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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [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: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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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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Fousekis FS, Mpakogiannis K, Filis P, Skamnelos A, Christodoulou DK, Mauri D, Katsanos KH. Exploring Chemoprevention in Colorectal Cancer for Patients with Inflammatory Bowel Disease: Mechanisms of Action and Clinical Aspects. Cancers (Basel) 2025; 17:229. [PMID: 39858011 PMCID: PMC11764170 DOI: 10.3390/cancers17020229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Inflammatory bowel diseases (IBDs) have been associated with a higher risk of colorectal cancer (CRC) development and chronic colonic inflammation seems to have a critical role in the pathogenesis of CRC in patients suffering from IBD. In respect to that, surveillance colonoscopy at regular intervals is recommended in patients with colitis. Objective: This review aims to explore the chemopreventive potential of a range of agents, including mesalazine, thiopurines, anti-TNF agents, statins, ursodeoxycholic acid, aspirin, folic acid, and nutraceuticals. Results: These agents target inflammation, oxidative stress, and oncogenic pathways, thereby offering the potential to reduce the risk of CRC in patients with IBD. Anti-TNF agents, such as infliximab and adalimumab, not only reduce colonic inflammation, but also play a protective role against CRC by lessening the carcinogenic effects associated with prolonged inflammatory processes. Furthermore, mesalazine and thiopurines have demonstrated established efficacy, while newer biologics, including interleukin inhibitors, show promising advancements. Although nutraceuticals and dietary interventions require further clinical validation, they offer additional possibilities for non-pharmacological prevention. Conclusion: Despite progress, knowledge gaps persist regarding the long-term safety, optimal dosing, and combined use of these agents. A significant reduction in the incidence of CRC in patients with IBD could be achieved by advancing chemoprevention and personalizing strategies.
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Affiliation(s)
- Fotios S. Fousekis
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Konstantinos Mpakogiannis
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Panagiotis Filis
- Department of Medical Oncology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 455 00 Ioannina, Greece (D.M.)
| | - Alexandros Skamnelos
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Dimitrios K. Christodoulou
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Davide Mauri
- Department of Medical Oncology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 455 00 Ioannina, Greece (D.M.)
| | - Konstantinos H. Katsanos
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
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Cançado GGL, Hirschfield GM. Management of primary sclerosing cholangitis: Current state-of-the-art. Hepatol Commun 2024; 8:e0590. [PMID: 39774274 PMCID: PMC11567710 DOI: 10.1097/hc9.0000000000000590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 10/08/2024] [Indexed: 01/11/2025] Open
Abstract
Primary sclerosing cholangitis is a chronic liver disease characterized by progressive inflammation and fibrosis of medium-large bile ducts, most commonly in association with inflammatory bowel disease. Most patients have a progressive disease course, alongside a heightened risk of hepatobiliary and colorectal cancer. Medical therapies are lacking, and this, in part, reflects a poor grasp of disease biology. As a result, current management is largely supportive, with liver transplantation an effective life-prolonging intervention when needed, but not one that cures disease. Emerging therapies targeting disease progression, as well as symptoms such as pruritus, continue to be explored. The trial design is increasingly cognizant of the application of thoughtful inclusion criteria, as well as better endpoints aimed at using surrogates of disease that can identify treatment benefits early. This is hoped to facilitate much-needed advances toward developing safe and effective interventions for patients.
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Duan Y, Dai J, Lu Y, Qiao H, Liu N. Disentangling the molecular mystery of tumour-microbiota interactions: Microbial metabolites. Clin Transl Med 2024; 14:e70093. [PMID: 39568157 PMCID: PMC11578933 DOI: 10.1002/ctm2.70093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/27/2024] [Accepted: 11/02/2024] [Indexed: 11/22/2024] Open
Abstract
The profound impact of the microbiota on the initiation and progression of cancer has been a focus of attention. In recent years, many studies have shown that microbial metabolites serve as key hubs that connect the microbiome and cancer progression, but the underlying molecular mechanisms have not been fully elucidated. Multiple mechanisms that influence tumour development and therapy resistance, including disrupting cellular signalling pathways, triggering oxidative stress, inducing metabolic reprogramming and reshaping tumour immune microenvironment, are reviewed. Focusing on recent advancements in this field, this review also summarises the methodological framework of studies regarding microbial metabolites. In this review, we outline the current state of research on tumour-associated microbial metabolites and describe the challenges in future scientific research and clinical applications. KEY POINTS: Metabolites derived from both gut and intratumoural microbiota play important roles in cancer initiation and progression. The dual roles of microbial metabolites pose an obstacle for clinical translations. Absolute quantification and tracing techniques of microbial metabolites are essential for addressing the gaps in studies on microbial metabolites. Integrating microbial metabolomics with multi-omics transcends current research paradigms.
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Affiliation(s)
- Yu‐Fei Duan
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouPR China
| | - Jia‐Hao Dai
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouPR China
| | - Ying‐Qi Lu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouPR China
| | - Han Qiao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouPR China
| | - Na Liu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouPR China
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6
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Saha B, A T R, Adhikary S, Banerjee A, Radhakrishnan AK, Duttaroy AK, Pathak S. Exploring the Relationship Between Diet, Lifestyle and Gut Microbiome in Colorectal Cancer Development: A Recent Update. Nutr Cancer 2024; 76:789-814. [PMID: 39207359 DOI: 10.1080/01635581.2024.2367266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 05/18/2024] [Accepted: 06/05/2024] [Indexed: 09/04/2024]
Abstract
Colorectal cancer (CRC) is one of the major causes of cancer-related mortality worldwide. Despite advances in treatment modalities, its prevalence continues to rise, notably among younger populations. Unhealthy dietary habits, sedentary routines, and obesity have been identified as one of the key contributors to the development of colorectal cancer, apart from genetic and epigenetic modifications. Recognizing the profound impact of diet and lifestyle on the intricate gut microbiota ecosystem offers a promising avenue for understanding CRC development and its treatment. Gut dysbiosis, characterized by imbalances favoring harmful microbes over beneficial ones, has emerged as a defining feature of CRC. Changes in diet and lifestyle can profoundly alter the composition of gut microbes and the metabolites they produce, potentially contributing to CRC onset. Focusing on recent evidence, this review discussed various dietary factors, such as high consumption of red and processed meats and low fiber intake, and lifestyle factors, including obesity, lack of physical activity, smoking, and excessive alcohol consumption, that influence the gut microbiome composition and elevate CRC risk.
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Affiliation(s)
- Biki Saha
- Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, India
| | - Rithi A T
- Department of Pharmacology, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai, India
| | - Subhamay Adhikary
- Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, India
| | - Antara Banerjee
- Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, India
| | - Arun Kumar Radhakrishnan
- Department of Pharmacology, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Surajit Pathak
- Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, India
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Sohal A, Kowdley KV. Novel preclinical developments of the primary sclerosing cholangitis treatment landscape. Expert Opin Investig Drugs 2024; 33:335-345. [PMID: 38480008 DOI: 10.1080/13543784.2024.2330738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 03/11/2024] [Indexed: 03/19/2024]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with inflammation, fibrosis, and destruction of intra- and extrahepatic bile ducts. Despite substantial recent advances in our understanding of PSC, the only proven treatment of PSC is liver transplantation. There is an urgent unmet need to find medical therapies for this disorder. AREAS COVERED Multiple drugs are currently under evaluation as therapeutic options for this disease. This article summarizes the literature on the various novel therapeutic options that have been investigated and are currently under development for the treatment of PSC. EXPERT OPINION In the next decade, more than one drug will likely be approved for the treatment of the disease, and we will be looking at combination therapies for the optimal management of the disease.
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Affiliation(s)
- Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, USA
| | - Kris V Kowdley
- Department of Hepatology, Liver Institute Northwest, Seattle, USA
- Elson S. Floyd College of Medicine, Washington State University, Spokane, USA
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Wheless WH, Russo MW. Treatment of Primary Sclerosing Cholangitis Including Transplantation. Clin Liver Dis 2024; 28:171-182. [PMID: 37945158 DOI: 10.1016/j.cld.2023.07.008] [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: 11/12/2023]
Abstract
Primary sclerosing cholangitis is a progressive cholestatic liver disease that causes stricturing of the intra and extrahepatic bile ducts that can lead to cirrhosis and end stage liver disease. Effective medical therapy has been elusive, but a course of ursodeoxycholic acid may be prescribed at doses of 17-23 mg/kg/day for up to a year to determine if a reduction in serum alkaline phosphatase is observed. A number of drugs are under investigation, including FXR agonists with choleretic and antimicrobial properties. Liver transplantation for PSC has one of the highest survival rates, but recurrent PSC is seen in up to 25% of recipients.
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Affiliation(s)
- William H Wheless
- Division of Hepatology, Atrium Health Wake Forest, Charlotte, NC, USA
| | - Mark W Russo
- Division of Hepatology, Atrium Health Wake Forest, Charlotte, NC, USA.
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Gordon H, Burisch J, Ellul P, Karmiris K, Katsanos K, Allocca M, Bamias G, Barreiro-de Acosta M, Braithwaite T, Greuter T, Harwood C, Juillerat P, Lobaton T, Müller-Ladner U, Noor N, Pellino G, Savarino E, Schramm C, Soriano A, Michael Stein J, Uzzan M, van Rheenen PF, Vavricka SR, Vecchi M, Zuily S, Kucharzik T. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis 2024; 18:1-37. [PMID: 37351850 DOI: 10.1093/ecco-jcc/jjad108] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Indexed: 06/24/2023]
Affiliation(s)
- Hannah Gordon
- Department of Gastroenterology, Barts Health NHS Trust, London, Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, UK
| | - Johan Burisch
- Gastrounit, medical division, Hvidovre Hospital, University of Copenhagen, Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | | | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina, Greece
| | - Mariangela Allocca
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Manuel Barreiro-de Acosta
- University Hospital Santiago De Compostela CHUS, Department of Gastroenterology - IBD Unit, Santiago De Compostela, Spain
| | - Tasanee Braithwaite
- School of Immunology and Microbiology, King's College London, The Medical Eye Unit, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Thomas Greuter
- Division of Gastroenterology and Hepatology, GZO - Zurich Regional Health Center, Wetzikon, Division of Gastroenterology and Hepatology, University Hospital Lausanne - CHUV, Lausanne, Switzerland; Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London; Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Pascal Juillerat
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland; Crohn and Colitis Center, Gastro-entérologie Beaulieu SA, Lausanne, Switzerland
| | - Triana Lobaton
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent; Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus Liebig University Giessen, Bad Nauheim, Germany
| | - Nurulamin Noor
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gianluca Pellino
- Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona UAB, Barcelona, Spain; Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua, Italy
| | - Christoph Schramm
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandra Soriano
- Gastroenterology Division and IBD Center, Internal Medicine Department, Azienda Unità Sanitaria Locale - IRCCS, 42122 Reggio Emilia, Italy
| | - Jürgen Michael Stein
- Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt/Main, Department of Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt/Main, Germany
| | - Mathieu Uzzan
- Department of Gastroenterology, Hôpital Henri Mondor, APHP, Créteil, France
| | - Patrick F van Rheenen
- Department of Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - Maurizio Vecchi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Stephane Zuily
- Vascular Medicine Division and French Referral Center for Rare Auto-Immune Diseases, Université de Lorraine, INSERM, DCAC and CHRU-Nancy, Nancy, France
| | - Torsten Kucharzik
- Department of Gastroenterology, Lüneburg Hospital, University of Münster, Lüneburg, Germany
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Qu Y, Gong X, Zhao Z, Zhang Z, Zhang Q, Huang Y, Xie Q, Liu Y, Wei J, Du H. Establishment and Validation of Novel Prognostic Subtypes in Hepatocellular Carcinoma Based on Bile Acid Metabolism Gene Signatures Using Bulk and Single-Cell RNA-Seq Data. Int J Mol Sci 2024; 25:919. [PMID: 38255993 PMCID: PMC10815120 DOI: 10.3390/ijms25020919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly detrimental cancer type and has limited therapeutic options, posing significant threats to human health. The development of HCC has been associated with a disorder in bile acid (BA) metabolism. In this study, we employed an integrative approach, combining various datasets and omics analyses, to comprehensively characterize the tumor microenvironment in HCC based on genes related to BA metabolism. Our analysis resulted in the classification of HCC samples into four subtypes (C1, C2a, C2b, and C3). Notably, subtype C2a, characterized by the highest bile acid metabolism score (BAMS), exhibited the highest survival probability. This subtype also demonstrated increased immune cell infiltration, lower cell cycle scores, reduced AFP levels, and a lower risk of metastasis compared to subtypes C1 and C3. Subtype C1 displayed poorer survival probability and elevated cell cycle scores. Importantly, the identified subtypes based on BAMS showed potential relevance to the gene expression of drug targets in currently approved drugs and those under clinical research. Genes encoding VEGFR (FLT4 and KDR) and MET were elevated in C2, while genes such as TGFBR1, TGFB1, ADORA3, SRC, BRAF, RET, FLT3, KIT, PDGFRA, and PDGFRB were elevated in C1. Additionally, FGFR2 and FGFR3, along with immune target genes including PDCD1 and CTLA4, were higher in C3. This suggests that subtypes C1, C2, and C3 might represent distinct potential candidates for TGFB1 inhibitors, VEGFR inhibitors, and immune checkpoint blockade treatments, respectively. Significantly, both bulk and single-cell transcriptome analyses unveiled a negative correlation between BA metabolism and cell cycle-related pathways. In vitro experiments further confirmed that the treatment of HCC cell lines with BA receptor agonist ursodeoxycholic acid led to the downregulation of the expression of cell cycle-related genes. Our findings suggest a plausible involvement of BA metabolism in liver carcinogenesis, potentially mediated through the regulation of tumor cell cycles and the immune microenvironment. This preliminary understanding lays the groundwork for future investigations to validate and elucidate the specific mechanisms underlying this potential association. Furthermore, this study provides a novel foundation for future precise molecular typing and the design of systemic clinical trials for HCC therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jinfen Wei
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou Higher Education Mega Centre, Panyu District, Guangzhou 510006, China; (Y.Q.); (X.G.); (Z.Z.); (Z.Z.); (Q.Z.); (Y.H.); (Q.X.); (Y.L.)
| | - Hongli Du
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou Higher Education Mega Centre, Panyu District, Guangzhou 510006, China; (Y.Q.); (X.G.); (Z.Z.); (Z.Z.); (Q.Z.); (Y.H.); (Q.X.); (Y.L.)
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11
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Pan Y, Zhang H, Li M, He T, Guo S, Zhu L, Tan J, Wang B. Novel approaches in IBD therapy: targeting the gut microbiota-bile acid axis. Gut Microbes 2024; 16:2356284. [PMID: 38769683 PMCID: PMC11110704 DOI: 10.1080/19490976.2024.2356284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and recurrent condition affecting the gastrointestinal tract. Disturbed gut microbiota and abnormal bile acid (BA) metabolism are notable in IBD, suggesting a bidirectional relationship. Specifically, the diversity of the gut microbiota influences BA composition, whereas altered BA profiles can disrupt the microbiota. IBD patients often exhibit increased primary bile acid and reduced secondary bile acid concentrations due to a diminished bacteria population essential for BA metabolism. This imbalance activates BA receptors, undermining intestinal integrity and immune function. Consequently, targeting the microbiota-BA axis may rectify these disturbances, offering symptomatic relief in IBD. Here, the interplay between gut microbiota and bile acids (BAs) is reviewed, with a particular focus on the role of gut microbiota in mediating bile acid biotransformation, and contributions of the gut microbiota-BA axis to IBD pathology to unveil potential novel therapeutic avenues for IBD.
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Affiliation(s)
- Yinping Pan
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Haojie Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Minghui Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Tingjing He
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Sihao Guo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Liancai Zhu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Jun Tan
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical engineering, Chongqing University of Education, Chongqing, PR China
| | - Bochu Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
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12
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He X, Lan H, Jin K, Liu F. Cholesterol in colorectal cancer: an essential but tumorigenic precursor? Front Oncol 2023; 13:1276654. [PMID: 38023258 PMCID: PMC10655112 DOI: 10.3389/fonc.2023.1276654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal human malignancies, and with the growth of societies and lifestyle changes, the rate of people suffering from it increases yearly. Important factors such as genetics, family history, nutrition, lifestyle, smoking, and alcohol can play a significant role in increasing susceptibility to this cancer. On the other hand, the metabolism of several macromolecules is also involved in the fate of tumors and immune cells. The evidence discloses that cholesterol and its metabolism can play a role in the pathogenesis of several cancers because there appears to be an association between cholesterol levels and CRC, and cholesterol-lowering drugs may reduce the risk. Furthermore, changes or mutations of some involved genes in cholesterol metabolism, such as CYP7A1 as well as signaling pathways, such as mitogen-activated protein kinase (MAPK), can play a role in CRC pathogenesis. This review summarized and discussed the role of cholesterol in the pathogenesis of CRC as well as available cholesterol-related therapeutic approaches in CRC.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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13
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Tan N, Lubel J, Kemp W, Roberts S, Majeed A. Current Therapeutics in Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2023; 11:1267-1281. [PMID: 37577219 PMCID: PMC10412694 DOI: 10.14218/jcth.2022.00068s] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/01/2023] [Accepted: 01/20/2023] [Indexed: 07/03/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.
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Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - John Lubel
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - William Kemp
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Stuart Roberts
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Ammar Majeed
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
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14
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Wentworth BJ, Khot R, Caldwell SH. The Many Faces of Primary Sclerosing Cholangitis: Controversy Abounds. Dig Dis Sci 2023; 68:3514-3526. [PMID: 37358638 DOI: 10.1007/s10620-023-08003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/10/2023] [Indexed: 06/27/2023]
Abstract
Primary sclerosing cholangitis (PSC) is notoriously challenging to manage given its heterogeneity with regard to diagnosis, management, and progression. The lack of disease-modifying therapy and variable rate of onset of cirrhosis, portal hypertension-related decompensating events, jaundice, pruritus, biliary complications, and need for liver transplantation is deeply unsettling to clinicians and patients alike. Recent updated practice guidance by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver endeavored to highlight some of these challenges. However, these references only briefly address clinical dilemmas that providers face on a daily basis. This review aims to further discuss these controversial topics, including providing insight into the utility of ursodeoxycolic acid, the significance of alkaline phosphatase normalization, when to consider PSC variants and mimickers, and the implications of continuous hepatobiliary malignancy screening. In particular, there has been a growing body of literature raising concern about repeat exposure to gadolinium-containing contrast. Patients with PSC are potentially at risk for large lifetime exposure to gadolinium related to frequent magnetic resonance imaging scans and whether this carries any negative long-term adverse effects remains unknown.
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Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology and Hepatology, School of Medicine, University of Virginia, PO Box 800708, Charlottesville, VA, 22908, USA.
| | - Rachita Khot
- Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, VA, USA
| | - Stephen H Caldwell
- Division of Gastroenterology and Hepatology, School of Medicine, University of Virginia, PO Box 800708, Charlottesville, VA, 22908, USA
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15
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Yin C, Zhong R, Zhang W, Liu L, Chen L, Zhang H. The Potential of Bile Acids as Biomarkers for Metabolic Disorders. Int J Mol Sci 2023; 24:12123. [PMID: 37569498 PMCID: PMC10418921 DOI: 10.3390/ijms241512123] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/15/2023] [Accepted: 07/22/2023] [Indexed: 08/13/2023] Open
Abstract
Bile acids (BAs) are well known to facilitate the absorption of dietary fat and fat-soluble molecules. These unique steroids also function by binding to the ubiquitous cell membranes and nuclear receptors. As chemical signals in gut-liver axis, the presence of metabolic disorders such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and even tumors have been reported to be closely related to abnormal levels of BAs in the blood and fecal metabolites of patients. Thus, the gut microbiota interacting with BAs and altering BA metabolism are critical in the pathogenesis of numerous chronic diseases. This review intends to summarize the mechanistic links between metabolic disorders and BAs in gut-liver axis, and such stage-specific BA perturbation patterns may provide clues for developing new auxiliary diagnostic means.
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Affiliation(s)
| | | | | | | | - Liang Chen
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (C.Y.); (R.Z.)
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (C.Y.); (R.Z.)
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16
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Long XQ, Liu MZ, Liu ZH, Xia LZ, Lu SP, Xu XP, Wu MH. Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease. World J Gastroenterol 2023; 29:4252-4270. [PMID: 37545642 PMCID: PMC10401658 DOI: 10.3748/wjg.v29.i27.4252] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/19/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.
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Affiliation(s)
- Xiong-Quan Long
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Zhu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Zi-Hao Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Lv-Zhou Xia
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Shi-Peng Lu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Xiao-Ping Xu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
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17
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Méndez-Sánchez N, Coronel-Castillo CE, Ordoñez-Vázquez AL. Current Therapies for Cholestatic Diseases. Biomedicines 2023; 11:1713. [PMID: 37371808 PMCID: PMC10296345 DOI: 10.3390/biomedicines11061713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/03/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Cholestasis is a condition characterized by decrease in bile flow due to progressive pathological states that lead to chronic cholestatic liver diseases which affect the biliary tree at the intrahepatic level and extrahepatic level. They induce complications such as cirrhosis, liver failure, malignancies, bone disease and nutritional deficiencies that merit close follow-up and specific interventions. Furthermore, as those conditions progress to liver cirrhosis, there will be an increase in mortality but also an important impact in quality of life and economic burden due to comorbidities related with liver failure. Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. With a general view of therapeutic options and their molecular targets, this review addresses the pathophysiology of cholangiopathies. The objective is to provide clinicians with an overview of the safety and efficacy of the treatment of cholangiopathies based on the current evidence.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Unit Liver Research, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Mexico City 14050, Mexico;
- Faculty of Medicine, National Autonomous University of Mexico, Av. Universidad 3004, Copilco Universidad, Coyoacán, Mexico City 04510, Mexico
| | - Carlos E. Coronel-Castillo
- Internal Medicine Section, Central Military Hospital, Manuel Ávila Camacho s/n, Militar, Miguel Hidalgo, Ciudad de México 11200, Mexico;
| | - Ana L. Ordoñez-Vázquez
- Unit Liver Research, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Mexico City 14050, Mexico;
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18
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Hochberg JT, Sohal A, Handa P, Maliken BD, Kim TK, Wang K, Gochanour E, Li Y, Rose JB, Nelson JE, Lindor KD, LaRusso NF, Kowdley KV. Serum miRNA profiles are altered in patients with primary sclerosing cholangitis receiving high-dose ursodeoxycholic acid. JHEP Rep 2023; 5:100729. [PMID: 37179785 PMCID: PMC10172698 DOI: 10.1016/j.jhepr.2023.100729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 02/02/2023] [Accepted: 02/27/2023] [Indexed: 05/15/2023] Open
Abstract
Background & Aims Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease that can lead to end-stage liver disease and cholangiocarcinoma. High-dose ursodeoxycholic acid (hd-UDCA, 28-30 mg/kg/day) was evaluated in a previous multicentre, randomised placebo-controlled trial; however, the study was discontinued early because of increased liver-related serious adverse events (SAEs), despite improvement in serum liver biochemical tests. We investigated longitudinal changes in serum miRNA and cytokine profiles over time among patients treated with either hd-UDCA or placebo in this trial as potential biomarkers for PSC and response to hd-UDCA, as well as to understand the toxicity associated with hd-UDCA treatment. Methods Thirty-eight patients with PSC were enrolled in a multicentred, randomised, double-blinded trial of hd-UDCA vs. placebo. Results Significant alterations in serum miRNA profiles were found over time in both patients treated with hd-UDCA or placebo. Additionally, there were striking differences between miRNA profiles in patients treated with hd-UDCA compared with placebo. In patients treated with placebo, the changes in concentration of serum miRNAs miR-26a, miR-199b-5p, miR-373, and miR-663 suggest alterations of inflammatory and cell proliferative processes consistent with disease progression. However, patients treated with hd-UDCA exhibited a more pronounced differential expression of serum miRNAs, suggesting that hd-UDCA induces significant cellular miRNA changes and tissue injury. Pathway enrichment analysis for UDCA-associated miRNAs suggested unique dysregulation of cell cycle and inflammatory response pathways. Conclusions Patients with PSC have distinct miRNAs in the serum and bile, although the implications of these unique patterns have not been studied longitudinally or in relation to adverse events related to hd-UDCA. Our study demonstrates marked changes in miRNA serum profiles with hd-UDCA treatment and suggests mechanisms for the increased liver toxicity with therapy. Impact and implications Using serum samples from patients with PSC enrolled in a clinical trial comparing hd-UDCA with placebo, our study found distinct miRNA changes in patients with PSC who are treated with hd-UDCA over a period of time. Our study also noted distinct miRNA patterns in patients who developed SAEs during the study period.
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Affiliation(s)
- Jessica T. Hochberg
- Liver Institute Northwest, Seattle, WA, USA
- Seattle Children’s Hospital/University of Washington, Seattle, WA, USA
- Miami Transplant Institute at University of Miami, Miami, FL, USA
| | | | - Priya Handa
- Benaroya Research Institute, Seattle, WA, USA
| | | | | | - Kai Wang
- Institute for Systems Biology, Seattle, WA, USA
| | | | - Yu Li
- Benaroya Research Institute, Seattle, WA, USA
| | | | | | - Keith D. Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, MN, USA
| | | | - Kris V. Kowdley
- Liver Institute Northwest, Seattle, WA, USA
- Corresponding author. Address: Liver Institute Northwest, 3216 NE 45th Pl Suite 212, Seattle, WA 98105, USA; Tel.: +1(206) 536-3030.
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19
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Yang Q, Wang B, Zheng Q, Li H, Meng X, Zhou F, Zhang L. A Review of Gut Microbiota-Derived Metabolites in Tumor Progression and Cancer Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207366. [PMID: 36951547 PMCID: PMC10214247 DOI: 10.1002/advs.202207366] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/15/2023] [Indexed: 05/27/2023]
Abstract
Gut microbiota-derived metabolites are key hubs connecting the gut microbiome and cancer progression, primarily by remodeling the tumor microenvironment and regulating key signaling pathways in cancer cells and multiple immune cells. The use of microbial metabolites in radiotherapy and chemotherapy mitigates the severe side effects from treatment and improves the efficacy of treatment. Immunotherapy combined with microbial metabolites effectively activates the immune system to kill tumors and overcomes drug resistance. Consequently, various novel strategies have been developed to modulate microbial metabolites. Manipulation of genes involved in microbial metabolism using synthetic biology approaches directly affects levels of microbial metabolites, while fecal microbial transplantation and phage strategies affect levels of microbial metabolites by altering the composition of the microbiome. However, some microbial metabolites harbor paradoxical functions depending on the context (e.g., type of cancer). Furthermore, the metabolic effects of microorganisms on certain anticancer drugs such as irinotecan and gemcitabine, render the drugs ineffective or exacerbate their adverse effects. Therefore, a personalized and comprehensive consideration of the patient's condition is required when employing microbial metabolites to treat cancer. The purpose of this review is to summarize the correlation between gut microbiota-derived metabolites and cancer, and to provide fresh ideas for future scientific research.
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Affiliation(s)
- Qiqing Yang
- General SurgeryCancer CenterDepartment of Breast SurgeryZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)Hangzhou310058China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Bin Wang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Qinghui Zheng
- General SurgeryCancer CenterDepartment of Breast SurgeryZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)Hangzhou310058China
| | - Heyu Li
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Xuli Meng
- General SurgeryCancer CenterDepartment of Breast SurgeryZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)Hangzhou310058China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
- International Biomed‐X Research CenterSecond Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhou310058China
- Center for Infection & Immunity of International Institutes of Medicine The Fourth Affiliated HospitalZhejiang University School of MedicineYiwu322000China
- Cancer CenterZhejiang UniversityHangzhou310058China
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20
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Duizer C, de Zoete MR. The Role of Microbiota-Derived Metabolites in Colorectal Cancer. Int J Mol Sci 2023; 24:8024. [PMID: 37175726 PMCID: PMC10178193 DOI: 10.3390/ijms24098024] [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: 03/19/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
The impact of bacterial members of the microbiota on the development of colorectal cancer (CRC) has become clear in recent years. However, exactly how bacteria contribute to the development of cancer is often still up for debate. The impact of bacteria-derived metabolites, which can influence the development of CRC either in a promoting or inhibiting manner, is undeniable. Here, we discuss the effects of the most well-studied bacteria-derived metabolites associated with CRC, including secondary bile acids, short-chain fatty acids, trimethylamine-N-oxide and indoles. We show that the effects of individual metabolites on CRC development are often nuanced and dose- and location-dependent. In the coming years, the array of metabolites involved in CRC development will undoubtedly increase further, which will emphasize the need to focus on causation and mechanisms and the clearly defined roles of bacterial species within the microbiota.
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Affiliation(s)
| | - Marcel R. de Zoete
- Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
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Abstract
Autoimmune liver diseases (AILD) are a group of immune-mediated liver inflammatory diseases with three major forms including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Interaction of both genetic and environmental factors leads to the breakdown of self-tolerance, hence resulting in hyper-responsive of autoantibodies and aggressive autoreactive immune cells. Genetic studies have identified dozens of risk loci associated with initiation and development of AILD. However, the role of exogenous factors remains unclear. Recently, both infectious and inflammatory diseases have been associated with microbiota, which colonizes multiple mucosal surfaces and participates in human physiological process and function in immune system, particularly influencing liver, and biliary system via gut-liver axis. Emerging evidence on the role of gut microbiota has expanded our knowledge of AILD in both pathogenesis and potential therapeutic targets, along with putative diagnosis biomarkers. Herein we review the relationship between host and gut microbiota, discuss their potential roles in disease onset and progression, and summarize the compositional and functional alterations of the microbiota in AILD. We also highlighted the microbiota-based therapeutics such as antibiotics and fecal microbiota transplantation (FMT).
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Affiliation(s)
- Qiwei Qian
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wei He
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruqi Tang
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiong Ma
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China -
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22
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Nevens F, Trauner M, Manns MP. Primary biliary cholangitis as a roadmap for the development of novel treatments for cholestatic liver diseases †. J Hepatol 2023; 78:430-441. [PMID: 36272496 DOI: 10.1016/j.jhep.2022.10.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022]
Abstract
The discovery of nuclear receptors and transporters has contributed to the development of new drugs for the treatment of cholestatic liver diseases. Particular progress has been made in the development of second-line therapies for PBC. These new drugs can be separated into compounds primarily targeting cholestasis, molecules targeting fibrogenesis and molecules with immune-mediated action. Finally, drugs aimed at symptom relief (pruritus and fatigue) are also under investigation. Obeticholic acid is currently the only approved second-line therapy for PBC. Drugs in the late phase of clinical development include peroxisome proliferator-activated receptor agonists, norursodeoxycholic acid and NADPH oxidase 1/4 inhibitors.
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Affiliation(s)
- Frederik Nevens
- Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium; Centre of ERN RARE-LIVER.
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Austria; Centre of ERN RARE-LIVER
| | - Michael P Manns
- Hannover Medical School, Hannover, Germany; Centre of ERN RARE-LIVER
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23
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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: 125] [Impact Index Per Article: 62.5] [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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24
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Zheng L. New insights into the interplay between intestinal flora and bile acids in inflammatory bowel disease. World J Clin Cases 2022; 10:10823-10839. [PMID: 36338232 PMCID: PMC9631134 DOI: 10.12998/wjcc.v10.i30.10823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/08/2022] [Accepted: 09/16/2022] [Indexed: 02/05/2023] Open
Abstract
Intestinal flora plays a key role in nutrient absorption, metabolism and immune defense, and is considered to be the cornerstone of maintaining the health of human hosts. Bile acids synthesized in the liver can not only promote the absorption of fat-soluble substances in the intestine, but also directly or indirectly affect the structure and function of intestinal flora. Under the action of intestinal flora, bile acids can be converted into secondary bile acids, which can be reabsorbed back to the liver through the enterohepatic circulation. The complex dialogue mechanism between intestinal flora and bile acids is involved in the development of intestinal inflammation such as inflammatory bowel disease (IBD). In this review, the effects of intestinal flora, bile acids and their interactions on IBD and the progress of treatment were reviewed.
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Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
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25
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Stürznickel J, Behler-Janbeck F, Baranowsky A, Schmidt T, Schwinge D, John C, Lohse AW, Schramm C, Heeren J, Schinke T, Amling M. Increased concentrations of conjugated bile acids are associated with osteoporosis in PSC patients. Sci Rep 2022; 12:16491. [PMID: 36192408 PMCID: PMC9530206 DOI: 10.1038/s41598-022-20351-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 09/12/2022] [Indexed: 11/17/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is an idiopathic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of intra- and extrahepatic bile ducts. Osteoporosis is a frequent comorbidity in PSC, and we could previously demonstrate that IL17-dependent activation of bone resorption is the predominant driver of bone loss in PSC. Since we additionally observed an unexpected heterogeneity of bone mineral density in our cohort of 238 PSC patients, the present study focused on a comparative analysis of affected individuals with diagnosed osteoporosis (PSCOPO, n = 10) or high bone mass (PSCHBM, n = 7). The two groups were not distinguishable by various baseline characteristics, including liver fibrosis or serum parameters for hepatic function. In contrast, quantification of serum bile acid concentrations identified significant increases in the PSCOPO group, including glycoursodeoxycholic acid (GUDCA), an exogenous bile acid administered to both patient groups. Although cell culture experiments did not support the hypothesis that an increase in circulating bile levels is a primary cause of PSC-associated osteoporosis, the remarkable differences of endogenous bile acids and GUDCA in the serum of PSCOPO patients strongly suggest a yet unknown impairment of biliary metabolism and/or hepatic bile acid clearance in this patient subgroup, which is independent of liver fibrosis.
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Affiliation(s)
- Julian Stürznickel
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestraße 59, 22529, Hamburg, Germany.,Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Friederike Behler-Janbeck
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Anke Baranowsky
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Tobias Schmidt
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestraße 59, 22529, Hamburg, Germany
| | - Dorothee Schwinge
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg Center for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Clara John
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg Center for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Christoph Schramm
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg Center for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, 20246, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Thorsten Schinke
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestraße 59, 22529, Hamburg, Germany
| | - Michael Amling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestraße 59, 22529, Hamburg, Germany.
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26
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Jiang X, Jiang Z, Cheng Q, Sun W, Jiang M, Sun Y. Cholecystectomy promotes the development of colorectal cancer by the alternation of bile acid metabolism and the gut microbiota. Front Med (Lausanne) 2022; 9:1000563. [PMID: 36213655 PMCID: PMC9540502 DOI: 10.3389/fmed.2022.1000563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/06/2022] [Indexed: 12/24/2022] Open
Abstract
The incidence and mortality of colorectal cancer (CRC) have been markedly increasing worldwide, causing a tremendous burden to the healthcare system. Therefore, it is crucial to investigate the risk factors and pathogenesis of CRC. Cholecystectomy is a gold standard procedure for treating symptomatic cholelithiasis and gallstone diseases. The rhythm of bile acids entering the intestine is altered after cholecystectomy, which leads to metabolic disorders. Nonetheless, emerging evidence suggests that cholecystectomy might be associated with the development of CRC. It has been reported that alterations in bile acid metabolism and gut microbiota are the two main reasons. However, the potential mechanisms still need to be elucidated. In this review, we mainly discussed how bile acid metabolism, gut microbiota, and the interaction between the two factors influence the development of CRC. Subsequently, we summarized the underlying mechanisms of the alterations in bile acid metabolism after cholecystectomy including cellular level, molecular level, and signaling pathways. The potential mechanisms of the alterations on gut microbiota contain an imbalance of bile acid metabolism, cellular immune abnormality, acid-base imbalance, activation of cancer-related pathways, and induction of toxin, inflammation, and oxidative stress.
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Affiliation(s)
- Xi Jiang
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhongxiu Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qi Cheng
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wei Sun
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- *Correspondence: Yan Sun,
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27
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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28
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Marabotto E, Kayali S, Buccilli S, Levo F, Bodini G, Giannini EG, Savarino V, Savarino EV. Colorectal Cancer in Inflammatory Bowel Diseases: Epidemiology and Prevention: A Review. Cancers (Basel) 2022; 14:cancers14174254. [PMID: 36077786 PMCID: PMC9454776 DOI: 10.3390/cancers14174254] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most serious potential complications of inflammatory bowel diseases (IBDs). The aging of patients affected by IBDs makes this issue a challenge that will increasingly be faced by clinicians in clinical practice, especially in light of the poorer prognosis for CRC in this group of people when compared with the general population. In this review, we summarize the current epidemiology, risk factors and various prevention strategies proposed for CRC in patients with IBDs. Abstract Colorectal cancer (CRC) is currently the third most frequent form of malignancy and the second in terms of mortality. Inflammatory bowel diseases (IBDs) are recognized risk factors for this type of cancer. Despite a worldwide increase in the incidence of CRC, the risk of CRC-related death in IBD patients has declined over time, probably because of successful surveillance strategies, the use of more effective drugs in the management of remission and improved indications to colectomy. This notwithstanding, CRC 5-year survival in patients with IBD is poorer than in the general population. This review provides a summary of the epidemiological features, risk factors and various prevention strategies proposed for CRC in IBD patients. Moreover, there is a special focus on reporting and highlighting the various prevention strategies proposed by the most important international scientific societies, both in terms of chemoprevention and endoscopic surveillance. Indeed, in conducting the analysis, we have given attention to the current primary, secondary and tertiary prevention guidelines, attempting to emphasize unresolved research and clinical problems related to this topic in order to improve diagnostic strategies and management.
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Affiliation(s)
- Elisa Marabotto
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy
| | - Stefano Kayali
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy
- Correspondence:
| | - Silvia Buccilli
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy
| | - Francesca Levo
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy
| | - Giorgia Bodini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy
| | - Vincenzo Savarino
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35137 Padua, Italy
- Gastroenterology Unit, Azienda Ospedale Università di Padova, 35128 Padua, Italy
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29
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Duszka K. Versatile Triad Alliance: Bile Acid, Taurine and Microbiota. Cells 2022; 11:2337. [PMID: 35954180 PMCID: PMC9367564 DOI: 10.3390/cells11152337] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/21/2022] [Accepted: 07/24/2022] [Indexed: 11/21/2022] Open
Abstract
Taurine is the most abundant free amino acid in the body, and is mainly derived from the diet, but can also be produced endogenously from cysteine. It plays multiple essential roles in the body, including development, energy production, osmoregulation, prevention of oxidative stress, and inflammation. Taurine is also crucial as a molecule used to conjugate bile acids (BAs). In the gastrointestinal tract, BAs deconjugation by enteric bacteria results in high levels of unconjugated BAs and free taurine. Depending on conjugation status and other bacterial modifications, BAs constitute a pool of related but highly diverse molecules, each with different properties concerning solubility and toxicity, capacity to activate or inhibit receptors of BAs, and direct and indirect impact on microbiota and the host, whereas free taurine has a largely protective impact on the host, serves as a source of energy for microbiota, regulates bacterial colonization and defends from pathogens. Several remarkable examples of the interaction between taurine and gut microbiota have recently been described. This review will introduce the necessary background information and lay out the latest discoveries in the interaction of the co-reliant triad of BAs, taurine, and microbiota.
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Affiliation(s)
- Kalina Duszka
- Department of Nutritional Sciences, University of Vienna, 1090 Vienna, Austria
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30
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Hitch TCA, Hall LJ, Walsh SK, Leventhal GE, Slack E, de Wouters T, Walter J, Clavel T. Microbiome-based interventions to modulate gut ecology and the immune system. Mucosal Immunol 2022; 15:1095-1113. [PMID: 36180583 PMCID: PMC9705255 DOI: 10.1038/s41385-022-00564-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/12/2022] [Accepted: 08/22/2022] [Indexed: 02/04/2023]
Abstract
The gut microbiome lies at the intersection between the environment and the host, with the ability to modify host responses to disease-relevant exposures and stimuli. This is evident in how enteric microbes interact with the immune system, e.g., supporting immune maturation in early life, affecting drug efficacy via modulation of immune responses, or influencing development of immune cell populations and their mediators. Many factors modulate gut ecosystem dynamics during daily life and we are just beginning to realise the therapeutic and prophylactic potential of microbiome-based interventions. These approaches vary in application, goal, and mechanisms of action. Some modify the entire community, such as nutritional approaches or faecal microbiota transplantation, while others, such as phage therapy, probiotics, and prebiotics, target specific taxa or strains. In this review, we assessed the experimental evidence for microbiome-based interventions, with a particular focus on their clinical relevance, ecological effects, and modulation of the immune system.
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Affiliation(s)
- Thomas C A Hitch
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany
| | - Lindsay J Hall
- Gut Microbes & Health, Quadram Institute Biosciences, Norwich, UK
- Intestinal Microbiome, School of Life Sciences, ZIEL-Institute for Food & Health, Technical University of Munich, Freising, Germany
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Sarah Kate Walsh
- School of Food and Nutritional Sciences, University College Cork, Cork, Ireland
- APC Microbiome Ireland, School of Microbiology and Department of Medicine, University College Cork, Cork, Ireland
| | | | - Emma Slack
- Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland
| | | | - Jens Walter
- APC Microbiome Ireland, School of Microbiology and Department of Medicine, University College Cork, Cork, Ireland
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany.
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31
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Shah SC, Itzkowitz SH. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. Gastroenterology 2022; 162:715-730.e3. [PMID: 34757143 PMCID: PMC9003896 DOI: 10.1053/j.gastro.2021.10.035] [Citation(s) in RCA: 394] [Impact Index Per Article: 131.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/14/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022]
Abstract
Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC), despite decreases in CRC incidence in recent years. Chronic inflammation is the driver of neoplastic progression, resulting in dysplastic precursor lesions that may arise in multiple areas of the colon through a process of field cancerization. Colitis-associated CRC shares many molecular similarities with sporadic CRC, and preclinical investigations have demonstrated a potential role for the microbiome in concert with the host immune system in the development of colitis-associated colorectal cancer (CAC). Some unique molecular differences occur in CAC, but their role in the pathogenesis and behavior of inflammation-associated cancers remains to be elucidated. Nonconventional types of dysplasia have been increasingly recognized, but their natural history is not well defined, and they have not been incorporated into surveillance algorithms. The concept of cumulative inflammatory burden highlights the importance of considering histologic inflammation over time as an important risk factor for CAC. Dysplasia is arguably the most important risk factor for developing CAC, and advances have been made in the endoscopic detection and removal of precancerous lesions, thereby deferring or avoiding surgical resection. Some of the agents used to treat IBD are chemopreventive. It is hoped that by gaining better control of the underlying inflammation with newer medications and better endoscopic detection and management, a more sophisticated appreciation of clinicopathologic risk factors, and growing awareness of the genetic, immunologic, and environmental causes of colitis- associated neoplasia, that colitis-associated colorectal neoplasia will become even more predictable and manageable in the coming years.
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Affiliation(s)
- Shailja C Shah
- Division of Gastroenterology, University of California San Diego, San Diego, California; GI Section, VA San Diego Healthcare Center, San Diego, California
| | - Steven H Itzkowitz
- The Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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32
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Abstract
PURPOSE OF REVIEW Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related deaths. Of the various established risk factors for this aggressive condition, diet is a notable modifiable risk factor. This review aims to summarize the mounting evidence to suggest the role of diet, the microbiota and their cross-talk in modulating an individual's risk of developing CRC. RECENT FINDINGS Specifically, the metabolism of bile acids and its symbiosis with the microbiota has gained weight given its basis on a high meat, high fat, and low fibre diet that is present in populations with the highest risk of CRC. Bacteria modify bile acids that escape enterohepatic circulation to increase the diversity of the human bile acid pool. The production of microbial bile acids contributes to this as well. Epidemiological studies have shown that changing the diet results in different levels and composition of bile acids, which has in turn modified the risk of CRC at a population level. Evidence to identify underlying mechanisms have tied into the microbiota-led digestions of various foods into fatty acids that feedback into bile acid physiology as well as modulation of endogenous receptors for bile acids. SUMMARY There is adequate evidence to support the role of microbiota in in the metabolism of bile acids, and how this relates to colorectal cancer. Further work is necessary to identify specific bacteriome involved and their underlying mechanistic pathways.
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33
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Abstract
Most patients with colorectal cancer (CRC) were diagnosed in advanced stage and the prognosis is poor. Therefore, early detection and prevention of CRC are very important. As with other cancers, there is also the tertiary prevention for CRC. The primary prevention is etiological prevention, which is mainly the treatment of adenoma or inflammation for preventing the development into cancer. The secondary prevention is the early diagnosis and early treatment for avoiding progressing to advanced cancer. The tertiary prevention belongs to the broad category of prevention, mainly for advanced CRC, through surgical treatment and postoperative adjuvant chemotherapy, radiotherapy, targeted therapy, immunotherapy for preventing tumor recurrence or metastasis. This consensus is based on the recent domestic and international consensus guidelines and the latest progress of international researches in the past five years. This consensus opinion seminar was hosted by the Chinese Society of Gastroenterology and Cancer Collaboration Group of Chinese Society of Gastroenterology, and was organized by the Division of Gastroenterology and Hepatology & Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University. The consensus opinion contains 60 statement clauses, the standard and basis of the evidence-based medicine grade and voting grade of the statement strictly complied with the relevant international regulations and practice.
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34
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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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35
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Fang Y, Yan C, Zhao Q, Xu J, Liu Z, Gao J, Zhu H, Dai Z, Wang D, Tang D. The roles of microbial products in the development of colorectal cancer: a review. Bioengineered 2021; 12:720-735. [PMID: 33618627 PMCID: PMC8806273 DOI: 10.1080/21655979.2021.1889109] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
A large number of microbes exist in the gut and they have the ability to process and utilize ingested food. It has been reported that their products are involved in colorectal cancer development. The molecular mechanisms which underlie the relationship between gut microbial products and CRC are still not fully understood. The role of some microbial products in CRC is particularly controversial. Elucidating the effects of gut microbiota products on CRC and their possible mechanisms is vital for CRC prevention and treatment. In this review, recent studies are examined in order to describe the contribution metabolites and toxicants which are produced by gut microbes make to CRC, primarily focusing on the involved molecular mechanisms.Abbreviations: CRC: colorectal cancer; SCFAs: short chain fatty acids; HDAC: histone deacetylase; TCA cycle: tricarboxylic acid cycle; CoA: cytosolic acyl coenzyme A; SCAD: short chain acyl CoA dehydrogenase; HDAC: histone deacetylase; MiR-92a: microRNA-92a; KLF4: kruppel-like factor; PTEN: phosphatase and tensin homolog; PI3K: phosphoinositide 3-kinase; PIP2: phosphatidylinositol 4, 5-biphosphate; PIP3: phosphatidylinositol-3,4,5-triphosphate; Akt1: protein kinase B subtype α; ERK1/2: extracellular signal-regulated kinases 1/2; EMT: epithelial-to-mesenchymal transition; NEDD9: neural precursor cell expressed developmentally down-regulated9; CAS: Crk-associated substrate; JNK: c-Jun N-terminal kinase; PRMT1: protein arginine methyltransferase 1; UDCA: ursodeoxycholic acid; BA: bile acids; CA: cholic acid; CDCA: chenodeoxycholic acid; DCA: deoxycholic acid; LCA: lithocholic acid; CSCs: cancer stem cells; MHC: major histocompatibility; NF-κB: NF-kappaB; GPR: G protein-coupled receptors; ROS: reactive oxygen species; RNS: reactive nitrogen substances; BER: base excision repair; DNA: deoxyribonucleic acid; EGFR: epidermal growth factor receptor; MAPK: mitogen activated protein kinase; ERKs: extracellular signal regulated kinases; AKT: protein kinase B; PA: phosphatidic acid; TMAO: trimethylamine n-oxide; TMA: trimethylamine; FMO3: flavin-containing monooxygenase 3; H2S: Hydrogen sulfide; SRB: sulfate-reducing bacteria; IBDs: inflammatory bowel diseases; NSAID: non-steroidal anti-inflammatory drugs; BFT: fragile bacteroides toxin; ETBF: enterotoxigenic fragile bacteroides; E-cadherin: extracellular domain of intercellular adhesive protein; CEC: colonic epithelial cells; SMOX: spermine oxidase; SMO: smoothened; Stat3: signal transducer and activator of transcription 3; Th17: T helper cell 17; IL17: interleukin 17; AA: amino acid; TCF: transcription factor; CDT: cytolethal distending toxin; PD-L1: programmed cell death 1 ligand 1.
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Affiliation(s)
- Yongkun Fang
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Cheng Yan
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Qi Zhao
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Jiaming Xu
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Zhuangzhuang Liu
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Jin Gao
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Hanjian Zhu
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Zhujiang Dai
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
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Zhang W, An Y, Qin X, Wu X, Wang X, Hou H, Song X, Liu T, Wang B, Huang X, Cao H. Gut Microbiota-Derived Metabolites in Colorectal Cancer: The Bad and the Challenges. Front Oncol 2021; 11:739648. [PMID: 34733783 PMCID: PMC8558397 DOI: 10.3389/fonc.2021.739648] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence from studies in humans and animal models has elucidated that gut microbiota, acting as a complex ecosystem, contributes critically to colorectal cancer (CRC). The potential mechanisms often reported emphasize the vital role of carcinogenic activities of specific pathogens, but in fact, a series of metabolites produced from exogenous dietary substrates or endogenous host compounds occupy a decisive position similarly. Detrimental gut microbiota-derived metabolites such as trimethylamine-N-oxide, secondary bile acids, hydrogen sulfide and N-nitroso compounds could reconstruct the ecological composition and metabolic activity of intestinal microorganisms and formulate a microenvironment that opens susceptibility to carcinogenic stimuli. They are implicated in the occurrence, progression and metastasis of CRC through different mechanisms, including inducing inflammation and DNA damage, activating tumorigenic signaling pathways and regulating tumor immunity. In this review, we mainly summarized the intimate relationship between detrimental gut microbiota-derived metabolites and CRC, and updated the current knowledge about detrimental metabolites in CRC pathogenesis. Then, multiple interventions targeting these metabolites for CRC management were critically reviewed, including diet modulation, probiotics/prebiotics, fecal microbiota transplantation, as well as more precise measures such as engineered bacteria, phage therapy and chemopreventive drugs. A better understanding of the interplay between detrimental microbial metabolites and CRC would hold great promise against CRC.
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Affiliation(s)
- Wanru Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yaping An
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xiali Qin
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xuemei Wu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xinyu Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Huiqin Hou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xueli Song
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xuan Huang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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Sönmezgöz E, Takci S, Gül A, Uysal M. Ursodeoxycholic acid protects neonatal rats from necrotizing enterocolitis: a biochemical, histopathological, and immunohistochemical study. J Matern Fetal Neonatal Med 2021; 34:3761-3767. [PMID: 32954879 DOI: 10.1080/14767058.2020.1818210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 08/13/2020] [Accepted: 08/30/2020] [Indexed: 01/28/2023]
Abstract
BACKGROUND The pathophysiology of necrotizing enterocolitis (NEC) includes the massive production of endogenous cytokines with exaggerated activation of inflammatory pathways. Ursodeoxycholic acid (UDCA) has been used as an anti-inflammatory, antioxidant, and anti-apoptotic agent. We investigated the possible protective effects of UDCA in a neonatal rat pup model of NEC. METHODS We randomly divided rat pups into three groups: a control group, a non-treated NEC group, and a UDCA-treated NEC group. We induced NEC by feeding formula enterally and via hypoxia/reoxygenation. Intestinal samples were collected for histopathological and immunohistochemical evaluation. Blood samples were taken for biochemical analyses. RESULTS UDCA significantly reduced the extents of terminal ileal and jejunal injuries compared to the NEC group (p < .01), reduced Bax and caspase-3 immunoreactivities (both p < .01), and lowered serum levels of platelet-activating factor and intestinal fatty acid-binding protein (p < .01, p = .023, respectively). CONCLUSIONS In a rat model of NEC, UDCA protects against adverse intestinal histological, immunohistochemical, and biochemical changes. UDCA significantly reduces the effects of NEC on the rat pup intestine.
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Affiliation(s)
- Ergün Sönmezgöz
- Department of Pediatrics, Gaziosmanpasa Universitesi, Tokat, Turkey
| | - Sahin Takci
- Department of Neonatology, Gaziosmanpasa Universitesi, Tokat, Turkey
| | - Ali Gül
- Department of Pediatrics, Gaziosmanpasa Universitesi, Tokat, Turkey
| | - Murat Uysal
- Department of Anatomy, Gaziosmanpasa Universitesi, Tokat, Turkey
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Wijnands AM, Mahmoud R, Lutgens MWMD, Oldenburg B. Surveillance and management of colorectal dysplasia and cancer in inflammatory bowel disease: Current practice and future perspectives. Eur J Intern Med 2021; 93:35-41. [PMID: 34481721 DOI: 10.1016/j.ejim.2021.08.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 12/30/2022]
Abstract
Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). Current guidelines recommend frequent surveillance colonoscopies for patients with at least left-sided ulcerative colitis, or Crohn's disease involving more than 30% of the colon. Surveillance allows for early detection and treatment of colorectal dysplasia and cancer. The first colonoscopy should be performed 8 to 10 years after onset of disease symptoms. European and British guidelines employ a risk-stratification algorithm that assigns patients to surveillance intervals of one, three or five years, whereas American guidelines recommend to perform surveillance every 1 to 3 years based on the (combined) presence of risk factors. Patients with concomitant primary sclerosing cholangitis are at an additionally increased risk, and should undergo annual surveillance starting immediately after the diagnosis. The current practice of surveillance is based on limited evidence, is resource intensive and cannot preclude the occurrence of interval carcinomas. Fortunately, advances in endoscopic techniques for mucosal visualisation, along with better control of inflammation, have resulted in a declining incidence of CRC in patients with IBD. Furthermore, advanced endoscopic resection techniques can be expected to result in a shift from surgical to endoscopic management of dysplastic lesions. In this review, we provide an up-to-date overview of colitis-associated CRC pathophysiology, epidemiology, surveillance practices, and management of dysplasia.
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Affiliation(s)
- Anouk M Wijnands
- Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Remi Mahmoud
- Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Maurice W M D Lutgens
- Department of Gastroenterology and Hepatology, Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands
| | - Bas Oldenburg
- Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands.
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Yang M, Gu Y, Li L, Liu T, Song X, Sun Y, Cao X, Wang B, Jiang K, Cao H. Bile Acid-Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside. Nutrients 2021; 13:nu13093143. [PMID: 34579027 PMCID: PMC8467364 DOI: 10.3390/nu13093143] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract, with increasing prevalence, and its pathogenesis remains unclear. Accumulating evidence suggested that gut microbiota and bile acids play pivotal roles in intestinal homeostasis and inflammation. Patients with IBD exhibit decreased microbial diversity and abnormal microbial composition marked by the depletion of phylum Firmicutes (including bacteria involved in bile acid metabolism) and the enrichment of phylum Proteobacteria. Dysbiosis leads to blocked bile acid transformation. Thus, the concentration of primary and conjugated bile acids is elevated at the expense of secondary bile acids in IBD. In turn, bile acids could modulate the microbial community. Gut dysbiosis and disturbed bile acids impair the gut barrier and immunity. Several therapies, such as diets, probiotics, prebiotics, engineered bacteria, fecal microbiota transplantation and ursodeoxycholic acid, may alleviate IBD by restoring gut microbiota and bile acids. Thus, the bile acid–gut microbiota axis is closely connected with IBD pathogenesis. Regulation of this axis may be a novel option for treating IBD.
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Affiliation(s)
- Min Yang
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
| | - Yu Gu
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
| | - Lingfeng Li
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
| | - Xueli Song
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
| | - Yue Sun
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
| | - Xiaocang Cao
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
| | - Kui Jiang
- Graduate School of Tianjin Medical University, Tianjin 300070, China
- Correspondence: (K.J.); (H.C.)
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; (M.Y.); (Y.G.); (L.L.); (T.L.); (X.S.); (Y.S.); (X.C.); (B.W.)
- Correspondence: (K.J.); (H.C.)
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Orozco-Aguilar J, Simon F, Cabello-Verrugio C. Redox-Dependent Effects in the Physiopathological Role of Bile Acids. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4847941. [PMID: 34527174 PMCID: PMC8437588 DOI: 10.1155/2021/4847941] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/17/2021] [Indexed: 12/17/2022]
Abstract
Bile acids (BA) are recognized by their role in nutrient absorption. However, there is growing evidence that BA also have endocrine and metabolic functions. Besides, the steroidal-derived structure gives BA a toxic potential over the biological membrane. Thus, cholestatic disorders, characterized by elevated BA on the liver and serum, are a significant cause of liver transplant and extrahepatic complications, such as skeletal muscle, central nervous system (CNS), heart, and placenta. Further, the BA have an essential role in cellular damage, mediating processes such as membrane disruption, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS) and oxidative stress. The purpose of this review is to describe the BA and their role on hepatic and extrahepatic complications in cholestatic diseases, focusing on the association between BA and the generation of oxidative stress that mediates tissue damage.
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Affiliation(s)
- Josué Orozco-Aguilar
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
| | - Felipe Simon
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8370146, Chile
- Laboratory of Integrative Physiopathology, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
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Zhang H, Xu H, Zhang C, Tang Q, Bi F. Ursodeoxycholic acid suppresses the malignant progression of colorectal cancer through TGR5-YAP axis. Cell Death Discov 2021; 7:207. [PMID: 34365464 PMCID: PMC8349355 DOI: 10.1038/s41420-021-00589-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/20/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023] Open
Abstract
The Hippo/YAP pathway plays an important role in the development of cancers. Previous studies have reported that bile acids can activate YAP (Yes Associated Protein) to promote tumorigenesis and tumor progression. Ursodeoxycholic acid (UDCA) is a long-established old drug used for cholestasis treatment. So far, the effect of UDCA on YAP signaling in colorectal cancer (CRC) is not well defined. This study means to explore relationship of UDCA and YAP in CRC. UDCA suppressed YAP signaling by activating the membrane G-protein-coupled bile acid receptor (TGR5). TGR5 mainly regulated cAMP/PKA signaling pathway to inhibit RhoA activity, thereby suppressing YAP signaling. Moreover, the restoration of YAP expression alleviated the inhibitory effect of UDCA on CRC cell proliferation. In AOM/DSS-induced CRC model, UDCA inhibited tumor growth in a concentration-dependent manner and decreased expression of YAP and Ki67. UDCA plays a distinguished role in regulating YAP signaling and CRC growth from the primary bile acids and partial secondary bile acids, demonstrating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. It also presents a potential therapeutic intervention for CRC.
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Affiliation(s)
- Huan Zhang
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Huanji Xu
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Chenliang Zhang
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qiulin Tang
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Feng Bi
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Leung KK, Deeb M, Fischer SE, Gulamhusein A. Recurrent Primary Sclerosing Cholangitis: Current Understanding, Management, and Future Directions. Semin Liver Dis 2021; 41:409-420. [PMID: 34182588 DOI: 10.1055/s-0041-1730950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Patients with primary sclerosing cholangitis (PSC) constitute 5 to 15% of patients listed for liver transplantation worldwide. Although post-transplant outcomes are favorable, recurrent PSC (rPSC) occurs in an important subset of patients, with higher prevalence rates reported with increasing time from transplant. Given its association with poor graft outcomes and risk of retransplant, effort has been made to understand rPSC, its pathophysiology, and risk factors. This review covers these facets of rPSC and focuses on implicated risk factors including pretransplant recipient characteristics, inflammatory bowel-disease-related factors, and donor-specific and transplant-specific factors. Confirming a diagnosis of rPSC requires thoughtful consideration of alternative etiologies so as to ensure confidence in diagnosis, management, subsequent risk assessment, and counseling for patients. Unfortunately, no cure exists for rPSC; however, future large-scale efforts are underway to better characterize the natural history of rPSC and its associated risk factors with hopes of identifying potential key targets for novel therapies.
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Affiliation(s)
- Kristel K Leung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Maya Deeb
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sandra E Fischer
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada
| | - Aliya Gulamhusein
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
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Mawardi M, Alalwan A, Fallatah H, Abaalkhail F, Hasosah M, Shagrani M, Alghamdi MY, Alghamdi AS. Cholestatic liver disease: Practice guidelines from the Saudi Association for the Study of Liver diseases and Transplantation. Saudi J Gastroenterol 2021; 27:S1-S26. [PMCID: PMC8411950 DOI: 10.4103/sjg.sjg_112_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/26/2021] [Accepted: 05/16/2021] [Indexed: 11/04/2022] Open
Abstract
Cholestatic liver diseases (CLDs) are a group of diseases characterized by jaundice and cholestasis as the main presentation with different complications, which have considerable impact on the liver and can lead to end-stage liver disease, cirrhosis, and liver-related complications. In the last few years, tremendous progress has been made in understanding the pathophysiology, diagnosis, and treatment of patients with these conditions. However, several aspects related to the management of CLDs remain deficient and unclear. Due to the lack of recommendations that can help in the management, treatment of those conditions, the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) has created a task force group to develop guidelines related to CLDs management in order to provide a standard of care for patients in need. These guidelines provide general guidance for health care professionals to optimize medical care for patients with CLDs for both adult and pediatric populations, in association with clinical judgments to be considered on a case-by-case basis. These guidelines describe common CLDs in Saudi Arabia, with recommendations on the best approach for diagnosis and management of different diseases based on the Grading of Recommendation Assessment (GRADE), combined with a level of evidence available in the literature.
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Affiliation(s)
- Mohammad Mawardi
- Department of Medicine, Gastroenterology Section, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
| | - Abduljaleel Alalwan
- Department of Hepatobiliary Sciences and Liver Transplantation, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Hind Fallatah
- Department of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Faisal Abaalkhail
- Department of Medicine, Gastroenterology Section, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Hasosah
- Department of Pediatrics, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Mohammad Shagrani
- Department of Liver and Small Bowel Transplantation, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Y Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahd Military Complex, Dhahran, Saudi Arabia
| | - Abdullah S Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahad General Hospital, Jeddah, Saudi Arabia
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Guzior DV, Quinn RA. Review: microbial transformations of human bile acids. MICROBIOME 2021; 9:140. [PMID: 34127070 PMCID: PMC8204491 DOI: 10.1186/s40168-021-01101-1] [Citation(s) in RCA: 399] [Impact Index Per Article: 99.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 05/24/2021] [Indexed: 05/05/2023]
Abstract
Bile acids play key roles in gut metabolism, cell signaling, and microbiome composition. While the liver is responsible for the production of primary bile acids, microbes in the gut modify these compounds into myriad forms that greatly increase their diversity and biological function. Since the early 1960s, microbes have been known to transform human bile acids in four distinct ways: deconjugation of the amino acids glycine or taurine, and dehydroxylation, dehydrogenation, and epimerization of the cholesterol core. Alterations in the chemistry of these secondary bile acids have been linked to several diseases, such as cirrhosis, inflammatory bowel disease, and cancer. In addition to the previously known transformations, a recent study has shown that members of our gut microbiota are also able to conjugate amino acids to bile acids, representing a new set of "microbially conjugated bile acids." This new finding greatly influences the diversity of bile acids in the mammalian gut, but the effects on host physiology and microbial dynamics are mostly unknown. This review focuses on recent discoveries investigating microbial mechanisms of human bile acids and explores the chemical diversity that may exist in bile acid structures in light of the new discovery of microbial conjugations. Video Abstract.
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Affiliation(s)
- Douglas V. Guzior
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824 USA
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 USA
| | - Robert A. Quinn
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 USA
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45
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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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46
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Rabbenou W, Ullman TA. Risk of Colon Cancer and Recommended Surveillance Strategies in Patients with Ulcerative Colitis. Gastroenterol Clin North Am 2020; 49:791-807. [PMID: 33121696 DOI: 10.1016/j.gtc.2020.08.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Longstanding and extensive ulcerative colitis (UC) are associated with the subsequent development of colorectal cancer (CRC). This article summarizes key strategies for colonoscopic surveillance, the most widely used and evidence-based method of CRC prevention. As currently constituted and practiced, surveillance examinations every 1 to 3 years with lesion detection and removal using high-definition endoscopic systems with or without pancolonic spray-dye chromoendoscopy is the best method for mitigating the development of CRC morbidity and mortality. For patients with primary sclerosing cholangitis with UC, surveillance should begin at the time of diagnosis and colonoscopy should be performed annually.
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Affiliation(s)
- Wendy Rabbenou
- Division of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine, 33030 Rochambeau Avenue, Bronx, NY 10461, USA
| | - Thomas A Ullman
- Division of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine, 33030 Rochambeau Avenue, Bronx, NY 10461, USA.
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47
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Culver EL, Bungay HK, Betts M, Forde C, Buchel O, Manganis C, Warren BF, Cummings FR, Keshav S, Travis SPL, Chapman RW. Prevalence and long-term outcome of sub-clinical primary sclerosing cholangitis in patients with ulcerative colitis. Liver Int 2020; 40:2744-2757. [PMID: 32841490 DOI: 10.1111/liv.14645] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 07/22/2020] [Accepted: 08/12/2020] [Indexed: 02/13/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is closely associated with inflammatory bowel disease, particularly ulcerative colitis (UC), with an increased risk of biliary and colorectal malignancy. We sought to clarify the prevalence, characteristics and long-term outcome of sub-clinical PSC diagnosed by magnetic resonance cholangiogram (MRC) in patients with UC and normal liver biochemistry, with or without colorectal dysplasia (CRD). METHODS In this prospective case-control study, 70 patients with UC and normal liver function (51 extensive UC, 19 CRD), 28 healthy volunteers (negative controls) and 28 patients with PSC and cholestasis (positive controls) underwent MRC and blood evaluation. MRC scans were interpreted blindly by two radiologists who graded individually, the scans as definitive for PSC, possible for PSC or normal. Clinical outcome was assessed by blood monitoring, abdominal imaging and endoscopic surveillance. RESULTS 7/51 (14%) with extensive UC and 4/19 (21%) with CRD had biliary abnormalities on MRC consistent with PSC. 7/11 (64%) with sub-clinical PSC had isolated intrahepatic duct involvement. Sub-clinical PSC was associated with advanced age (P = .04), non-smoking (P = .03), pANCA (P = .04), quiescent colitis (P = .02), absence of azathioprine (P = .04) and high-grade CRD (P = .03). Inter-observer (kappa = 0.88) and intra-observer (kappa = 0.96) agreement for MRC interpretation was high. No negative controls were assessed as definite PSC, 4/28 were considered on blinding as possible PSC. During follow-up of sub-clinical PSC (median 10.1(3.1-11.9) years), four patients developed abnormal liver biochemistry, two had radiological progression of PSC and seven developed malignancy, including two biliary and one colorectal carcinoma. CONCLUSIONS Prevalence of sub-clinical PSC appears high in patients with extensive UC and normal liver biochemistry, with or without CRD. Disease progression and malignancy were identified on long-term follow-up. MRC should be considered for all patients with extensive UC or CRD to stratify surveillance.
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Affiliation(s)
- Emma L Culver
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Helen K Bungay
- Radiology Department, John Radcliffe Hospital and Churchill Hospital, Oxford, UK
| | - Margaret Betts
- Radiology Department, John Radcliffe Hospital and Churchill Hospital, Oxford, UK
| | - Colm Forde
- Radiology Department, John Radcliffe Hospital and Churchill Hospital, Oxford, UK.,Radiology Department, Queen Elizabeth Hospital, Birmingham, UK
| | - Otto Buchel
- Rondebosch Medical Centre, Cape Town, South Africa
| | - Charis Manganis
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Bryan F Warren
- Histopathology Department, John Radcliffe Hospital, Oxford, UK
| | - Fraser R Cummings
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Gastroenterology Department, Southampton General Hospital, Southampton, UK
| | - Satish Keshav
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Simon P L Travis
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Roger W Chapman
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
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48
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Guillo L, D'Amico F, Serrero M, Angioi K, Loeuille D, Costanzo A, Danese S, Peyrin-Biroulet L. Assessment of extraintestinal manifestations in inflammatory bowel diseases: A systematic review and a proposed guide for clinical trials. United European Gastroenterol J 2020; 8:1013-1030. [PMID: 32778004 DOI: 10.1177/2050640620950093] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND AIMS Extraintestinal manifestations are common in inflammatory bowel disease patients, although there are few data available on their diagnosis, management and follow-up. We systematically reviewed the literature evidence to evaluate tools and investigations used for the diagnosis and for the assessment of the treatment response in inflammatory bowel disease patients with extraintestinal manifestations. METHODS We searched in PubMed, Embase and Web of Science from January 1999-December 2019 for all interventional and non-interventional studies published in English assessing diagnostic tools and investigations used in inflammatory bowel disease patients with extraintestinal manifestations. RESULTS Forty-five studies (16 interventional and 29 non-interventional) were included in our systematic review, enrolling 7994 inflammatory bowel disease patients. The diagnostic assessment of extraintestinal manifestations was performed by dedicated specialists in a percentage of cases ranging from 60-100% depending on the specific condition. The clinical examination was the most frequent diagnostic strategy, accounting for 35 studies (77.8%). In patients with primary sclerosing cholangitis or rheumatological symptoms, biochemical and imaging tests were also performed. Anti-TNF agents were the most used biological drugs for the treatment of extraintestinal manifestations (20 studies, 44.4%), and the treatment response varied from 59.1% in axial spondyloarthritis to 88.9% in ocular manifestations. No benefit was detected in primary sclerosing cholangitis patients after treatment with biologics. CONCLUSIONS In the clinical management of inflammatory bowel disease patients with extraintestinal manifestations the collaboration of dedicated specialists for diagnostic investigations and follow-up is key to ensure the best of care approach. However, international guidelines are needed to homogenise and standardise the assessment of extraintestinal manifestations.
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Affiliation(s)
- Lucas Guillo
- Department of Gastroenterology, University Hospital of Marseille Nord, University of Aix-Marseille, Marseille, France
| | - Ferdinando D'Amico
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Mélanie Serrero
- Department of Gastroenterology, University Hospital of Marseille Nord, University of Aix-Marseille, Marseille, France
| | - Karine Angioi
- Department of Ophthalmology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
| | - Damien Loeuille
- Ingénierie Moléculaire et Ingénierie Articulaire (IMoPA), UMR-7365 CNRS, University of Lorraine and University Hospital of Nancy, Nancy, France
| | - Antonio Costanzo
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Dermatology, Humanitas Clinical and Research Center - IRCCS, Milan, Italy
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Department of Gastroenterology, Humanitas Clinical and Research Center - IRCCS, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
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Abstract
Cholangiocarcinoma is a highly lethal biliary epithelial tumor that is rare in the general population but has increased rates in patients with primary sclerosing cholangitis (PSC). It is heterogenous, and management varies by location. No effective prevention exists, and screening is likely only feasible in PSC. Patients often present in an advanced state with jaundice, weight loss, and cholestatic liver enzymes. Diagnosis requires imaging with magnetic resonance cholangiopancreatography, laboratory testing, and endoscopic retrograde cholangiopancreatography. Potentially curative options include resection and liver transplant with neoadjuvant or adjuvant chemoradiation. Chemotherapy, radiation, and locoregional therapy provide some survival benefit in unresectable disease.
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Affiliation(s)
- Adam P Buckholz
- Division of Gastroenterology and Hepatology, NewYork-Presbyterian/Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, NewYork-Presbyterian/Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA.
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50
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Diesinger T, Buko V, Lautwein A, Dvorsky R, Belonovskaya E, Lukivskaya O, Naruta E, Kirko S, Andreev V, Buckert D, Bergler S, Renz C, Schneider E, Kuchenbauer F, Kumar M, Günes C, Büchele B, Simmet T, Müller-Enoch D, Wirth T, Haehner T. Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis. PLoS One 2020; 15:e0235990. [PMID: 32701948 PMCID: PMC7377376 DOI: 10.1371/journal.pone.0235990] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 06/25/2020] [Indexed: 02/07/2023] Open
Abstract
Background and aims Alcoholic steatohepatitis (ASH)—the inflammation of fatty liver—is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation—the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH. Methods In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies. Results A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol. Conclusions Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH.
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Affiliation(s)
- Torsten Diesinger
- Donauklinik Neu-Ulm, Abteilung für Innere Medizin, Neu-Ulm, Germany
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
- Department of Internal Medicine, Neu-Ulm Hospital, Neu-Ulm, Germany
- * E-mail:
| | - Vyacheslav Buko
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
- Department of Biotechnology, University of Medical Sciences, Bialystok, Poland
| | - Alfred Lautwein
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Radovan Dvorsky
- Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
- Max Planck Institute of Molecular Physiology, Dortmund, Germany
| | - Elena Belonovskaya
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
| | - Oksana Lukivskaya
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
| | - Elena Naruta
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
| | - Siarhei Kirko
- Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Substances, Grodno, Belarus
| | - Viktor Andreev
- Department of Medical Biology and Genetics, Grodno State Medical University, Grodno, Belarus
| | - Dominik Buckert
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
- Department of Internal Medicine II, University Hospital Ulm, Ulm, Germany
| | | | - Christian Renz
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Edith Schneider
- Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
| | - Florian Kuchenbauer
- Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
- University of British Columbia, Terry Fox Laboratory, Vancouver, Canada
| | - Mukesh Kumar
- Department of Urology, University Hospital Ulm, Ulm, Germany
| | - Cagatay Günes
- Department of Urology, University Hospital Ulm, Ulm, Germany
| | - Berthold Büchele
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Ulm, Germany
| | - Thomas Simmet
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Ulm, Germany
| | | | - Thomas Wirth
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Thomas Haehner
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
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