disease in patients with raised transaminases. Doppler ultrasound of hepatic vasculature is useful when assessing splenomegaly to differentiate extra-hepatic portal hypertension from inherent liver disease.
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Affiliation(s)
- Looi C Ee
- Department of Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Queensland, Australia
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41
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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.
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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
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Ali AH, Damman J, Shah SB, Davies Y, Hurwitz M, Stephen M, Lemos LM, Carey EJ, Lindor KD, Buness CW, Alrabadi L, Berquist WE, Cox KL. Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis. Scand J Gastroenterol 2020; 55:941-950. [PMID: 32633158 DOI: 10.1080/00365521.2020.1787501] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV. METHODS Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline. RESULTS 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n = 59; median age was 13.5 years [range, 1.5-44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2-14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events. CONCLUSION In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.
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Affiliation(s)
- Ahmad Hassan Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA.,Division of Hepatology, University of Missouri-Columbia, Columbia, MO, USA.,Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Jennifer Damman
- Lucile Packard Children's Hospital, Stanford University, Palo Alto, CA, USA
| | - Shamita B Shah
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA, USA.,Division of Gastroenterology, Ochsner Clinic Foundation, New Orleans, LA, USA
| | - Yinka Davies
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA, USA
| | - Melissa Hurwitz
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA
| | - Mariam Stephen
- Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA
| | - Leta M Lemos
- Sacramento Pediatric Gastroenterology, Sacramento, CA, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA.,College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | - Cynthia W Buness
- National Patient Advocate Foundation, Arizona State University, Phoenix, AZ, USA
| | - Leina Alrabadi
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA, USA
| | - William E Berquist
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA
| | - Kenneth L Cox
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA
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Vlăduţ C, Ciocîrlan M, Bilous D, Șandru V, Stan-Ilie M, Panic N, Becheanu G, Jinga M, Costache RS, Costache DO, Diculescu M. An Overview on Primary Sclerosing Cholangitis. J Clin Med 2020; 9:754. [PMID: 32168787 PMCID: PMC7141307 DOI: 10.3390/jcm9030754] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 12/12/2022] Open
Abstract
Primary sclerosing cholangitis is a progressive liver disease characterized by chronic inflammation leading to liver fibrosis and cirrhosis. Even though the exact pathogenesis is still unclear, a combination of autoimmune, environmental, and ischemic factors could explain certain aspects of the disease. The most important diagnostic step is cholangiography, which can be obtained either by endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiography (MRCP as the gold standard), or percutaneous transhepatic cholangiography. It shows multifocal short biliary duct strictures leading to the "beaded" aspect. Cholangiocarcinoma and colorectal adenocarcinoma are the most feared complications in patients with Primary sclerosing cholangitis (PSC). Continuous screening consists of annual clinical, biochemical, and ultrasound assessments in asymptomatic patients and annual colonoscopy in patients with PSC and inflammatory bowel disease. In newly diagnosed patients with PSC, colonoscopy is mandatory and, if negative, then, a repeat colonoscopy should be performed in 3-5 years. The lack of efficient curative medical treatment makes invasive treatments such as liver transplant and endoscopy the mainstream for managing PSC and its complications. Until now, even though only ursodeoxycholic acid has shown a moderate clinical, biochemical, and even histological improvement, it has no significant influence on the risk of cholangiocarcinoma, liver transplant need, or death risk and it is no longer recommended in treating early PSC. Further studies are in progress to establish the effect of molecular-targeted therapies in PSC.
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Affiliation(s)
- Cătălina Vlăduţ
- Department of Gastroenterology, Prof Dr Agrippa Ionescu Clinical Emergency Hospital, 7000 Bucharest, Romania;
- Carol Davila University of Medicine and Pharmacy, 7000 Bucharest, Romania; (D.B.); (M.S.-I.); (M.J.); (M.D.)
| | - Mihai Ciocîrlan
- Department of Gastroenterology, Prof Dr Agrippa Ionescu Clinical Emergency Hospital, 7000 Bucharest, Romania;
- Carol Davila University of Medicine and Pharmacy, 7000 Bucharest, Romania; (D.B.); (M.S.-I.); (M.J.); (M.D.)
| | - Dana Bilous
- Carol Davila University of Medicine and Pharmacy, 7000 Bucharest, Romania; (D.B.); (M.S.-I.); (M.J.); (M.D.)
| | - Vasile Șandru
- Department of Gastroenterology, Clinical Emergency Hospital Bucharest, 7000 Bucharest, Romania;
| | - Mădălina Stan-Ilie
- Carol Davila University of Medicine and Pharmacy, 7000 Bucharest, Romania; (D.B.); (M.S.-I.); (M.J.); (M.D.)
- Department of Gastroenterology, Clinical Emergency Hospital Bucharest, 7000 Bucharest, Romania;
| | - Nikola Panic
- Dr. Dragisa Misovic-Dedinje University Clinic, 11000 Belgrade, Serbia;
| | - Gabriel Becheanu
- Department of Anatomopathology, Fundeni Clinical Institute, 7000 Bucharest, Romania;
| | - Mariana Jinga
- Carol Davila University of Medicine and Pharmacy, 7000 Bucharest, Romania; (D.B.); (M.S.-I.); (M.J.); (M.D.)
- Department of Gastroenterology, Carol Davila University Central Emergency Military Central Hospital, 7000 Bucharest, Romania
| | - Raluca S. Costache
- Carol Davila University of Medicine and Pharmacy, 7000 Bucharest, Romania; (D.B.); (M.S.-I.); (M.J.); (M.D.)
- Department of Gastroenterology, Carol Davila University Central Emergency Military Central Hospital, 7000 Bucharest, Romania
| | - Daniel O. Costache
- Department of Dermatology, Carol Davila University Central Emergency Military Central Hospital, 7000 Bucharest, Romania;
| | - Mircea Diculescu
- Carol Davila University of Medicine and Pharmacy, 7000 Bucharest, Romania; (D.B.); (M.S.-I.); (M.J.); (M.D.)
- Department of Gastroenterology, Fundeni Clinical Institute, 7000 Bucharest, Romania
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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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45
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Baker SS, Baker RD. Gut Microbiota and Liver Injury (II): Chronic Liver Injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1238:39-54. [PMID: 32323179 DOI: 10.1007/978-981-15-2385-4_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic liver injury mainly comprises viral hepatitis, fatty liver disease, autoimmune hepatitis, cirrhosis and liver cancer. It is well established that gut microbiota serves as the key upstream modulator for chronic liver injury progression. Indeed, the term "gut-liver axis" was mostly applied for chronic liver injury. In the current chapter, we will summarize the relationship between gut microbiota and chronic liver injury, including the interaction between them based on latest clinic and basic research.
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Affiliation(s)
- Susan S Baker
- Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, USA. .,39 Irving Place, Buffalo, NY, 14201, USA.
| | - Robert D Baker
- Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, USA
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46
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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: 57] [Impact Index Per Article: 11.4] [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.
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47
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Sundaram S, Jearth V. Primary Sclerosing Cholangitis: A Clinical Update. EUROPEAN MEDICAL JOURNAL 2019. [DOI: 10.33590/emj/10313809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic disorder of the liver, with strictures in the bile ducts leading to cirrhosis of the liver in a proportion of patients. PSC is commonly associated with inflammatory bowel disease and increased risk of cholangiocarcinoma, gall bladder cancer, colorectal cancer, and hepatocellular carcinoma. Medical therapies are primarily aimed at symptom management and disease-modifying therapies are limited. Endoscopic therapies are used in patients with dominant strictures and liver transplantation is a last resort. In this article, the authors aim to comprehensively review the epidemiology, diagnosis, and management of PSC with emphasis on risk of malignancies and management of PSC. The authors also survey the advances in pathogenesis understanding and novel medical therapies for PSC.
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Affiliation(s)
- Sridhar Sundaram
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Vaneet Jearth
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Centre, Mumbai, India
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48
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Black DD, Mack C, Kerkar N, Miloh T, Sundaram SS, Anand R, Gupta A, Alonso E, Arnon R, Bulut P, Karpen S, Lin CH, Rosenthal P, Ryan M, Squires RH, Valentino P, Elsea SH, Shneider BL. A Prospective Trial of Withdrawal and Reinstitution of Ursodeoxycholic Acid in Pediatric Primary Sclerosing Cholangitis. Hepatol Commun 2019; 3:1482-1495. [PMID: 31701072 PMCID: PMC6824074 DOI: 10.1002/hep4.1421] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 07/27/2019] [Indexed: 12/15/2022] Open
Abstract
Ursodeoxycholic acid (UDCA) is commonly used to treat several liver disorders in adults and children, including primary sclerosing cholangitis (PSC) for which it is not U.S. Food and Drug Administration approved. UDCA treatment has an uncertain impact on disease outcomes and has been reported in high doses to be associated with worse outcome in adults with PSC. In this context, controlled withdrawal and reintroduction of UDCA in children with PSC were studied. Prior to study initiation, participants were required to have alanine aminotransferase (ALT) and gamma‐glutamyl transpeptidase (GGT) <2 times the upper limit of normal on stable UDCA dosing. The study included four phases: I (stable dosing), II (50% UDCA reduction), III (UDCA discontinuation), IV (UDCA reintroduction), with a primary endpoint of change in ALT and GGT between phases I and III. We enrolled 27 participants (22 completed) between March 2011 and June 2016. Changes in mean ALT and GGT between phases I and III were ALT, +29.5 IU/L (P = 0.105) and GGT, +60.4 IU/L (P = 0.003). In 7 participants, ALT and GGT ≤29 IU/L did not rise above 29 IU/L (null response group). Eight participants had increases of ALT or GGT >100 IU/L (flare group). None developed elevated bilirubin. All flares responded to UDCA reinstitution. Serum GGT, interleukin‐8, and tumor necrosis factor α levels were higher in the flare group at baseline. Liver biochemistries increased in children with PSC during controlled UDCA withdrawal; one third increased above 100 IU/L and one third remained normal during UDCA withdrawal. Conclusion: The impact of prolonged UDCA use in childhood PSC and the significance of a biochemical flare are unclear. Further studies of the natural history and treatment of pediatric PSC and UDCA use are needed.
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Affiliation(s)
- Dennis D Black
- Pediatrics University of Tennessee Health Science Center Memphis TN
| | - Cara Mack
- Pediatrics University of Colorado School of Medicine Aurora CO
| | - Nanda Kerkar
- Pediatrics University of Rochester Medical Center Rochester NY.,Pediatrics Keck School of Medicine of University of Southern California Los Angeles CA
| | - Tamir Miloh
- Pediatrics Baylor College of Medicine Houston TX
| | | | | | | | - Estella Alonso
- Pediatrics Northwestern University College of Medicine Chicago IL
| | - Ronen Arnon
- Pediatrics Mount Sinai Icahn School of Medicine New York NY
| | - Pinar Bulut
- Pediatrics Phoenix Children's Hospital Phoenix AZ
| | - Saul Karpen
- Pediatrics Emory University School of Medicine Atlanta GA
| | - Chuan-Hao Lin
- Pediatrics Keck School of Medicine of University of Southern California Los Angeles CA
| | - Philip Rosenthal
- Pediatrics School of Medicine University of California, San Francisco San Francisco CA
| | - Matthew Ryan
- Pediatrics Children's Hospital of Philadelphia Philadelphia PA
| | - Robert H Squires
- Pediatrics University of Pittsburgh School of Medicine Pittsburgh PA
| | | | - Sarah H Elsea
- Molecular and Human Genetics Baylor College of Medicine Houston TX
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49
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Ayers TD, Leonard-Puppa E, Kader HA, Waddell J, Watkins RD, Blanchard SS, Safta AM, Rawal N. Oral Vancomycin as an Adjuvant Treatment in IBD. CROHN'S & COLITIS 360 2019. [DOI: 10.1093/crocol/otz015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstract
Objective
To study the efficacy of oral vancomycin (POV) treatment in pediatric inflammatory bowel disease (IBD).
Methods
We conducted retrospective and prospective chart reviews, identifying patients using the Division’s Inflammatory Bowel Disease (IBD) registry, ICD-9 and ICD-10 codes for IBD, and recall of patients receiving POV. Patients aged 2–21 years with active IBD at initiation of POV were included unless they had Clostridium difficile infection or primary sclerosing cholangitis (PSC). Pre- and posttreatment analysis included a Physician Global Assessment (PGA), pediatric ulcerative colitis (UC) activity index (PUCAI), and an abbreviated pediatric Crohn’s disease (CD) activity index (PCDAI). The Wilcoxon Signed Ranks test, determined if pre- and post-POV rankings of symptom severity differed. Mann–Whitney U tests assessed improvement in presenting symptoms.
Results
Nineteen patients met inclusion criteria (12 CD and 7 UC). POV improved the PGA score in 16 of 19 patients (P < 0.001). Mean PGA score pretreatment was 3 ± 0.471; posttreatment mean of 1.58 ± 0.769. Abdominal pain (P < 0.001), diarrhea (P < 0.002), anemia (P < 0.002), and blood in stool (P < 0.001) showed significant improvement. PUCAI and PCDAI scores, pretreatment means of 50 ± 17 and 33 ± 9, respectively, also improved with mean score reduction of 23 in CD and 38 in UC patients after POV initiation (P-value < 0.0001). This improvement was noted for both IBD subtypes.
Conclusions
POV may be an effective adjuvant treatment for pediatric IBD. Its effectiveness is likely due to a combination of its anti-tumor necrosis factor alpha-α activity and its influence on the gut microbiome. Further controlled studies of POV in IBD are warranted to determine the most efficacious use of POV in pediatric IBD.
Aim
This study attempts to expand on the current literature to determine efficacy of POV as an adjuvant therapy in treating active IBD in children.
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Affiliation(s)
- Travis D Ayers
- Pediatric GI, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, AR
| | | | - Howard A Kader
- Pediatric GI, University of Maryland School of Medicine, Baltimore, MD
| | - Jaylyn Waddell
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD
| | - Runa D Watkins
- Pediatric GI, University of Maryland School of Medicine, Baltimore, MD
| | - Samra S Blanchard
- Pediatric GI, University of Maryland School of Medicine, Baltimore, MD
| | - Anca M Safta
- Pediatric GI, Wake Forest School of Medicine, Winston-Salem, NC
| | - Nidhi Rawal
- Pediatric GI, University of Maryland School of Medicine, Baltimore, MD
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50
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Allegretti JR, Kassam Z, Carrellas M, Mullish BH, Marchesi JR, Pechlivanis A, Smith M, Gerardin Y, Timberlake S, Pratt DS, Korzenik JR. Fecal Microbiota Transplantation in Patients With Primary Sclerosing Cholangitis: A Pilot Clinical Trial. Am J Gastroenterol 2019; 114:1071-1079. [PMID: 30730351 DOI: 10.14309/ajg.0000000000000115] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with no effective medical therapies. A perturbation of the gut microbiota has been described in association with PSC, and fecal microbiota transplantation (FMT) has been reported to restore the microbiome in other disease states. Accordingly, we aimed at evaluating the safety, change in liver enzymes, microbiota, and metabolomic profiles in patients with PSC after FMT. METHODS An open-label pilot study of patients with PSC with concurrent inflammatory bowel disease and alkaline phosphatase (ALP) > 1.5× the upper limit of normal was conducted. The patients underwent a single FMT by colonoscopy. Liver enzyme profiles and stool microbiome and metabolomic analysis were conducted at baseline and weeks 1, 4, 8, 12, and 24 post-FMT. The primary outcome was safety, and the secondary outcome was a decrease in ALP levels ≥50% from baseline by week 24 post-FMT; stool microbiota (by 16S rRNA gene profiling) and metabonomic dynamics were assessed. RESULTS Ten patients underwent FMT. Nine patients had ulcerative colitis, and 1 had Crohn's colitis. The mean baseline ALP level was 489 U/L. There were no related adverse events. Overall, 30% (3/10) experienced a ≥50% decrease in ALP levels. The diversity increased in all patients post-FMT, as early as week 1 (P < 0.01). Importantly, abundance of engrafter operational taxonomic units in patients post-FMT correlated with decreased ALP levels (P = 0.02). DISCUSSION To our knowledge, this is the first study to demonstrate that FMT in PSC is safe. In addition, increases in bacterial diversity and engraftment may correlate with an improvement in ALP among patients with PSC.
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Affiliation(s)
- Jessica R Allegretti
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Zain Kassam
- Finch Therapeutics Group, Somerville, Massachusetts, USA
| | - Madeline Carrellas
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Benjamin H Mullish
- Division of Integrative Systems Medicine and Digestive Disease, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Julian R Marchesi
- Division of Integrative Systems Medicine and Digestive Disease, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Alexandros Pechlivanis
- Division of Integrative Systems Medicine and Digestive Disease, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Mark Smith
- Finch Therapeutics Group, Somerville, Massachusetts, USA
| | | | | | - Daniel S Pratt
- Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Joshua R Korzenik
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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