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Tatscher E, Mady S, Fickert P. Emerging Targets for the Treatment of Primary Sclerosing Cholangitis. Semin Liver Dis 2025. [PMID: 40418973 DOI: 10.1055/a-2601-9426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/28/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a rare, progressive cholestatic disease of unknown etiology and characterized by inflammation and stricturing of intrahepatic and/or extrahepatic bile ducts. This process leads to bile duct scarring, progressive liver fibrosis, and end-stage liver disease. PSC is often associated with a specific form of inflammatory bowel disease and patients face a significant risk of developing cholangiocarcinoma and colorectal cancer. The clinical course of PSC can differ significantly between subtypes and affected individuals, representing a major obstacle to successful medical treatment trials. Numerous innovative therapeutic targets have been identified and, at least in part, explored, including nuclear and membrane receptors regulating bile acid metabolism and transport, modulation of gut microbiota, and signaling molecules involved in liver inflammation and fibrosis. Successful drug testing in preclinical PSC models as well as positive signals from some clinical studies justify hope. However, no medical treatment has so far been proven to improve transplant-free survival or overall survival in PSC patients. Disease-modifying drugs are urgently awaited. Despite ongoing efforts to improve study designs and implement treatment trials for novel drug targets, a central breakthrough has not yet been convincingly achieved. This situation might change in the near future. This article summarizes current research efforts aimed at developing medical treatments for PSC.
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Affiliation(s)
- Elisabeth Tatscher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Samy Mady
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Özdirik B, Berger H, Tonetti FR, Cabré N, Treichel N, Clavel T, Tacke F, Sigal M, Schnabl B. Faecal Cytolysin is Associated With Worse Survival in Patients With Primary Sclerosing Cholangitis. Liver Int 2025; 45:e16181. [PMID: 40083245 DOI: 10.1111/liv.16181] [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: 08/18/2024] [Revised: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 03/16/2025]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy without treatment options beyond liver transplantation. The gut-liver axis, especially the role of gut microbes, has emerged as a crucial pathway contributing to PSC pathogenesis. Recent research has revealed Enterococcus (E.) faecalis and its virulence factor cytolysin to increase mortality risk in patients with alcohol-associated hepatitis. Thus, we studied the role of enterococci, particularly E. faecalis and its virulence factor genes cytolysin and gelatinase, in faecal samples from patients with PSC. METHODS To assess the relevance of Enterococcus species, we performed 16S rRNA gene amplicon analysis in faecal samples from 60 patients with PSC. We validated our findings by qPCR of faecal microbial DNA in an extended cohort of 105 patients with PSC, 104 patients with inflammatory bowel disease (IBD) and 68 healthy subjects. RESULTS High-throughput 16S rRNA amplicon analysis revealed an increased relative abundance of enterococci in PSC patients compared with healthy controls and IBD patients, respectively, (p < 0.0001). PSC patients with high enterococci abundance had a decreased probability of transplant-free survival (p = 0.028). E. faecalis and its virulence factors cytolysin and gelatinase were more abundant in patients with PSC. Higher faecal cytolysin was associated with lower overall survival (p = 0.04), while survival was independent of gelatinase levels. CONCLUSION Our data highlight the association of E. faecalis and faecal cytolysin with lower survival in patients with PSC. These data should prompt further research into the pathogenic role of cytolysin-positive E. faecalis, and to explore its role as a potential therapeutic target.
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Affiliation(s)
- Burcin Özdirik
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Hilmar Berger
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fernanda Raya Tonetti
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Noemí Cabré
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Nicole Treichel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
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Grimmler M, Frömel T, Masetto A, Müller H, Leber T, Peter C. Performance evaluation of enzymatic total bile acid (TBA) routine assays: systematic comparison of five fifth-generation TBA cycling methods and their individual bile acid recovery from HPLC-MS/MS reference. Clin Chem Lab Med 2025; 63:753-763. [PMID: 39607980 DOI: 10.1515/cclm-2024-1029] [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: 09/03/2024] [Accepted: 11/15/2024] [Indexed: 11/30/2024]
Abstract
OBJECTIVES Serum total bile acid (TBA) levels are frequently assessed in clinical routine for the early detection of hepatobiliary dysfunction. However, the comparability of current 5th-generation TBA cycle assays based on 3α-hydroxysteroid dehydrogenase (3α-HSD) and their ability to quantify individual bile acids has not been systematically addressed. METHODS Patient serum samples (n=60) across the diagnostically relevant TBA range (1-200 μmol/L) were analyzed using five TBA routine assays from Abbott, DiaSys, Diazyme, Beijing Strong (BSBE) and Randox on the same analyzer (BioMajesty® JCA-BM6010/C). The assays were compared using Passing-Bablok regression and the recovery of 11 individual BAs was evaluated against RP-HPLC-MS/MS as non-enzymatic reference method. RESULTS Despite excellent correlation (Spearman r ≥0.99), the assays showed proportional differences (slope) ranging from 0.99 (BSBE/Randox) to 1.24 (Abbott/DiaSys). The assays showed considerable deviation in the recovery of competitor's calibrators and controls, and large heterogeneity in the recovery of individual BAs, with mean deviations from reference value between 13 % (DiaSys) and 42 % (Abbott). CA and TCA were measured most accurately and consistently, whereas GCA, CDCA, DCA, UDCA, and conjugates were over- or undermeasured to varying degrees. CONCLUSIONS The linear relationship and constant proportional bias between all five routine assays enable the harmonization of TBA measurements up to 60 μmol/L. However, for patient samples with high TBA levels and disease-specific overrepresentation of individual BAs, harmonization will require: i) optimized reaction conditions to equalize substrate specificity, and ii) calibration to a common, commutable reference material with well-defined BA composition instead of internal standards spiked with different BAs.
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Affiliation(s)
- Matthias Grimmler
- Institute for Biomolecular Research, Hochschulen Fresenius gemeinnützige Trägergesellschaft mbH, University of Applied Sciences, Idstein, Germany
- DiaSys Diagnostic Systems GmbH, Holzheim, Germany
| | - Tobias Frömel
- Institute for Analytical Research, Hochschulen Fresenius gemeinnützige Trägergesellschaft mbH, University of Applied Sciences, Idstein, Germany
| | - Angelique Masetto
- Institute for Biomolecular Research, Hochschulen Fresenius gemeinnützige Trägergesellschaft mbH, University of Applied Sciences, Idstein, Germany
- DiaSys Diagnostic Systems GmbH, Holzheim, Germany
| | | | - Tina Leber
- DiaSys Diagnostic Systems GmbH, Holzheim, Germany
| | - Christoph Peter
- Institute of Molecular Medicine I, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Zhou H, Zhou X, Huang G, Zhao Y, Lan P, Chen Z. Inhibition of ferroptosis protects intrahepatic bile duct cells against ischemia-reperfusion and bile salt toxicity. Biochem Pharmacol 2025; 233:116788. [PMID: 39890033 DOI: 10.1016/j.bcp.2025.116788] [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: 09/03/2024] [Revised: 01/21/2025] [Accepted: 01/28/2025] [Indexed: 02/03/2025]
Abstract
Ischemia-reperfusion injury (IRI) and bile salt toxicity are significant contributors to post-transplant cholangiopathy. Ferroptosis appears to play a critical role in intrahepatic bile duct injury induced by ischemia-reperfusion (I/R) and bile salt toxicity. Our study aimed to elucidate the role of ferroptosis in bile duct injuries and its potential as a therapeutic target for liver diseases. Mouse models of liver ischemia-reperfusion (I/R) and α-naphthyl isocyanate (ANIT)-induced liver cholestasis were employed to investigate the role of ferroptosis in intrahepatic bile duct injury in vivo. Hypoxia-reoxygenation (H/R) and bile salt treatment models were utilized to simulate the post-transplant bile duct injury process in vitro. In mouse models of liver I/R and cholestasis, we observed a downregulation of glutathione peroxidase 4 (GPX4) and an upregulation of lipid peroxidation levels in bile duct cells. Furthermore, the ferroptosis inhibitor Liproxstatin-1 (Lip-1) significantly attenuated intrahepatic bile duct injuries. Ferroptosis inhibitors alleviated cell death and lipid peroxide accumulation in human intrahepatic biliary epithelial cells (HiBECs) subjected to H/R or glycochenodeoxycholate (GCDCA) treatment. GCDCA treatment led to ferroptosis in HiBECs along with ferritin degradation. Inhibition of autophagy alleviated GCDCA-induced bile duct cell death. Our study suggested that ferroptosis played an important role of in the intrahepatic bile duct injury during I/R or cholestasis.
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Affiliation(s)
- Huisheng Zhou
- Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China
| | - Xi Zhou
- Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China
| | - Guobin Huang
- Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China
| | - Peixiang Lan
- Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China.
| | - Zhishui Chen
- Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China.
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Singh P, Singh R, Pasricha C, Kumari P. Navigating liver health with metabolomics: A comprehensive review. Clin Chim Acta 2025; 566:120038. [PMID: 39536895 DOI: 10.1016/j.cca.2024.120038] [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: 09/21/2024] [Revised: 11/06/2024] [Accepted: 11/10/2024] [Indexed: 11/16/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease worldwide, affecting one-fourth of the world's population. With more than half of the world's population, the Asia-Pacific region contributed 62.6 % of liver-related fatal incidents in 2015. Currently, liver imaging techniques such as computed tomography (CT), nuclear magnetic resonance (NMR) spectroscopy, and ultrasound are non-invasive imaging methods to diagnose the disease. A liver biopsy is the gold standard test for establishing the definite diagnosis of non-alcoholic steatohepatitis (NASH). However, there are still significant problems with sample variability and the procedure's invasiveness. Numerous studies have indicated various non-invasive biomarkers for both fibrosis and steatosis to counter the invasiveness of diagnostic procedures. Metabolomics could be a promising method for detecting early liver diseases, investigating pathophysiology, and developing drugs. Metabolomics, when utilized with other omics technologies, can result in a deeper understanding of biological systems. Metabolomics has emerged as a prominent research topic, offering extensive opportunities to investigate biomarkers for liver diseases that are both sensitive and specific. In this review, we have described the recent studies involving the use of a metabolomics approach in the diagnosis of liver diseases, which would be beneficial for the early detection and treatment of liver diseases.
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Affiliation(s)
- Preetpal Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Ravinder Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Chirag Pasricha
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Pratima Kumari
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Liu Z, You C. The bile acid profile. Clin Chim Acta 2025; 565:120004. [PMID: 39419312 DOI: 10.1016/j.cca.2024.120004] [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: 07/22/2024] [Revised: 10/13/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024]
Abstract
As a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.
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Affiliation(s)
- Zhenhua Liu
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Chongge You
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
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Łuczykowski K, Warmuzińska N, Jaroch K, Kollmann D, Selzner M, Bojko B. Recent solid-phase microextraction-based analytical approaches for the profiling of biliary bile acids in pre-transplant assessments of liver grafts subjected to normothermic ex vivo liver perfusion. Anal Chim Acta 2024; 1318:342954. [PMID: 39067930 DOI: 10.1016/j.aca.2024.342954] [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: 05/28/2024] [Revised: 07/05/2024] [Accepted: 07/06/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Liver transplantation is the definitive treatment for end-stage liver failure, but the scarcity of donor organs remains a significant challenge. Leveraging organs from extended criteria donors (ECD) offers a potential avenue to address worldwide shortages, though these organs are more susceptible to post-reperfusion injury. This study explores the use of normothermic ex vivo liver perfusion (NEVLP) as a method for organ preservation - an approach that sustains liver metabolism and facilitates pre-transplant assessments of organ viability via bile analysis. The focal point of this study revolves on the development of analytical methods for determining the bile acid profile throughout the peritransplantation period as a potential indicator of liver function and viability. RESULTS The study optimized and validated a high-throughput analytical method to quantify selected bile acids in bile samples using a thin-film microextraction-liquid chromatography-mass spectrometry (TFME-LC-MS) platform. Furthermore, it introduced a solid-phase microextraction-microfluidic open interface-mass spectrometry (SPME-MOI-MS) method for rapid direct analysis of bile acid isobar groups. In the animal study, discernible variations in the concentrations of specific bile acids were observed between donors after circulatory death (DCD) and heart-beating donors (HBD), particularly following normothermic perfusion and reperfusion. Noteworthy fluctuations in individual bile acid concentrations were observed throughout the entire organ transplantation process, with taurocholic acid (TCA), glycocholic acid (GCA), and glycochenodeoxycholic acid (GCDCA) emerging as promising indicators of organ quality. The efficacy of the SPME-MOI-MS platform in corroborating these trends highlights its potential for real-time bile acid analysis during liver transplantation procedures. SIGNIFICANCE Our findings underscore the efficacy of NEVLP in tandem with advanced bile acid analysis methods as a reliable strategy for pre-transplant assessments of organ viability, potentially increasing the use of ECD organs and reducing organ shortages. The ability to monitor bile acid profiles in real-time provides crucial insights into liver function and ischemic injury, making significant strides in improving transplant outcomes and patient survival rates.
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Affiliation(s)
- Kamil Łuczykowski
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Natalia Warmuzińska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Karol Jaroch
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Dagmar Kollmann
- Department of Surgery, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Markus Selzner
- Department of Surgery, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland.
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Dimou A, Zachou K, Kostara C, Azariadis K, Giannoulis G, Lyberopoulou A, Bairaktari E, Dalekos GN. NMR-based metabolomic signature: An important tool for the diagnosis and study of pathogenesis of autoimmune hepatitis. Hepatology 2024; 80:266-277. [PMID: 38305739 DOI: 10.1097/hep.0000000000000767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 12/08/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND AND AIMS Metabolomics is used to predict, diagnose, and monitor metabolic disorders but altered metabolomic signatures have also been reported in diverse diseases, including autoimmune disorders. However, the metabolomic profile in autoimmune hepatitis (AIH) has not been investigated in depth. Therefore, we investigated the metabolomic signature of AIH and its significance as a diagnostic and pathogenetic tool. APPROACH AND RESULTS Metabolites in plasma samples from 50 patients with AIH at diagnosis, 43 healthy controls, 72 patients with primary biliary cholangitis (PBC), 26 patients with metabolic dysfunction-associated liver disease, and 101 patients with chronic viral hepatitis were determined by 1 H NMR (nuclear magnetic resonance) spectroscopy. Fifty-two metabolites were quantified, and metabolic pathway analysis was performed. Multivariate analysis revealed that AIH could be differentiated from healthy controls and each of the disease controls ( p <0.001). Fifteen metabolites differentiated AIH from disease controls (PBC+chronic viral hepatitis+metabolic dysfunction-associated liver disease) (95% sensitivity and 92% specificity). Ten distinct metabolic pathways were altered in AIH compared to disease controls. The metabolic pathway of branched-chain amino acids (lower valine, leucine, and isoleucine levels and their catabolic intermediates in PBC), methionine (lower methionine, 2-aminobutyrate, and 2-hydroxybutyrate levels in PBC), alanine-aspartate-glutamate (lower metabolites in PBC), and that of metabolites associated with gut microbiota (lower choline, betaine, and dimethylamine levels in PBC) were significantly different between AIH and PBC ( p <0.01). CONCLUSIONS 1 H NMR spectroscopy could be a promising novel tool to diagnose and study AIH pathogenesis as there is no need for much sample handling, is highly reproducible with high sensitivity and specificity, and low cost.
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Affiliation(s)
- Aikaterini Dimou
- Department of Biochemistry, Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Christina Kostara
- Department of Biochemistry, Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - George Giannoulis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Eleni Bairaktari
- Department of Biochemistry, Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
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Qiu H, Huang L, Wang H, Tao C, Ran Z, Xu J, Sun H, Wang P. Effects of Lactobacillus acidophilus AC on the growth, intestinal flora and metabolism of zebrafish (Danio rerio). FISH & SHELLFISH IMMUNOLOGY 2024; 149:109570. [PMID: 38643956 DOI: 10.1016/j.fsi.2024.109570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 04/12/2024] [Accepted: 04/15/2024] [Indexed: 04/23/2024]
Abstract
The intensive aquaculture model has resulted in a heightened prevalence of diseases among farmed animals. It is imperative to identify healthy and efficacious alternatives to antibiotics for the sustainable progression of aquaculture. In this investigation, a strain of Lactobacillus acidophilus AC was introduced into the cultural water at varying concentrations (105 CFU/mL, 106 CFU/mL, 107 CFU/mL) to nourish zebrafish (Danio rerio). The findings revealed that L. acidophilus AC effectively increased the growth performance of zebrafish, improved the ion exchange capacity of gills, and enhanced hepatic antioxidant and immune-enzyme activities. Furthermore, L. acidophilus AC notably enhanced the intestinal morphology and augmented the activity of digestive enzymes within the intestinal tract. Analysis of intestinal flora revealed that L. acidophilus AC exerted a significant impact on the intestinal flora community, manifested by a reduction in the relative abundance of Burkholderiales, Candidatus_Saccharibacteria_bacterium, and Sutterellaceae, coupled with an increase in the relative abundance of Cetobacterium. Metabolomics analysis demonstrated that L. acidophilus AC significantly affected intestinal metabolism of zebrafish. PG (i-19:0/PGE2) and 12-Hydroxy-13-O-d-glucuronoside-octadec-9Z-enoate were the metabolites with the most significant up- and down-regulation folds, respectively. Finally, L. acidophilus AC increased the resistance of zebrafish to Aeromonas hydrophila. In conclusion, L. acidophilus AC was effective in enhancing the health and immunity of zebrafish. Thus, our findings suggested that L. acidophilus AC had potential applications and offered a reference for its use in aquaculture.
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Affiliation(s)
- Haoyu Qiu
- College of Marine Science and Technology, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Ling Huang
- College of Marine Science and Technology, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Hanying Wang
- National Marine Facility Aquaculture Engineering and Technology Research Center, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Chenzhi Tao
- College of Marine Science and Technology, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Zhiqiang Ran
- College of Marine Science and Technology, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Jiahang Xu
- College of Marine Science and Technology, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Haofeng Sun
- College of Marine Science and Technology, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Ping Wang
- College of Marine Science and Technology, Zhejiang Ocean University, Zhoushan, 316022, China.
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Yang L, Wang F, Liu S, Xian Z, Yang S, Xu Y, Shu L, Yan X, He J, Li X, Peng C, Bi C, Yuan Y, Chen S, Han L, Yang R, Li Y. Unique metabolomics characteristics for distinguishing cirrhosis related to different liver diseases: A systematic review and meta-analysis. Diabetes Metab Syndr 2024; 18:103068. [PMID: 38959546 DOI: 10.1016/j.dsx.2024.103068] [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: 11/09/2023] [Revised: 05/24/2024] [Accepted: 06/28/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND AND AIM Clinical evidence for early identification and diagnosis of liver cirrhosis (LC) caused by different types of liver disease is limited. We investigated this topic through a meta-analysis of quantitative metabolomics. METHODS Four databases were searched until October 31, 2022 for studies comparing metabolite levels between patients with different types of liver disease and control individuals. A random-effects model was applied for the meta-analysis. RESULTS This study included 55 studies with 8266 clinical participants, covering 348 metabolites. In LC related to drug-induced liver injury (DILI), hepatitis B virus (HBV) infection, and non-alcoholic fatty liver disease (NAFLD), the primary bile acid biosynthesis (taurocholic acid: SMD, 1.08[0.81, 1.35]; P < 0.00001; glycocholic acid: SMD, 1.35[1.07, 1.62]; P < 0.00001; taurochenodeoxycholic acid: SMD, 1.36[0.94, 1.78]; P < 0.00001; glycochenodeoxycholic acid: SMD, 1.49[0.93, 2.06]; P < 0.00001), proline and arginine (l-proline: SMD, 1.06[0.53, 1.58]; P < 0.0001; hydroxyproline: SMD, 0.81[0.30, 1.33]; P = 0.002), and fatty acid biosynthesis (palmitic acid: SMD, 0.44[0.21, 0.67]; P = 0.0002; oleic acid: SMD, 0.46[0.19, 0.73]; P = 0.0008; stearic acid: SMD, 0.37[0.07, 0.68]; P = 0.02) metabolic pathways were significantly altered. CONCLUSION We identified key biomarkers and metabolic characteristics for distinguishing and identifying LC related to different types of liver disease, providing a new perspective for early diagnosis, disease monitoring, and precise treatment.
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Affiliation(s)
- Liu Yang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Fang Wang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Sijia Liu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Zicheng Xian
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Shenshen Yang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yanyan Xu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Lexin Shu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xingxu Yan
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Junjie He
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xia Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Cheng Peng
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Chenghao Bi
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yu Yuan
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Siyu Chen
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Liwen Han
- Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
| | - Rongrong Yang
- Public Health Science and Engineering College, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Yubo Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China.
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11
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Zhou J, Zhu D, Xu Y, Chen C, Wang K. Genetically predicted gut microbiota mediate the association between plasma lipidomics and primary sclerosing cholangitis. BMC Gastroenterol 2024; 24:158. [PMID: 38720308 PMCID: PMC11080140 DOI: 10.1186/s12876-024-03246-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 04/29/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a complex disease with pathogenic mechanisms that remain to be elucidated. Previous observational studies with small sample sizes have reported associations between PSC, dyslipidemia, and gut microbiota dysbiosis. However, the causality of these associations is uncertain, and there has been no systematic analysis to date. METHODS The datasets comprise data on PSC, 179 lipid species, and 412 gut microbiota species. PSC data (n = 14,890) were sourced from the International PSC Study Group, while the dataset pertaining to plasma lipidomics originated from a study involving 7174 Finnish individuals. Data on gut microbiota species were derived from the Dutch Microbiome Project study, which conducted a genome-wide association study involving 7738 participants. Furthermore, we employed a two-step Mendelian randomization (MR) analysis to quantify the proportion of the effect of gut microbiota-mediated lipidomics on PSC. RESULTS Following a rigorous screening process, our MR analysis revealed a causal relationship between higher levels of gene-predicted Phosphatidylcholine (O-16:1_18:1) (PC O-16:1_18:1) and an increased risk of developing PSC (inverse variance-weighted method, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.03-1.63). There is insufficient evidence to suggest that gene-predicted PSC impacts the levels of PC O-16:1_18:1 (OR 1.01, 95% CI 0.98-1.05). When incorporating gut microbiota data into the analysis, we found that Eubacterium rectale-mediated genetic prediction explains 17.59% of the variance in PC O-16:1_18:1 levels. CONCLUSION Our study revealed a causal association between PC O-16:1_18:1 levels and PSC, with a minor portion of the effect mediated by Eubacterium rectale. This study aims to further explore the pathogenesis of PSC and identify promising therapeutic targets. For patients with PSC who lack effective treatment options, the results are encouraging.
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Affiliation(s)
- Jie Zhou
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, No. 2, Yongning North Road, Changzhou, 213003, Jiangsu Province, China
- Department of General Surgery, The Wujin Clinical college of Xuzhou Medical University, Changzhou, 213003, China
| | - Dagang Zhu
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, No. 2, Yongning North Road, Changzhou, 213003, Jiangsu Province, China.
- Department of General Surgery, The Wujin Clinical college of Xuzhou Medical University, Changzhou, 213003, China.
| | - Yixin Xu
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, No. 2, Yongning North Road, Changzhou, 213003, Jiangsu Province, China
- Department of General Surgery, The Wujin Clinical college of Xuzhou Medical University, Changzhou, 213003, China
| | - Chao Chen
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, No. 2, Yongning North Road, Changzhou, 213003, Jiangsu Province, China
- Department of General Surgery, The Wujin Clinical college of Xuzhou Medical University, Changzhou, 213003, China
| | - Kun Wang
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, No. 2, Yongning North Road, Changzhou, 213003, Jiangsu Province, China
- Department of General Surgery, The Wujin Clinical college of Xuzhou Medical University, Changzhou, 213003, China
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12
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Islam D, Israr I, Taleb MAB, Rao A, Yosief R, Sultana R, Sampaziotis F, Tysoe OC, Trauner M, Karpen SJ, Ghanekar A, Kamath BM. A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway. Hepatol Commun 2024; 8:e0389. [PMID: 38407207 PMCID: PMC10898671 DOI: 10.1097/hc9.0000000000000389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 12/09/2023] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Ductular reactivity is central to the pathophysiology of cholangiopathies. Mechanisms underlying the reactive phenotype activation by exogenous inflammatory mediators and bile acids are poorly understood. METHODS Using human extrahepatic cholangiocyte organoids (ECOs) we developed an injury model emulating the cholestatic microenvironment with exposure to inflammatory mediators and various pathogenic bile acids. Moreover, we explored roles for the bile acid activated Sphingosine-1-phosphate receptor 2 (S1PR2) and potential beneficial effects of therapeutic bile acids UDCA and norUDCA. RESULTS Synergistic exposure to bile acids (taurocholic acid, glycocholic acid, glycochenodeoxycholic acid) and TNF-α for 24 hours induced a reactive state as measured by ECO diameter, proliferation, lactate dehydrogenase activity and reactive phenotype markers. While NorUDCA and UDCA treatments given 8 hours after injury induction both suppressed reactive phenotype activation and most injury parameters, proliferation was improved by NorUDCA only. Extrahepatic cholangiocyte organoid stimulation with S1PR2 agonist sphingosine-1-phosphate reproduced the cholangiocyte reactive state and upregulated S1PR2 downstream mediators; these effects were suppressed by S1PR2 antagonist JET-013 (JET), downstream mediator extracellular signal-regulated kinase 1/2 inhibitor, and by norUDCA or UDCA treatments. JET also partially suppressed reactive phenotype after bile acid injury. CONCLUSIONS We developed a novel model to study the reactive cholangiocyte state in response to pathological stimuli in cholestasis and demonstrated a contributory role of S1PR2 signaling in both injury and NorUDCA/UDCA treatments. This model is a valuable tool to further explore the pathophysiology of human cholangiopathies.
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Affiliation(s)
- Diana Islam
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Izza Israr
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Mohamed A. B. Taleb
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Aditya Rao
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Robel Yosief
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rukhsar Sultana
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Fotios Sampaziotis
- Wellcome–MRC Cambridge Stem Cell Institute, Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK
- Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK
| | - Olivia C. Tysoe
- Wellcome–MRC Cambridge Stem Cell Institute, Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Saul J. Karpen
- Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology, and Nutrition, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, USA
| | - Anand Ghanekar
- Division of General Surgery, Department of Surgery, University Health Network & The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Binita M. Kamath
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
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13
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Marciano LPA, Costa LF, Cardoso NS, Freire J, Feltrim F, Oliveira GS, Paula FBA, Silvério ACP, Martins I. Biomonitoring and risk assessment of human exposure to triazole fungicides. Regul Toxicol Pharmacol 2024; 147:105565. [PMID: 38185363 DOI: 10.1016/j.yrtph.2024.105565] [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: 08/30/2023] [Revised: 12/23/2023] [Accepted: 01/04/2024] [Indexed: 01/09/2024]
Abstract
Risk assessment and biomarkers were evaluated in volunteers exposed to triazole fungicides in southern Minas Gerais, Brazil. Volunteers were divided into two groups: occupationally and environmentally exposed to pesticides (n = 140) and those unexposed (n = 50) from urban areas. Urine samples were analyzed by GC-MS for triazoles, and samples from men and women in the exposed group were quantified. Groups were further stratified by sex to evaluate the biomarkers results. Oxidative stress was indicated by biomarker analysis for occupationally exposed men with elevated malondialdehyde levels and reduced superoxide dismutase and catalase activity (p < 0.0001). Bile acid levels were also elevated in the exposed group (p < 0.0001). Biomarkers in this study suggest recent, reversible changes due to pesticide exposure. Liver enzyme levels showed no significant differences. The highest Estimated Daily Intake for epoxiconazole ranged from 0.534 to 6.31 μg/kg-bw/day for men and 0.657-8.77 μg/kg-bw/day for women in the exposed group. Considering the highest detected urinary triazole value, the calculated Hazard Quotient for epoxiconazole was 0.789 for men and 1.1 for women. Results indicate a health risk associated with environmental triazole exposure, highlighting the importance of biomonitoring in risk assessment to prevent intoxication and assist in mitigating adverse health effects from chronic pesticide exposure.
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Affiliation(s)
- Luiz P A Marciano
- Laboratory of Toxicant and Drug Analyses, Department of Clinical and Toxicological Analysis, Gabriel Monteiro da Silva St. 700, Federal University of Alfenas - Unifal-MG, 37130-000, Alfenas, MG, Brazil.
| | - Luiz F Costa
- Laboratory of Toxicant and Drug Analyses, Department of Clinical and Toxicological Analysis, Gabriel Monteiro da Silva St. 700, Federal University of Alfenas - Unifal-MG, 37130-000, Alfenas, MG, Brazil.
| | - Naiane S Cardoso
- Clinical and Experimental Analysis Laboratory, Department of Clinical and Toxicological Analysis, Gabriel Monteiro da Silva St. 700, Federal University of Alfenas - Unifal-MG, 37130-000, Alfenas, MG, Brazil.
| | - Josiane Freire
- Laboratory of Toxicant and Drug Analyses, Department of Clinical and Toxicological Analysis, Gabriel Monteiro da Silva St. 700, Federal University of Alfenas - Unifal-MG, 37130-000, Alfenas, MG, Brazil.
| | - Fernando Feltrim
- Laboratory of Toxicant and Drug Analyses, Department of Clinical and Toxicological Analysis, Gabriel Monteiro da Silva St. 700, Federal University of Alfenas - Unifal-MG, 37130-000, Alfenas, MG, Brazil.
| | - Geovana S Oliveira
- Laboratory of Toxicant and Drug Analyses, Department of Clinical and Toxicological Analysis, Gabriel Monteiro da Silva St. 700, Federal University of Alfenas - Unifal-MG, 37130-000, Alfenas, MG, Brazil.
| | - Fernanda B A Paula
- Clinical and Experimental Analysis Laboratory, Department of Clinical and Toxicological Analysis, Gabriel Monteiro da Silva St. 700, Federal University of Alfenas - Unifal-MG, 37130-000, Alfenas, MG, Brazil.
| | | | - Isarita Martins
- Laboratory of Toxicant and Drug Analyses, Department of Clinical and Toxicological Analysis, Gabriel Monteiro da Silva St. 700, Federal University of Alfenas - Unifal-MG, 37130-000, Alfenas, MG, Brazil.
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14
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van Munster KN, Bergquist A, Ponsioen CY. Inflammatory bowel disease and primary sclerosing cholangitis: One disease or two? J Hepatol 2024; 80:155-168. [PMID: 37940453 DOI: 10.1016/j.jhep.2023.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 09/01/2023] [Accepted: 09/29/2023] [Indexed: 11/10/2023]
Abstract
Primary sclerosing cholangitis (PSC) was declared one of the biggest unmet needs in hepatology during International Liver Congress 2016 in Berlin. Since then, not much has changed unfortunately, largely due to the still elusive pathophysiology of the disease. One of the most striking features of PSC is its association with inflammatory bowel disease (IBD), with the majority of patients with PSC being diagnosed with extensive colitis. This review describes the epidemiology of IBD in PSC, its specific phenotype, complications and potential pathophysiological mechanisms connecting the two diseases. Whether PSC is merely an extra-intestinal manifestation of IBD or if PSC and IBD are two distinct diseases that happen to share a common susceptibility that leads to a dual phenotype is debated. Implications for the management of the two diseases together are also discussed. Overall, this review summarises the available data in PSC-IBD and discusses whether PSC and IBD are one or two disease(s).
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Affiliation(s)
- Kim N van Munster
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Annika Bergquist
- Department of Medicine Huddinge, Division of Hepatology, Karolinska Institutet, Department of Upper GI Disease, Karolinska University Hospital, Stockholm, Sweden
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands.
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15
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van Vorstenbosch R, van Munster K, Pachen D, Mommers A, Stavropoulos G, van Schooten FJ, Ponsioen C, Smolinska A. The Detection of Primary Sclerosing Cholangitis Using Volatile Metabolites in Fecal Headspace and Exhaled Breath. Metabolites 2023; 14:23. [PMID: 38248826 PMCID: PMC10819709 DOI: 10.3390/metabo14010023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/20/2023] [Accepted: 12/26/2023] [Indexed: 01/23/2024] Open
Abstract
Up to 5% of inflammatory bowel disease patients may at some point develop primary sclerosing cholangitis (PSC). PSC is a rare liver disease that ultimately results in liver damage, cirrhosis and liver failure. It typically remains subclinical until irreversible damage has been inflicted. Hence, it is crucial to screen IBD patients for PSC, but its early detection is challenging, and the disease's etiology is not well understood. This current study aimed at the early detection of PSC in an IBD population using Volatile Organic Compounds in fecal headspace and exhaled breath. To this aim, fecal material and exhaled breath were collected from 73 patients (n = 16 PSC/IBD; n = 8 PSC; n = 49 IBD), and their volatile profile were analyzed using Gas Chromatography-Mass Spectrometry. Using the most discriminatory features, PSC detection resulted in areas under the ROC curve (AUCs) of 0.83 and 0.84 based on fecal headspace and exhaled breath, respectively. Upon data fusion, the predictive performance increased to AUC 0.92. The observed features in the fecal headspace relate to detrimental microbial dysbiosis and exogenous exposure. Future research should aim for the early detection of PSC in a prospective study design.
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Affiliation(s)
- Robert van Vorstenbosch
- Department of Toxicology, Nutrition and Toxicology Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (D.P.); (A.M.); (F.-J.v.S.)
| | - Kim van Munster
- Department of Gastroenterology and Hepathology, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (K.v.M.); (C.P.)
| | - Danielle Pachen
- Department of Toxicology, Nutrition and Toxicology Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (D.P.); (A.M.); (F.-J.v.S.)
| | - Alex Mommers
- Department of Toxicology, Nutrition and Toxicology Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (D.P.); (A.M.); (F.-J.v.S.)
| | - Georgios Stavropoulos
- Department of Toxicology, Nutrition and Toxicology Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (D.P.); (A.M.); (F.-J.v.S.)
| | - Frederik-Jan van Schooten
- Department of Toxicology, Nutrition and Toxicology Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (D.P.); (A.M.); (F.-J.v.S.)
| | - Cyriel Ponsioen
- Department of Gastroenterology and Hepathology, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (K.v.M.); (C.P.)
| | - Agnieszka Smolinska
- Department of Toxicology, Nutrition and Toxicology Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (D.P.); (A.M.); (F.-J.v.S.)
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16
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Özdirik B, Schnabl B. Microbial Players in Primary Sclerosing Cholangitis: Current Evidence and Concepts. Cell Mol Gastroenterol Hepatol 2023; 17:423-438. [PMID: 38109970 PMCID: PMC10837305 DOI: 10.1016/j.jcmgh.2023.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with progressive biliary inflammation, destruction of the biliary tract, and fibrosis, resulting in liver cirrhosis and end-stage liver disease. To date, liver transplantation is the only definitive treatment option for PSC. The precise etiology of PSC remains elusive, but it is widely accepted to involve a complex interplay between genetic predisposition, immunologic dysfunction, and environmental influence. In recent years, the gut-liver axis has emerged as a crucial pathway contributing to the pathogenesis of PSC, with particular focus on the role of gut microbiota. However, the role of the fungal microbiome or mycobiome has been overlooked for years, resulting in a lack of comprehensive studies on its involvement in PSC. In this review, we clarify the present clinical and mechanistic data and concepts concerning the gut bacterial and fungal microbiota in the context of PSC. This review sheds light on the role of specific microbes and elucidates the dynamics of bacterial and fungal populations. Moreover, we discuss the latest insights into microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism.
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Affiliation(s)
- Burcin Özdirik
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California.
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17
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Mayer C, Nehring S, Kücken M, Repnik U, Seifert S, Sljukic A, Delpierre J, Morales‐Navarrete H, Hinz S, Brosch M, Chung B, Karlsen T, Huch M, Kalaidzidis Y, Brusch L, Hampe J, Schafmayer C, Zerial M. Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease. EMBO Rep 2023; 24:e57181. [PMID: 37522754 PMCID: PMC10481669 DOI: 10.15252/embr.202357181] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 07/11/2023] [Accepted: 07/13/2023] [Indexed: 08/01/2023] Open
Abstract
Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.
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Affiliation(s)
- Carlotta Mayer
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Sophie Nehring
- Department of Medicine I, Gastroenterology and HepatologyUniversity Hospital Carl‐Gustav‐Carus, Technische Universität Dresden (TU Dresden)DresdenGermany
| | - Michael Kücken
- Center for Information Services and High‐Performance ComputingTechnische Universität DresdenDresdenGermany
| | - Urska Repnik
- Central Microscopy, Department of BiologyChristian‐Albrechts‐Universtät zu Kiel (CAU)KielGermany
| | - Sarah Seifert
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Aleksandra Sljukic
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Julien Delpierre
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | | | - Sebastian Hinz
- Department of General SurgeryUniversity Hospital RostockRostockGermany
| | - Mario Brosch
- Department of Medicine I, Gastroenterology and HepatologyUniversity Hospital Carl‐Gustav‐Carus, Technische Universität Dresden (TU Dresden)DresdenGermany
- Center for Regenerative Therapies Dresden (CRTD)Technische Universität Dresden (TU Dresden)DresdenGermany
| | - Brian Chung
- Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research CenterOslo University Hospital RikshospitaletOsloNorway
- Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and TransplantationOslo University Hospital and University of OsloOsloNorway
| | - Tom Karlsen
- Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research CenterOslo University Hospital RikshospitaletOsloNorway
- Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and TransplantationOslo University Hospital and University of OsloOsloNorway
| | - Meritxell Huch
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Yannis Kalaidzidis
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Lutz Brusch
- Center for Information Services and High‐Performance ComputingTechnische Universität DresdenDresdenGermany
| | - Jochen Hampe
- Department of Medicine I, Gastroenterology and HepatologyUniversity Hospital Carl‐Gustav‐Carus, Technische Universität Dresden (TU Dresden)DresdenGermany
- Center for Regenerative Therapies Dresden (CRTD)Technische Universität Dresden (TU Dresden)DresdenGermany
| | | | - Marino Zerial
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
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18
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Caballero-Camino FJ, Rodrigues PM, Wångsell F, Agirre-Lizaso A, Olaizola P, Izquierdo-Sanchez L, Perugorria MJ, Bujanda L, Angelin B, Straniero S, Wallebäck A, Starke I, Gillberg PG, Strängberg E, Bonn B, Mattsson JP, Madsen MR, Hansen HH, Lindström E, Åkerblad P, Banales JM. A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans. Hepatology 2023; 78:709-726. [PMID: 36999529 PMCID: PMC10442107 DOI: 10.1097/hep.0000000000000376] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND AND AIMS Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. APPROACH AND RESULTS A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2-/- mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro . In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. CONCLUSIONS The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases.
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Affiliation(s)
- Francisco J. Caballero-Camino
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Pedro M. Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), Madrid, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | | | - Aloña Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), Madrid, Spain
| | - Laura Izquierdo-Sanchez
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), Madrid, Spain
| | - Maria J. Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), Madrid, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), Madrid, Spain
| | - Bo Angelin
- CardioMetabolic Unit, Department of Medicine and Clinical Department of Endocrinology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Sara Straniero
- CardioMetabolic Unit, Department of Medicine and Clinical Department of Endocrinology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | | | | | | | | | | | | | | | | | | | | | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), Madrid, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
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19
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Lawson KL, Wang HL. Primary Sclerosing Cholangitis, Small Duct Primary Sclerosing Cholangitis, IgG4-Related Sclerosing Cholangitis, and Ischemic Cholangiopathy: Diagnostic Challenges on Biopsy. Surg Pathol Clin 2023; 16:533-548. [PMID: 37536887 DOI: 10.1016/j.path.2023.04.008] [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: 08/05/2023]
Abstract
Pathologists face many challenges when diagnosing sclerosing biliary lesions on liver biopsy. First, histologic findings tend to be nonspecific with similar to identical features seen in numerous conditions, from benign to outright malignant. In addition, the patchy nature of many of these entities amplifies the inherent limitations of biopsy sampling. The end result often forces pathologists to issue descriptive sign outs that require careful clinical correlation; however, certain clinical, radiologic, and histologic features may be of diagnostic assistance. In this article, we review key elements of four sclerosing biliary processes whose proper identification has significant prognostic and therapeutic implications.
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Affiliation(s)
- Katy L Lawson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Ronald Reagan UCLA Medical Center, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Ronald Reagan UCLA Medical Center, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
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20
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Mujalli A, Farrash WF, Alghamdi KS, Obaid AA. Metabolite Alterations in Autoimmune Diseases: A Systematic Review of Metabolomics Studies. Metabolites 2023; 13:987. [PMID: 37755267 PMCID: PMC10537330 DOI: 10.3390/metabo13090987] [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: 07/25/2023] [Revised: 08/24/2023] [Accepted: 08/30/2023] [Indexed: 09/28/2023] Open
Abstract
Autoimmune diseases, characterized by the immune system's loss of self-tolerance, lack definitive diagnostic tests, necessitating the search for reliable biomarkers. This systematic review aims to identify common metabolite changes across multiple autoimmune diseases. Following PRISMA guidelines, we conducted a systematic literature review by searching MEDLINE, ScienceDirect, Google Scholar, PubMed, and Scopus (Elsevier) using keywords "Metabolomics", "Autoimmune diseases", and "Metabolic changes". Articles published in English up to March 2023 were included without a specific start date filter. Among 257 studies searched, 88 full-text articles met the inclusion criteria. The included articles were categorized based on analyzed biological fluids: 33 on serum, 21 on plasma, 15 on feces, 7 on urine, and 12 on other biological fluids. Each study presented different metabolites with indications of up-regulation or down-regulation when available. The current study's findings suggest that amino acid metabolism may serve as a diagnostic biomarker for autoimmune diseases, particularly in systemic lupus erythematosus (SLE), multiple sclerosis (MS), and Crohn's disease (CD). While other metabolic alterations were reported, it implies that autoimmune disorders trigger multi-metabolite changes rather than singular alterations. These shifts could be consequential outcomes of autoimmune disorders, representing a more complex interplay. Further studies are needed to validate the metabolomics findings associated with autoimmune diseases.
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Affiliation(s)
- Abdulrahman Mujalli
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah 24381, Saudi Arabia; (W.F.F.); (A.A.O.)
| | - Wesam F. Farrash
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah 24381, Saudi Arabia; (W.F.F.); (A.A.O.)
| | - Kawthar S. Alghamdi
- Department of Biology, College of Science, University of Hafr Al Batin, Hafar Al-Batin 39511, Saudi Arabia;
| | - Ahmad A. Obaid
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah 24381, Saudi Arabia; (W.F.F.); (A.A.O.)
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21
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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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22
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Minowa K, Rodriguez-Agudo D, Suzuki M, Muto Y, Hirai S, Wang Y, Su L, Zhou H, Chen Q, Lesnefsky EJ, Mitamura K, Ikegawa S, Takei H, Nittono H, Fuchs M, Pandak WM, Kakiyama G. Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease. J Lipid Res 2023; 64:100363. [PMID: 36966904 PMCID: PMC10182330 DOI: 10.1016/j.jlr.2023.100363] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 03/09/2023] [Accepted: 03/21/2023] [Indexed: 04/07/2023] Open
Abstract
CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3βHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1-/- mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3βHCA levels were maintained at basal levels in ND-fed Cyp7b1-/- mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1-/- mice developed insulin resistance (IR) with subsequent 26HC/3βHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1-/- mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3βHCA accumulation. The results suggest 26HC/3βHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3βHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease.
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Affiliation(s)
- Kei Minowa
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Daniel Rodriguez-Agudo
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yamato Muto
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Saeko Hirai
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yaping Wang
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA
| | - Lianyong Su
- Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA; Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Huiping Zhou
- Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA; Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Qun Chen
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA
| | - Edward J Lesnefsky
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA
| | - Kuniko Mitamura
- Department of Pharmaceutical Sciences, Kindai University, Osaka, Japan
| | - Shigeo Ikegawa
- Division of Research and Development, Genmaikoso Co. Ltd., Sapporo, Hokkaido, Japan
| | - Hajime Takei
- Junshin Clinic Bile Acid Institute, Tokyo, Japan
| | | | - Michael Fuchs
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA
| | - William M Pandak
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Genta Kakiyama
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA.
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23
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Chen Y, Chen S, Chuang Y, Chiang B. Attenuation of the severity and changes in the microbiota in an animal model of primary biliary cholangitis by FOXP3 − regulatory T cells. CLINICAL AND TRANSLATIONAL DISCOVERY 2023; 3. [DOI: 10.1002/ctd2.187] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/16/2023] [Indexed: 01/04/2025]
Abstract
AbstractBackgroundPrimary biliary cholangitis (PBC), an autoimmune liver disease, presents with progressive damage to the intrahepatic bile ducts with infiltrating mononuclear cells and the appearance of anti‐mitochondrial antibodies (AMAs). The initiation of autoimmune liver disease is permissively mediated by dysfunctional regulatory T cells (Treg cells). Naïve CD4+ T cells cultured with splenic B220+ cells without additional cytokines or chemicals can differentiate into specific types of Treg cells (Treg/B cells) without expressing forkhead box P3. In this study, we explored the effects of Treg/B cells on disease severity and changes in intestinal microbiota in a murine model of PBC.MethodsTreg/B cells were administered to 2‐octenoic acid‐induced PBC mice. Enzyme‐linked immunosorbent assay, flow cytometry and histopathological techniques were used to evaluate the severity of PBC and to assess its therapeutic effect. Diversity of the intestinal microbiota was determined using 16S rRNA sequencing. The suppressive mechanisms of Treg/B cells were investigated using the bone marrow‐derived dendritic cells (BMDCs).ResultsTreg/B‐cell treatment significantly decreased the levels of serum AMAs against pyruvate dehydrogenase complex E2, lowered the levels of serum bile acids, attenuated inflammatory cell infiltration, reduced dendritic cell activation, altered the population of T cells in the liver and alleviated liver collagen synthesis in PBC mice. In addition, the Treg/B‐cell treatment changed the faecal microbial diversity in PBC mice. Furthermore, Treg/B‐cell treatment decreased the levels of proinflammatory cytokines and expression of costimulatory molecules in BMDCs. This inhibitory effect was partially mediated by the cytotoxic T‐lymphocyte‐associated antigen 4 pathway.ConclusionTreatment with Treg/B cells in a murine model of PBC attenuated liver inflammation and altered the gut microbiota. Immune regulation of Treg/B cells may be a potential therapeutic strategy for treating autoimmune liver disease.
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Affiliation(s)
- Yi‐Lien Chen
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
| | - Szu‐Ying Chen
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
| | - Ya‐Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology College of Medicine National Taiwan University Taipei Taiwan
| | - Bor‐Luen Chiang
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
- Department of Medical Research National Taiwan University Hospital Taipei Taiwan
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24
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Aseem SO, Hylemon PB, Zhou H. Bile Acids and Biliary Fibrosis. Cells 2023; 12:cells12050792. [PMID: 36899928 PMCID: PMC10001305 DOI: 10.3390/cells12050792] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Biliary fibrosis is the driving pathological process in cholangiopathies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholangiopathies are also associated with cholestasis, which is the retention of biliary components, including bile acids, in the liver and blood. Cholestasis may worsen with biliary fibrosis. Furthermore, bile acid levels, composition and homeostasis are dysregulated in PBC and PSC. In fact, mounting data from animal models and human cholangiopathies suggest that bile acids play a crucial role in the pathogenesis and progression of biliary fibrosis. The identification of bile acid receptors has advanced our understanding of various signaling pathways involved in regulating cholangiocyte functions and the potential impact on biliary fibrosis. We will also briefly review recent findings linking these receptors with epigenetic regulatory mechanisms. Further detailed understanding of bile acid signaling in the pathogenesis of biliary fibrosis will uncover additional therapeutic avenues for cholangiopathies.
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Affiliation(s)
- Sayed Obaidullah Aseem
- Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence:
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Central Virginia Veterans Healthcare System, Richmond, VA 23249, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Central Virginia Veterans Healthcare System, Richmond, VA 23249, USA
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25
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Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023; 20:135-154. [PMID: 36352157 DOI: 10.1038/s41575-022-00690-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut-liver axis owing to the close association between liver disease and colonic inflammation. It is well established that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut-liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut-liver axis.
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Affiliation(s)
- Johannes R Hov
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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26
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Yuan Z, Wang J, Zhang H, Chai Y, Xu Y, Miao Y, Yuan Z, Zhang L, Jiang Z, Yu Q. Glycocholic acid aggravates liver fibrosis by promoting the up-regulation of connective tissue growth factor in hepatocytes. Cell Signal 2023; 101:110508. [PMID: 36341984 DOI: 10.1016/j.cellsig.2022.110508] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/18/2022] [Accepted: 10/26/2022] [Indexed: 11/25/2022]
Abstract
AIMS The precise role of bile acid in the progression of liver fibrosis has yet to be elucidated. In this study, common bile duct ligation was used as an in vivo mouse model for the evaluation of bile acids that promote liver connective tissue growth factor expression. MAIN METHODS Primary rat and mice hepatocytes, as well as primary rat hepatic stellate and HepaRG cells were evaluated as in vitro models for promoting the expression of connective tissue growth factor by bile acids. KEY FINDINGS Compared with taurochenodeoxycholic acid, glycochenodeoxycholic acid, and taurocholic acid, glycocholic acid (GCA) most strongly promoted the secretion of connective tissue growth factor in mouse primary hepatocytes, rat primary hepatocytes and HepaRGs. GCA did not directly promote the activation of hepatic stellate cells. The administration of GCA in mice with ligated bile ducts promotes the progression of liver fibrosis, which may promote the yes-associated protein of hepatocytes into the nucleus, resulting in the hepatocytes secreting more connective tissue growth factor for hepatic stellate cell activation. In conclusion, our data showed that GCA can induce the expression of connective tissue growth factor in hepatocytes by promoting the nuclear translocation of yes-associated protein, thereby activating hepatic stellate cells. SIGNIFICANCE Our findings help to elucidate the contribution of GCA to the progression of hepatic fibrosis in cholestatic disease and aid the clinical monitoring of cholestatic liver fibrosis development.
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Affiliation(s)
- Zihang Yuan
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Jie Wang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Haoran Zhang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanyuan Chai
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yunxia Xu
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yingying Miao
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Ziqiao Yuan
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Luyong Zhang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhenzhou Jiang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
| | - Qinwei Yu
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
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27
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Braadland PR, Schneider KM, Bergquist A, Molinaro A, Lövgren-Sandblom A, Henricsson M, Karlsen TH, Vesterhus M, Trautwein C, Hov JR, Marschall HU. Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100561. [PMID: 36176935 PMCID: PMC9513776 DOI: 10.1016/j.jhepr.2022.100561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/08/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022]
Abstract
Background & Aims Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy. Methods Concentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort. Results The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis. Conclusions Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation. Lay summary We show, by measuring the level of the metabolite C4 in the blood from patients with primary sclerosing cholangitis (PSC), that low production of bile acids in the liver predicts a more rapid progression to severe disease. Many people with PSC appear to have fully suppressed bile acid production, and both established and new drugs that aim to reduce bile acid production may therefore be futile for them. We propose C4 as a test to find those likely to respond to these treatments.
The bile acid synthesis marker C4 associated negatively with bile acid levels in patients with PSC. Suppression of bile acid synthesis was likely nearly complete in advanced PSC. UDCA treatment contributed significantly to total circulating bile acids but did not appear to affect bile acid synthesis. Attempts to inhibit bile acid synthesis in patients with low C4 may be futile, and such drugs may be contraindicated. Patients with PSC and low circulating C4 had shorter liver transplantation-free survival in two independent cohorts.
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Key Words
- 7α-Hydroxy-4-cholesten-3-one
- AOM, Amsterdam–Oxford model
- ASBT, apical sodium-dependent bile acid cotransporter
- Biliary disease
- C4
- C4, 7α-hydroxy-4-cholesten-3-one
- CYP7A1, cytochrome P450 family 7 subfamily A member 1
- Cholestasis
- Cholestatic liver disease
- FGF19, fibroblast growth factor 19
- FXR, farnesoid X receptor
- GUDCA, glycooursodeoxycholic acid
- HR, hazard ratio
- IBAT, ileal bile acid transporter
- Liver transplantation
- Liver transplantation-free survival
- MELD, model for end-stage liver disease
- PBC, primary biliary cholangitis
- PSC, primary sclerosing cholangitis
- STROBE, Strengthening the Reporting of Observational Studies in Epidemiology
- TUDCA, tauroursodeoxycholic acid
- UDCA, ursodeoxycholic acid
- UPLC-MS/MS, ultraperformance liquid chromatography–tandem mass spectrometry
- Ursodeoxycholic acid
- c-index, concordance index
- liver
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Affiliation(s)
- Peder Rustøen Braadland
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Kai Markus Schneider
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.,Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Annika Bergquist
- Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Antonio Molinaro
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital Gothenburg, Gothenburg, Sweden
| | | | - Marcus Henricsson
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Johannes Roksund Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital Gothenburg, Gothenburg, Sweden
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Impact of Blueberry Consumption on the Human Fecal Bileacidome: A Pilot Study of Bile Acid Modulation by Freeze-Dried Blueberry. Nutrients 2022; 14:nu14183857. [PMID: 36145234 PMCID: PMC9501813 DOI: 10.3390/nu14183857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/11/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022] Open
Abstract
Cholesterol-derived bile acids (BAs) affect numerous physiological functions such as glucose homeostasis, lipid metabolism and absorption, intestinal inflammation and immunity, as well as intestinal microbiota diversity. Diet influences the composition of the BA pool. In the present study, we analyzed the impact of a dietary supplementation with a freeze-dried blueberry powder (BBP) on the fecal BA pool composition. The diet of 11 men and 13 women at risk of metabolic syndrome was supplemented with 50 g/day of BBP for 8 weeks, and feces were harvested before (pre) and after (post) BBP consumption. BAs were profiled using liquid chromatography coupled with tandem mass spectrometry. No significant changes in total BAs were detected when comparing pre- vs. post-BBP consumption samples. However, post-BBP consumption samples exhibited significant accumulations of glycine-conjugated BAs (p = 0.04), glycochenodeoxycholic (p = 0.01), and glycoursodeoxycholic (p = 0.01) acids, as well as a significant reduction (p = 0.03) in the secondary BA levels compared with pre-BBP feces. In conclusion, the fecal bileacidome is significantly altered after the consumption of BBP for 8 weeks. While additional studies are needed to fully understand the underlying mechanisms and physiological implications of these changes, our data suggest that the consumption of blueberries can modulate toxic BA elimination.
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29
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Adil N, Siddiqui AJ, Musharraf SG. Metabolomics‐based Researches in Autoimmune Liver Disease: A
Mini‐Review. Scand J Immunol 2022. [DOI: 10.1111/sji.13208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Nurmeen Adil
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences University of Karachi Karachi Pakistan
| | - Amna Jabbar Siddiqui
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences University of Karachi Karachi Pakistan
| | - Syed Ghulam Musharraf
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences University of Karachi Karachi Pakistan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences University of Karachi Karachi Pakistan
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30
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Ma Y, Liu X, Liu D, Yin Z, Yang X, Zeng M. Oyster ( Crassostrea gigas) Polysaccharide Ameliorates High-Fat-Diet-Induced Oxidative Stress and Inflammation in the Liver via the Bile Acid-FXR-AMPKα Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:8662-8671. [PMID: 35797440 DOI: 10.1021/acs.jafc.2c02490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Oyster polysaccharides (OPS) have a variety of biological activities. In this study, we aimed to investigate the potential mechanisms of OPS to ameliorate hepatic oxidative stress and inflammation in mice induced by a high-fat diet (HFD). The results showed that OPS reduced the HFD-induced increases in serum transaminase levels and alleviated hepatic oxidative stress and inflammation. Moreover, OPS regulated bile acid metabolism and increased bile acid content in the liver, serum, and feces. Serum bile acid profile results indicated that OPS reduced levels of chenodeoxycholic acid, deoxycholic acid, and lithocholic acid associated with high-affinity agonists of Farnesol X receptor (FXR). Western blot analysis showed that OPS accelerated bile acid metabolism by downregulating hepatic FXR expression and promoting its downstream CYP7A1, CYP27A1, and CYP8B1 protein expression. Meanwhile, OPS ameliorated oxidative stress and inflammation in the liver by modulating FXR-AMPKα-Nrf2/NF-κB signaling to reduce p-IκBα/IκBα, p-NF-κB p65/NF-κB p65, IL-1β, and TNF-α expression and increase p-Nrf2/Nrf2, HO-1, and NQO-1 expression. This study was the first to explore the possible mechanism of OPS in improving liver oxidative stress and inflammation from the perspective of bile acid metabolism, providing a theoretical basis for OPS as a new source of functional food.
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Affiliation(s)
- Yuyang Ma
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, Shandong, China
| | - Xue Liu
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, Shandong, China
| | - Defu Liu
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, Shandong, China
| | - Zihao Yin
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, Shandong, China
| | - Xinyi Yang
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, Shandong, China
| | - Mingyong Zeng
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, Shandong, China
- Qingdao Engineering Research Center for Preservation Technology of Marine Foods, Qingdao 266003, Shandong, China
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31
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Li W, Chen H, Qian Y, Wang S, Luo Z, Shan J, Kong X, Gao Y. Integrated Lipidomics and Metabolomics Study of Four Chemically Induced Mouse Models of Acute Intrahepatic Cholestasis. Front Pharmacol 2022; 13:907271. [PMID: 35754480 PMCID: PMC9213752 DOI: 10.3389/fphar.2022.907271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/18/2022] [Indexed: 12/05/2022] Open
Abstract
Lithocholic acid (LCA), alpha-naphthyl isothiocyanate (ANIT), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), and ethinyl estradiol (EE) are four commonly used chemicals for the construction of acute intrahepatic cholestasis. In order to better understand the mechanisms of acute cholestasis caused by these chemicals, the metabolic characteristics of each model were summarized using lipidomics and metabolomics techniques. The results showed that the bile acid profile was altered in all models. The lipid metabolism phenotype of the LCA group was most similar to that of primary biliary cirrhosis (PBC) patients. The ANIT group and the DDC group had similar metabolic disorder characteristics, which were speculated to be related to hepatocyte necrosis and inflammatory pathway activation. The metabolic profile of the EE group was different from other models, suggesting that estrogen-induced cholestasis had its special mechanism. Ceramide and acylcarnitine accumulation was observed in all model groups, indicating that acute cholestasis was closely related to mitochondrial dysfunction. With a deeper understanding of the mechanism of acute intrahepatic cholestasis, this study also provided a reference for the selection of appropriate chemicals for cholestatic liver disease models.
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Affiliation(s)
- Weiwei Li
- Department of Formulaology, School of Basic Medicine Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui Chen
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yihan Qian
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shouchuan Wang
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zichen Luo
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinjun Shan
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoni Kong
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yueqiu Gao
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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32
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Selective PPARδ agonist seladelpar suppresses bile acid synthesis by reducing hepatocyte CYP7A1 via the fibroblast growth factor 21 signaling pathway. J Biol Chem 2022; 298:102056. [PMID: 35605662 PMCID: PMC9214809 DOI: 10.1016/j.jbc.2022.102056] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 12/30/2022] Open
Abstract
Peroxisome proliferator–activated receptor delta (PPARδ) agonists have been shown to exert beneficial effects in liver disease and reduce total bile acid levels. The mechanism(s) whereby PPARδ agonism reduces bile acid levels are, however, unknown, and therefore the aim of the present study was to investigate the molecular pathways responsible for reducing bile acid synthesis in hepatocytes, following treatment with the selective PPARδ agonist, seladelpar. We show that administration of seladelpar to WT mice repressed the liver expression of cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme for bile acid synthesis, and decreased plasma 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of Cyp7a1. In primary mouse hepatocytes, seladelpar significantly reduced the expression of Cyp7a1 independent of the nuclear bile acid receptor, Farnesoid X receptor. In addition, seladelpar upregulated fibroblast growth factor 21 (Fgf21) in mouse liver, serum, and in cultured hepatocytes. We demonstrate that recombinant Fgf21 protein activated the c-Jun N-terminal kinase (JNK) signaling pathway and repressed Cyp7a1 gene expression in primary hepatocytes. The suppressive effect of seladelpar on Cyp7a1 expression was blocked by a JNK inhibitor as well as in the absence of Fgf21, indicating that Fgf21 plays an indispensable role in PPARδ-mediated downregulation of Cyp7a1. Finally, reduction of CYP7A1 expression by seladelpar was confirmed in primary human hepatocytes. In conclusion, we show that seladelpar reduces bile acid synthesis via an FGF21-dependent mechanism that signals at least partially through JNK to repress CYP7A1.
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33
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Liu Q, Li B, Li Y, Wei Y, Huang B, Liang J, You Z, Li Y, Qian Q, Wang R, Zhang J, Chen R, Lyu Z, Chen Y, Shi M, Xiao X, Wang Q, Miao Q, Fang JY, Gershwin ME, Lian M, Ma X, Tang R. Altered faecal microbiome and metabolome in IgG4-related sclerosing cholangitis and primary sclerosing cholangitis. Gut 2022; 71:899-909. [PMID: 34035120 DOI: 10.1136/gutjnl-2020-323565] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 05/16/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC. DESIGN We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling. RESULTS Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host-microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host-microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes. CONCLUSIONS Our data reveal that IgG4-SC and PSC possess divergent host-microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.
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Affiliation(s)
- Qiaoyan Liu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yikang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yiran Wei
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Bingyuan Huang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jubo Liang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qiwei Qian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jun Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhuwan Lyu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Mingxia Shi
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Merrill Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California Davis, Davis, California, USA
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
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Steuer C, Quattrini D, Raeber J, Waser P, Steuer AE. Easy and convenient millimole-scale synthesis of new, potential biomarkers for gamma-hydroxybutyric acid (GHB) intake - feasible for analytical laboratories. Drug Test Anal 2022; 14:1460-1470. [PMID: 35415886 PMCID: PMC9544675 DOI: 10.1002/dta.3273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 11/06/2022]
Abstract
New biomarkers indicating the abuse of drugs and alcohol are still of major interest for clinical and forensic sciences. The endogenous neurotransmitter and approved drug, gamma-hydroxybutyric acid (GHB), is often illegally used for drug-facilitated crimes by spiking GHB into alcoholic beverages. Analytical detection windows of only 6 hours in blood and 12 hours in urine often too short to provide reliable proof of GHB ingestion. Therefore, new biomarkers are needed to prove exogenous GHB administration. Previously, amino-acid GHB conjugates were discovered in an untargeted metabolomics screening and fatty acid esters with GHB were recently discussed as promising biomarkers to enlarge the analytical detection time windows. However, the development of analytical methods is still slowed down since reference compounds for targeted screenings are still missing. In this paper, we describe simple procedures for the rapid synthesis and purification of amino acid-GHB conjugates as well as fatty acid esters, which can be adopted in analytical and clinical/forensic laboratories. Structural characterization data, together with IR, 1 H-NMR, 13 C-NMR, high resolution mass spectra (MS), and MS/MS spectra in positive and negative ionization mode are reported for all obtained GHB-conjugates and GHB-conjugate precursors.
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Affiliation(s)
- Christian Steuer
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Switzerland
| | - Dario Quattrini
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Switzerland
| | - Justine Raeber
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Switzerland
| | - Philipp Waser
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Switzerland
| | - Andrea E Steuer
- Zurich Institute of Forensic Medicine (ZIFM), Department of Forensic Pharmacology and Toxicology, University of Zurich, Switzerland
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35
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Urinary BA Indices as Prognostic Biomarkers for Complications Associated with Liver Diseases. Int J Hepatol 2022; 2022:5473752. [PMID: 35402050 PMCID: PMC8986411 DOI: 10.1155/2022/5473752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 02/25/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatobiliary diseases and their complications cause the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues, which may exacerbate the underlying condition and lead to unfavorable prognosis. To develop and validate prognostic biomarkers for the prediction of complications of cholestatic liver disease based on urinary BA indices, liquid chromatography-tandem mass spectrometry was used to analyze urine samples from 257 patients with cholestatic liver diseases during a 7-year follow-up period. The urinary BA profile and non-BA parameters were monitored, and logistic regression models were used to predict the prognosis of hepatobiliary disease-related complications. Urinary BA indices were applied to quantify the composition, metabolism, hydrophilicity, and toxicity of the BA profile. We have developed and validated the bile-acid liver disease complication (BALDC) model based on BA indices using logistic regression model, to predict the prognosis of cholestatic liver disease complications including ascites. The mixed BA and non-BA model was the most accurate and provided higher area under the receiver operating characteristic (ROC) and smaller akaike information criterion (AIC) values compared to both non-BA and MELD (models for end stage liver disease) models. Therefore, the mixed BA and non-BA model could be used to predict the development of ascites in patients diagnosed with liver disease at early stages of intervention. This will help physicians to make a better decision when treating hepatobiliary disease-related ascites.
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Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep 2022; 4:100479. [PMID: 35469167 PMCID: PMC9034302 DOI: 10.1016/j.jhepr.2022.100479] [Citation(s) in RCA: 147] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies.
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Meinel K, Szabo D, Dezsofi A, Pohl S, Strini T, Greimel T, Aguiriano-Moser V, Haidl H, Wagner M, Schlagenhauf A, Jahnel J. The Covert Surge: Murine Bile Acid Levels Are Associated With Pruritus in Pediatric Autoimmune Sclerosing Cholangitis. Front Pediatr 2022; 10:903360. [PMID: 35633951 PMCID: PMC9130722 DOI: 10.3389/fped.2022.903360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES The exact etiology of pruritus in chronic cholestasis is unknown. Pruritus intensity does not correlate with common biochemical indices and there is a lack of biomarkers guiding diagnosis and treatment. We explored profiles of bile acids (BA) and muricholic acids (MCA) as well as autotaxin (ATX) antigen levels as potential circulating biomarkers of pruritus in pediatric patients. METHODS In 27 pediatric cholestatic patients [autoimmune sclerosing cholangitis (ASC) n = 20 (with pruritus n = 6, without pruritus n = 14); progressive familial intrahepatic cholestasis (PFIC) n = 7 (with pruritus n = 5, without pruritus n = 2)] and 23 age-matched controls pruritus was assessed by a visual analog scale of pruritus (PVAS). We obtained profiles of serum human BA including MCA using a mass-spectrometry assay and ATX antigen levels with a commercial ELISA. RESULTS PFIC and ASC patients exhibited significantly higher BA-, and MCA levels, than healthy controls, but only PFIC patients showed elevated ATX antigen levels higher [median: 1,650 ng/ml, interquartile rang (IQR): 776.9-3,742] compared to controls (median: 315.9 ng/ml, IQR: 251.1-417.2; PFIC p = 0.0003). ASC patients with pruritus showed only a minor increase in total BA (tBA) levels (median: 76.5 μmol/L, IQR: 54.7-205), but strikingly higher T-conjugated BA (median: 16.4 μmol/L, IQR: 8.9-41.4) and total MCA (tMCA) (median: 1.15 μmol/L, IQR: 0.77-2.44) levels compared to ASC patients without pruritus (tBA median: 24.3 μmol/L, IQR: 16.2-80.8; p < 0.0408; T-conjugated BA median: 1.3 μmol/L, IQR: 0.8-4.9; p = 0.0023; tMCA median: 0.30 μmol/L, IQR: 0.13-0.64, p = 0.0033). BA/MCA profiles distinctly differed depending on presence/absence of pruritus. Different from PFIC patients, ATX antigen levels were not significantly elevated in ASC patients with (median: 665.8 ng/ml, IQR: 357.8-1,203) and without pruritus (median: 391.0 ng/ml, IQR: 283.2-485.6). In ASC patients, tBA, tMCA, and ATX antigen levels did not correlate with pruritus severity. CONCLUSION Despite the same underlying disease, pediatric ASC patients with pruritus exhibit significantly altered BA profiles and MCA levels compared to ASC patients without pruritus. ATX antigen levels seem to have little diagnostic or prognostic meaning in ASC patients. An increased ATX activity alone seems not to be causal for pruritus genesis in ASC patients. CLINICAL TRIAL REGISTRATION [www.drks.de], identifier [DRKS00026913].
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Affiliation(s)
- Katharina Meinel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Doloresz Szabo
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Antal Dezsofi
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Sina Pohl
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Tanja Strini
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Theresa Greimel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Victor Aguiriano-Moser
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Harald Haidl
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Martin Wagner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Axel Schlagenhauf
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Jörg Jahnel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
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Xie AJ, Mai CT, Zhu YZ, Liu XC, Xie Y. Bile acids as regulatory molecules and potential targets in metabolic diseases. Life Sci 2021; 287:120152. [PMID: 34793769 DOI: 10.1016/j.lfs.2021.120152] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/06/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023]
Abstract
Bile acids are important hydroxylated steroids that are synthesized in the liver from cholesterol for intestinal absorption of lipids and other fatty-nutrient. They also display remarkable and immense functions such as regulating immune responses, managing the apoptosis of cells, participating in glucose metabolism, and so on. Some bile acids were used for the treatment or prevention of diseases such as gallstones, primary biliary cirrhosis, and colorectal cancer. Meanwhile, the accumulation of toxic bile acids leads to apoptosis, necrosis, and inflammation. Alteration of bile acids metabolism, as well as the gut microbiota that interacted with bile acids, contributes to the pathogenesis of metabolic diseases. Therefore, the purpose of this review is to summarize the current functions and pre-clinical or clinical applications of bile acids, and to further discuss the alteration of bile acids in metabolic disorders as well as the manipulation of bile acids metabolism as potential therapeutic targets.
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Affiliation(s)
- Ai-Jin Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Chu-Tian Mai
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Yi-Zhun Zhu
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Xian-Cheng Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
| | - Ying Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau.
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Heintze T, Wilhelm D, Schmidlin T, Hofmann U, Zanger UM, Schwab M, Klein K. Effects of Diminished NADPH:cytochrome P450 Reductase in Human Hepatocytes on Lipid and Bile Acid Homeostasis. Front Pharmacol 2021; 12:769703. [PMID: 34867397 PMCID: PMC8634102 DOI: 10.3389/fphar.2021.769703] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/11/2021] [Indexed: 12/16/2022] Open
Abstract
NADPH:cytochrome P450 oxidoreductase (POR) is the obligate electron donor for microsomal cytochrome P450 (CYP) enzymes involved in the biosynthesis of endogenous substances like bile acids and other steroids as well as in the oxidative metabolism of xenobiotics. P450 oxidoreductase also supports other redox enzymes in fatty acid and cholesterol pathways. Recently, we have established CRISPR/Cas9-mediated POR knockdown in a human hepatic cell model, HepaRG, and demonstrated the differential effects of limited POR expression on CYP activity. The aim of the present work was to systematically investigate the impact of POR knockdown with a focus on the expression of ADME (absorption, distribution, metabolism, and excretion) genes and related regulators. Functional consequences have been assessed using quantitative mass spectrometry for targeted metabolomics covering bile acids, and cholesterol and its precursors, and for untargeted proteomics. In addition to the previously described alteration of RNA expression of CYP genes, we showed significant downregulation of transcriptional regulators of drug metabolism and transport, including NR1I3 (CAR), NR1I2 (PXR), NR1H4 (FXR), and NR1H3 (LXRα) in cells with POR gene disruption. Furthermore, POR knockdown resulted in deregulated bile acid and cholesterol biosynthesis demonstrated by low levels of cholic acid derivates and increased concentrations of chenodeoxycholic acid derivates, respectively. Systemic effects of POR knockdown on global protein expression were indicated by downregulation of several metabolic pathways including lipid metabolism and biological oxidation reactions. The deduced protein network map corroborates CYP enzymes as direct interaction partners, whereas changes in lipid metabolism and homeostasis are the result of indirect effects. In summary, our results emphasize a widespread role of POR in various metabolic pathways and provide the first human data on the effects of diminished POR expression on drug and endogenous metabolism in a genomeedited HepaRG cell model.
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Affiliation(s)
- Tamara Heintze
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,Eberhard Karls University, Tübingen, Germany
| | - Denise Wilhelm
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
| | - Thierry Schmidlin
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,Eberhard Karls University, Tübingen, Germany.,Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Ute Hofmann
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,Eberhard Karls University, Tübingen, Germany
| | - Ulrich M Zanger
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,Eberhard Karls University, Tübingen, Germany
| | - Matthias Schwab
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,Departments of Clinical Pharmacology and Biochemistry and Pharmacy, University of Tuebingen, Tübingen, Germany.,Cluster of Excellence IFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Kathrin Klein
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,Eberhard Karls University, Tübingen, Germany
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Gallucci GM, Trottier J, Hemme C, Assis DN, Boyer JL, Barbier O, Ghonem NS. Adjunct Fenofibrate Up-regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis. Hepatol Commun 2021; 5:2035-2051. [PMID: 34558841 PMCID: PMC8631103 DOI: 10.1002/hep4.1787] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/10/2021] [Accepted: 06/25/2021] [Indexed: 12/26/2022] Open
Abstract
Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator-activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up-regulate BA-glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13-15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145-160 mg/day) as standard of care. Serum BA and BA-glucuronide concentrations were measured by liquid chromatography-mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (-76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (-54%), and increased serum BA-glucuronides (+2.1-fold, P < 0.01) versus ursodiol monotherapy. The major serum BA-glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid-6G (+3.7-fold, P < 0.01), hyocholic acid-6G (+2.6-fold, P < 0.05), chenodeoxycholic acid (CDCA)-3G (-36%), and lithocholic acid (LCA)-3G (-42%) versus ursodiol monotherapy. Fenofibrate also up-regulated the expression of uridine 5'-diphospho-glucuronosyltransferases and multidrug resistance-associated protein 3 messenger RNA in primary human hepatocytes. Pearson's correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA-3G (r2 = 0.62, P < 0.0001), deoxycholic acid (DCA)-3G (r2 = 0.48, P < 0.0001), and LCA-3G (r2 = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA-glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA-glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα-mediated anti-cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA-glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.
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Affiliation(s)
- Gina M. Gallucci
- College of Pharmacy, Biomedical and Pharmaceutical SciencesUniversity of Rhode IslandKingstonRIUSA
| | - Jocelyn Trottier
- Laboratory of Molecular PharmacologyEndocrinology and Nephrology AxisCHU de Québec Research CenterLavalQuébecCanada
| | - Christopher Hemme
- College of Pharmacy, Biomedical and Pharmaceutical SciencesUniversity of Rhode IslandKingstonRIUSA
- RI‐INBRE Bioinformatics CoreKingstonRIUSA
| | | | | | - Olivier Barbier
- Laboratory of Molecular PharmacologyEndocrinology and Nephrology AxisCHU de Québec Research CenterLavalQuébecCanada
- Faculty of PharmacyLaval UniversityLavalQuébecCanada
| | - Nisanne S. Ghonem
- College of Pharmacy, Biomedical and Pharmaceutical SciencesUniversity of Rhode IslandKingstonRIUSA
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Petrov PD, Soluyanova P, Sánchez-Campos S, Castell JV, Jover R. Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol 2021; 158:112664. [PMID: 34767876 DOI: 10.1016/j.fct.2021.112664] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/14/2021] [Accepted: 11/04/2021] [Indexed: 12/12/2022]
Abstract
Treatment of β-lactamase positive bacterial infections with a combination of amoxicillin (AMOX) and clavulanic acid (CLAV) causes idiosyncratic drug-induced liver injury (iDILI) in a relevant number of patients, often with features of intrahepatic cholestasis. This study aims to determine serum bile acid (BA) levels in amoxicillin/clavulanate (A+C)-iDILI patients and to investigate the mechanism of cholestasis by A+C in human in vitro hepatic models. In six A+C-iDILI patients, significant elevations of serum primary conjugated BA definitely demonstrated A+C-induced cholestasis. In cultured human Upcyte hepatocytes and HepG2 cells, CLAV was more cytotoxic than AMOX, and, at subcytotoxic concentrations, it altered the expression of more than 1,300 genes. CLAV, but not AMOX, downregulated the expression of key genes for BA transport (BSEP, NTCP, OSTα and MDR2) and synthesis (CYP7A1 and CYP8B1). CLAV also caused early oxidative stress, with reduced GSH/GSSG ratio, along with induction of antioxidant nuclear factor erythroid 2-related factor 2 (NRF2) target genes. Activation of NRF2 by sulforaphane also resulted in downregulation of NTCP, OSTα, ABCG5, CYP7A1 and CYP8B1. CLAV also inhibited the BA-sensor farnesoid X receptor (FXR), in agreement with the downregulation of FXR targets BSEP, OSTα and ABCG5. We conclude that CLAV, the culprit molecule in A+C, downregulates several key biliary transporters by modulating NRF2 and FXR signaling, thus likely promoting intrahepatic cholestasis. On top of that, increased ROS production and GSH depletion may aggravate the cholestatic injury by A+C.
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Affiliation(s)
- Petar D Petrov
- Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain; CIBERehd, ISCIII, Madrid, Spain
| | | | - Sonia Sánchez-Campos
- CIBERehd, ISCIII, Madrid, Spain; Biomedicine Institute (IBIOMED), University of León, Spain
| | - José V Castell
- Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain; CIBERehd, ISCIII, Madrid, Spain; Dep. Biochemistry & Molecular Biology, University of Valencia, Spain
| | - Ramiro Jover
- Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain; CIBERehd, ISCIII, Madrid, Spain; Dep. Biochemistry & Molecular Biology, University of Valencia, Spain.
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Azer SA, Hasanato R. Use of bile acids as potential markers of liver dysfunction in humans: A systematic review. Medicine (Baltimore) 2021; 100:e27464. [PMID: 34731122 PMCID: PMC8519223 DOI: 10.1097/md.0000000000027464] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/05/2021] [Accepted: 09/20/2021] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE This study aimed to determine the effectiveness of using total, individual serum, or urinary bile acids (BA) as potential markers of liver dysfunction. METHODS We searched the PubMed and Web of Science databases using the following keywords- "serum bile acids," "liver dysfunction," "liver injury," "liver disease," "traditional liver function tests," "Chronic liver disease," "acute liver injury". The search was complemented by manual screening of the list of references for relevant articles. We selected only English-language manuscripts for adult patients based on predetermined inclusion and exclusion criteria. Animal studies and studies on neonates and children were not included. OUTCOME MEASURES Changes in BA concentrations or ratios at or prior to changes in liver function tests. RESULTS A total of 547 studies were identified, of which 28 were included after reading the entire manuscript. These studies included 1630 patients and 836 controls published between 1990 and 2017. The methods used in BA assays varied significantly, and the studies did not agree. on specific individual BA or BA ratios as biomarkers of specific liver injury or dysfunction. Except for the prognostic value of BA in intrahepatic cholestasis of pregnancy (ICP), studies have failed to provide evidence for BA as a liver biomarker. CONCLUSIONS Despite the research conducted on BA for over 27 years, there are inconsistencies in the reported results and a lack of solid evidence to support the use of individual BA or BA ratios as biomarkers of liver injury. Adequately conducted studies needed to resolve this limitation in the literature.
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Affiliation(s)
- Samy A. Azer
- Gastroenterologist and Chair of Curriculum Development and Research Unit, Department of Medical Education, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Rana Hasanato
- Clinical Biochemistry Consultant and Chair of Biochemistry Unit, Director of the Laboratories at King Saud University Medical City, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Łuczykowski K, Warmuzińska N, Bojko B. Current approaches to the analysis of bile and the determination of bile acids in various biological matrices as supportive tools to traditional diagnostic testing for liver dysfunction and biliary diseases. Trends Analyt Chem 2021. [DOI: 10.1016/j.trac.2021.116307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Maverakis E, Merleev AA, Park D, Kailemia MJ, Xu G, Ruhaak LR, Kim K, Hong Q, Li Q, Leung P, Liakos W, Wan YJY, Bowlus CL, Marusina AI, Lal NN, Xie Y, Luxardi G, Lebrilla CB. Glycan biomarkers of autoimmunity and bile acid-associated alterations of the human glycome: Primary biliary cirrhosis and primary sclerosing cholangitis-specific glycans. Clin Immunol 2021; 230:108825. [PMID: 34403816 DOI: 10.1016/j.clim.2021.108825] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/13/2022]
Abstract
We have recently introduced multiple reaction monitoring (MRM) mass spectrometry as a novel tool for glycan biomarker research and discovery. Herein, we employ this technique to characterize the site-specific glycan alterations associated with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Glycopeptides associated with disease severity were also identified. Multinomial regression modelling was employed to construct and validate multi-analyte diagnostic models capable of accurately distinguishing PBC, PSC, and healthy controls from one another (AUC = 0.93 ± 0.03). Finally, to investigate how disease-relevant environmental factors can influence glycosylation, we characterized the ability of bile acids known to be differentially expressed in PBC to alter glycosylation. We hypothesize that this could be a mechanism by which altered self-antigens are generated and become targets for immune attack. This work demonstrates the utility of the MRM method to identify diagnostic site-specific glycan classifiers capable of distinguishing even related autoimmune diseases from one another.
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Affiliation(s)
- Emanual Maverakis
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA.
| | - Alexander A Merleev
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Dayoung Park
- Department of Chemistry, University of California Davis, Davis, CA, USA; Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Wyss Institute of Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | | | - Gege Xu
- Department of Chemistry, University of California Davis, Davis, CA, USA
| | - L Renee Ruhaak
- Department of Chemistry, University of California Davis, Davis, CA, USA; Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, ZA, Leiden, the Netherlands
| | - Kyoungmi Kim
- Division of Biostatistics, Department of Public Health Sciences, University of California Davis, Davis, CA, USA
| | - Qiuting Hong
- Department of Chemistry, University of California Davis, Davis, CA, USA
| | - Qiongyu Li
- Department of Chemistry, University of California Davis, Davis, CA, USA
| | - Patrick Leung
- Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis, CA, USA
| | - William Liakos
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, UC Davis School of Medicine, CA, USA
| | - Alina I Marusina
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Nelvish N Lal
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Yixuan Xie
- Department of Chemistry, University of California Davis, Davis, CA, USA
| | - Guillaume Luxardi
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Carlito B Lebrilla
- Department of Chemistry, University of California Davis, Davis, CA, USA; Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA; Foods for Health Institute, University of California Davis, Davis, CA, USA
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Alamoudi JA, Li W, Gautam N, Olivera M, Meza J, Mukherjee S, Alnouti Y. Bile acid indices as biomarkers for liver diseases I: Diagnostic markers. World J Hepatol 2021; 13:433-455. [PMID: 33959226 PMCID: PMC8080550 DOI: 10.4254/wjh.v13.i4.433] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/11/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis. AIM To discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS We analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between 300 patients with hepatobiliary diseases vs 103 healthy controls by statistical analysis. The BA profile was characterized using BA indices, which quantifies the composition, metabolism, hydrophilicity, and toxicity of the BA profile. BA indices have much lower inter- and intra-individual variability compared to absolute concentrations of BA. In addition, BA indices demonstrate high area under the receiver operating characteristic curves, and changes of BA indices are associated with the risk of having a liver disease, which demonstrates their use as diagnostic biomarkers for cholestatic liver diseases. RESULTS Total and individual BA concentrations were higher in all patients. The percentage of secondary BA (lithocholic acid and deoxycholic acid) was significantly lower, while the percentage of primary BA (chenodeoxycholic acid, cholic acid, and hyocholic acid) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients than controls. The increase in the non-12α-OH BA was more profound than 12α-OH BA (cholic acid and deoxycholic acid) causing a decrease in the 12α-OH/ non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases. CONCLUSION BA indices have much lower inter- and intra-individual variability compared to absolute BA concentrations and changes of BA indices are associated with the risk of developing liver diseases.
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Affiliation(s)
- Jawaher Abdullah Alamoudi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Wenkuan Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Nagsen Gautam
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Marco Olivera
- Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Jane Meza
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Sandeep Mukherjee
- Department of Internal Medicine, College of Medicine, Creighton University Medical Center, Omaha, NE 68124, United States
| | - Yazen Alnouti
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States.
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Blesl A, Stadlbauer V. The Gut-Liver Axis in Cholestatic Liver Diseases. Nutrients 2021; 13:nu13031018. [PMID: 33801133 PMCID: PMC8004151 DOI: 10.3390/nu13031018] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
The gut-liver axis describes the physiological interplay between the gut and the liver and has important implications for the maintenance of health. Disruptions of this equilibrium are an important factor in the evolution and progression of many liver diseases. The composition of the gut microbiome, the gut barrier, bacterial translocation, and bile acid metabolism are the key features of this cycle. Chronic cholestatic liver diseases include primary sclerosing cholangitis, the generic term secondary sclerosing cholangitis implying the disease secondary sclerosing cholangitis in critically ill patients and primary biliary cirrhosis. Pathophysiology of these diseases is not fully understood but seems to be multifactorial. Knowledge about the alterations of the gut-liver axis influencing the pathogenesis and the outcome of these diseases has considerably increased. Therefore, this review aims to describe the function of the healthy gut-liver axis and to sum up the pathological changes in these cholestatic liver diseases. The review compromises the actual level of knowledge about the gut microbiome (including the mycobiome and the virome), the gut barrier and the consequences of increased gut permeability, the effects of bacterial translocation, and the influence of bile acid composition and pool size in chronic cholestatic liver diseases. Furthermore, therapeutic implications and future scientific objectives are outlined.
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Affiliation(s)
- Andreas Blesl
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Correspondence:
| | - Vanessa Stadlbauer
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
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Pieters A, Gijbels E, Cogliati B, Annaert P, Devisscher L, Vinken M. Biomarkers of cholestasis. Biomark Med 2021; 15:437-454. [PMID: 33709780 DOI: 10.2217/bmm-2020-0691] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cholestasis is a major pathological manifestation, often resulting in detrimental liver conditions, which occurs in a variety of indications collectively termed cholestatic liver diseases. The frequent asymptomatic character and complexity of cholestasis, together with the lack of a straightforward biomarker, hampers early detection and treatment of the condition. The 'omics' era, however, has resulted in a plethora of cholestatic indicators, yet a single clinically applicable biomarker for a given cholestatic disease remains missing. The criteria to fulfil as an ideal biomarker as well as the challenging molecular pathways in cholestatic liver diseases advocate for a scenario in which multiple biomarkers, originating from different domains, will be assessed concomitantly. This review gives an overview of classical clinical and novel molecular biomarkers in cholestasis, focusing on their benefits and drawbacks.
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Affiliation(s)
- Alanah Pieters
- Department of In Vitro Toxicology & Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, 1090, Belgium
| | - Eva Gijbels
- Department of In Vitro Toxicology & Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, 1090, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine & Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, Cidade Universitária, SP, 05508-270, Brazil
| | - Pieter Annaert
- Drug Delivery & Disposition, Department of Pharmaceutical & Pharmacological Sciences, Katholieke Universiteit Leuven, ON II Herestraat 49, Box 921, Leuven, 3000, Belgium
| | - Lindsey Devisscher
- Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Faculty of Medicine & Health Sciences, Ghent University, C Heymanslaan 10, Ghent, 9000, Belgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology & Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, 1090, Belgium
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Langedijk JAGM, Beuers UH, Oude Elferink RPJ. Cholestasis-Associated Pruritus and Its Pruritogens. Front Med (Lausanne) 2021; 8:639674. [PMID: 33791327 PMCID: PMC8006388 DOI: 10.3389/fmed.2021.639674] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
Pruritus is a debilitating symptom of various cholestatic disorders, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inherited progressive familial intrahepatic cholestasis (PFIC). The molecular mechanisms leading to cholestasis-associated pruritus are still unresolved and the involved pruritogens are indecisive. As a consequence of pruritus, patients suffer from sleep deprivation, loss of daytime concentration, auto-mutilation and sometimes even suicidal ideations. Current guideline-approved therapy of cholestasis-associated pruritus includes stepwise administration of several medications, which may alleviate complaints in some, but not all affected patients. Therefore, also experimental therapeutic approaches are required to improve patients' quality of life. This article reviews the current state of research on pruritogens and their receptors, and shortly discusses the most recent experimental therapies.
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Affiliation(s)
| | | | - Ronald P. J. Oude Elferink
- Amsterdam University Medical Centers, Tytgat Institute for Liver and Intestinal Research, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), University of Amsterdam, Amsterdam, Netherlands
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Gagnon M, Trottier J, Weisnagel SJ, Gagnon C, Carreau A, Barbier O, Morisset A. Bile acids during pregnancy: Trimester variations and associations with glucose homeostasis. Health Sci Rep 2021; 4:e243. [PMID: 33614980 PMCID: PMC7875570 DOI: 10.1002/hsr2.243] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/08/2020] [Accepted: 01/11/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS Bile acids are known to contribute to hepatic glucose and lipid metabolism regulation. Although glucose homeostasis sustains well-characterized modifications during uncomplicated pregnancies, changes in bile acids concentrations and relative proportions throughout pregnancy remain unknown. Furthermore, literature shows strong associations between bile acids profiles and glucose homeostasis under normal metabolic conditions. We seek, first, to characterize bile acids' metabolic changes across trimesters and, second, to evaluate associations between changes in bile acids and glucose homeostasis indexes in the first and second trimesters. METHODS A total of 78 women were recruited and followed at each trimester of pregnancy. Fasting serum samples were collected once per trimester in which quantitative measurement of 30 different bile acids' molecules were performed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Glucose homeostasis indexes were measured in the first and second trimesters, after a 12-hour fast and following a 75 g oral glucose tolerance test. RESULTS Total bile acids increased from the first trimester to late pregnancy, along with the cholic acid: chenodeoxycholic acid and conjugated: unconjugated bile acids ratios. Changes in bile acids were positively associated with elevated peripheral and hepatic insulin resistance indexes, as well as with trimestral changes in these indexes. CONCLUSION Our findings suggest that modifications occurring in bile acids' profiles during normal pregnancy are associated with changes in glucose homeostasis. Further research is needed to examine the nature of those associations and the possible outcome of bile acids changes on pathological glucose homeostasis alterations during pregnancy.
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Affiliation(s)
- Marianne Gagnon
- School of NutritionLaval UniversityQuebecCanada
- Endocrinology and Nephrology UnitCHU of Québec‐Université Laval Research CenterQuebecCanada
- Centre NUTRISS, Institute of Nutrition and Functional FoodsLaval UniversityQuebecCanada
| | - Jocelyn Trottier
- Endocrinology and Nephrology UnitCHU of Québec‐Université Laval Research CenterQuebecCanada
- Laboratory of Molecular PharmacologyCHU of Québec‐Université Laval Research CenterQuebecCanada
| | - S. John Weisnagel
- Endocrinology and Nephrology UnitCHU of Québec‐Université Laval Research CenterQuebecCanada
- Department of MedicineLaval UniversityQuebecCanada
| | - Claudia Gagnon
- Endocrinology and Nephrology UnitCHU of Québec‐Université Laval Research CenterQuebecCanada
- Department of MedicineLaval UniversityQuebecCanada
| | - Anne‐Marie Carreau
- Endocrinology and Nephrology UnitCHU of Québec‐Université Laval Research CenterQuebecCanada
- Department of MedicineLaval UniversityQuebecCanada
| | - Olivier Barbier
- Endocrinology and Nephrology UnitCHU of Québec‐Université Laval Research CenterQuebecCanada
- Laboratory of Molecular PharmacologyCHU of Québec‐Université Laval Research CenterQuebecCanada
- Faculty of PharmacyLaval UniversityQuebecCanada
| | - Anne‐Sophie Morisset
- School of NutritionLaval UniversityQuebecCanada
- Endocrinology and Nephrology UnitCHU of Québec‐Université Laval Research CenterQuebecCanada
- Centre NUTRISS, Institute of Nutrition and Functional FoodsLaval UniversityQuebecCanada
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50
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Stepien M, Keski-Rahkonen P, Kiss A, Robinot N, Duarte-Salles T, Murphy N, Perlemuter G, Viallon V, Tjønneland A, Rostgaard-Hansen AL, Dahm CC, Overvad K, Boutron-Ruault MC, Mancini FR, Mahamat-Saleh Y, Aleksandrova K, Kaaks R, Kühn T, Trichopoulou A, Karakatsani A, Panico S, Tumino R, Palli D, Tagliabue G, Naccarati A, Vermeulen RCH, Bueno-de-Mesquita HB, Weiderpass E, Skeie G, Ramón Quirós J, Ardanaz E, Mokoroa O, Sala N, Sánchez MJ, Huerta JM, Winkvist A, Harlid S, Ohlsson B, Sjöberg K, Schmidt JA, Wareham N, Khaw KT, Ferrari P, Rothwell JA, Gunter M, Riboli E, Scalbert A, Jenab M. Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study. Int J Cancer 2021; 148:609-625. [PMID: 32734650 DOI: 10.1002/ijc.33236] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 06/16/2020] [Accepted: 06/26/2020] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.
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Affiliation(s)
- Magdalena Stepien
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Pekka Keski-Rahkonen
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Agneta Kiss
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Nivonirina Robinot
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Talita Duarte-Salles
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
- Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain
| | - Neil Murphy
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Gabriel Perlemuter
- INSERM UMRS U996 - Intestinal Microbiota, Macrophages and Liver Inflammation, Clamart, France
- Université Paris-Sud, Clamart, France
- AP-HP, Hepato-gastroenterology and Nutrition, Antoine-Béclère Hospital, Clamart, France
| | - Vivian Viallon
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Anne Tjønneland
- Diet, Genes and Environment Unit, Danish Cancer Society Research Center, Copenhagen, Denmark
| | | | - Christina C Dahm
- Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Kim Overvad
- Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
- Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
| | - Marie-Christine Boutron-Ruault
- CESP, Faculté de médecine-Université Paris-Sud, Faculté de médecine-UVSQ, INSERM, Université Paris-Saclay, Villejuif, France
- Institut Gustave Roussy, Villejuif, France
| | - Francesca Romana Mancini
- CESP, Faculté de médecine-Université Paris-Sud, Faculté de médecine-UVSQ, INSERM, Université Paris-Saclay, Villejuif, France
- Institut Gustave Roussy, Villejuif, France
| | - Yahya Mahamat-Saleh
- CESP, Faculté de médecine-Université Paris-Sud, Faculté de médecine-UVSQ, INSERM, Université Paris-Saclay, Villejuif, France
- Institut Gustave Roussy, Villejuif, France
| | - Krasimira Aleksandrova
- Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept. of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Karakatsani
- Hellenic Health Foundation, Athens, Greece
- Second Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, Haidari, Greece
| | - Salvatore Panico
- Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
| | - Rosario Tumino
- Cancer Registry and Histopathology Department, Provincial Health Authority (ASP) Ragusa, Ragusa, Italy
| | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy
| | - Giovanna Tagliabue
- Lombardy Cancer Registry Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessio Naccarati
- Molecular and Genetic Epidemiology Unit, Italian Institute for Genomic Medicine (IIGM) Torino, Torino, Italy
| | - Roel C H Vermeulen
- Institute of Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | - Hendrik Bastiaan Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Elisabete Weiderpass
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Guri Skeie
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | | | - Eva Ardanaz
- Navarra Public Health Institute, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Olatz Mokoroa
- CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Public Health Division of Gipuzkoa, Biodonostia Research Institute, San Sebastian, Spain
| | - Núria Sala
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain
| | - Maria-Jose Sánchez
- CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs. Granada. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
| | - José María Huerta
- CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain
| | - Anna Winkvist
- The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
- Department of Public Health and Clinical Medicine, Nutrition Research, Umeå University, Umeå, Sweden
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Bodil Ohlsson
- Skåne University Hospital, Department of Internal Medicine, Lund University, Malmö, Sweden
| | - Klas Sjöberg
- Skåne University Hospital, Department of Gastroenterology and Nutrition, Lund University, Malmö, Sweden
| | - Julie A Schmidt
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Nick Wareham
- MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Kay-Tee Khaw
- University of Cambridge, School of Clinical Medicine, Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, UK
| | - Pietro Ferrari
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Joseph A Rothwell
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
- Institut Gustave Roussy, Villejuif, France
| | - Marc Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Augustin Scalbert
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Mazda Jenab
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
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