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Kim DY, Shin SC, Kim GJ, Eom JI, Han CH, Pan CH, Lee JK. The Beneficial Effects of Ethanol Extract of the Microalga Phaeodactylum tricornutum in Alcoholic Liver Disease. Int J Mol Sci 2025; 26:3851. [PMID: 40332498 PMCID: PMC12027534 DOI: 10.3390/ijms26083851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/13/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
Alcoholic liver disease (ALD) is a condition resulting from liver damage linked to excessive drinking over a brief duration. It poses a significant public health challenge globally, with its prevalence and morbidity rising annually due to escalating rates of alcohol abuse, which adversely affect human health. Phaeodactylum tricornutum (PT), a diatom species of microalgae, is reported to possess active components that provide anti-inflammatory and antioxidant benefits. This study aimed to investigate the preventive and therapeutic effects of PT extract on ALD. To address our purpose, we used ethanol diet induced live disease model. Mice fed an ethanol diet showed less weight gain and higher levels of AST and ALT compared to those fed a regular diet. PT extract suppressed the inhibition of weight gain and the increase in AST/ALT levels caused by an ethanol diet. In addition, PT extract also prevented liver tissue damage caused by an ethanol diet. Thus, the effect of PT on ALD was found to be related to the inhibition of mitogen-activated protein kinase (MAP kinases) phosphorylation and TNF-α production.
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Affiliation(s)
- Dae Yoon Kim
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea;
| | - Seung Cheol Shin
- Department of Biology Education, College of Education, Chungbuk National University, Cheongju 28160, Republic of Korea; (S.C.S.); (G.J.K.)
| | - Gab Jung Kim
- Department of Biology Education, College of Education, Chungbuk National University, Cheongju 28160, Republic of Korea; (S.C.S.); (G.J.K.)
| | - Jae-In Eom
- Microalgae Ask Us Co., Ltd., Gangneung 25441, Republic of Korea; (J.-I.E.); (C.-H.H.)
| | - Cheol-Ho Han
- Microalgae Ask Us Co., Ltd., Gangneung 25441, Republic of Korea; (J.-I.E.); (C.-H.H.)
| | - Cheol-Ho Pan
- Microalgae Ask Us Co., Ltd., Gangneung 25441, Republic of Korea; (J.-I.E.); (C.-H.H.)
| | - Jae Kwon Lee
- Department of Biology Education, College of Education, Chungbuk National University, Cheongju 28160, Republic of Korea; (S.C.S.); (G.J.K.)
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Li W, Xia Y, Yang J, Sanyal AJ, Shah VH, Chalasani NP, Yu Q. Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis. Front Immunol 2024; 15:1377236. [PMID: 39640267 PMCID: PMC11617321 DOI: 10.3389/fimmu.2024.1377236] [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] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024] Open
Abstract
Background Alcoholic hepatitis (AH) is characterized by intense systemic and liver inflammation, posing significant risks of health complications and mortality. While inflammation is a crucial defense mechanism against injury and infection, its timely resolution is essential to prevent tissue damage and restore tissue homeostasis. The resolution of inflammation is primarily governed by specialized pro-resolving mediators (SPMs), lipid metabolites derived from w-6 and w-3 poly-unsaturated fatty acids (PUFAs). Currently, the balance between pro-inflammatory lipid mediators (PLMs) and SPMs in the w-6 and w-3 PUFA metabolic pathways and the impact of alcohol abstinence on profiles of PLMs and SPMs in AH patients are not well studied. Methods In this study, we used LC-MS/MS and ELISA to quantify levels of lipid mediators (LMs) and their precursors in the plasma samples from 58 AH patients, 29 heavy drinkers without overt liver diseases (HDCs), and 35 healthy controls (HCs). Subsequently, we assessed correlations of altered LMs with clinical parameters and inflammatory mediators. Furthermore, we conducted a longitudinal study to analyze the effects of alcohol abstinence on LMs over 6- and 12-month follow-ups. Results AH patients exhibited significantly higher plasma levels of w-6 PLMs (PGD2 and LTB4) and SPM RvE1 compared to HDCs or HCs. Conversely, the SPM LXA4 was significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity and various inflammatory cytokines. Particularly, the LTB4/LXA4 ratio was substantially elevated in AH patients relative to HDCs and HCs. This altered ratio displayed a positive correlation with the MELD score. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence.
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Affiliation(s)
- Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Ying Xia
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Jing Yang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Arun J. Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Naga P. Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
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Castillo-Castañeda SM, Rivera-Espinosa L, Gómez-Garduño J, Cordova-Gallardo J, Chávez-Pacheco JL, Méndez-Sánchez N. Identification and quantification of the molecular species of bilirubin BDG, BMG and UCB by LC‒MS/MS in hyperbilirubinemic human serum. PLoS One 2024; 19:e0313044. [PMID: 39561208 PMCID: PMC11575834 DOI: 10.1371/journal.pone.0313044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 10/18/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND AND AIMS Unconjugated bilirubin (UCB) is a byproduct of the heme group that indicates irregularities in the metabolism of several important biological molecules, such as hemoglobin. UCB is processed by hepatic UGT1A1, which catalyzes its conjugation to the metabolites bilirubin diglucuronide (BDG) and bilirubin monoglucuronide (BMG). The serum concentrations of BDG and BMG may indicate liver injury or dysfunction. The aim of this study was to standardize and validate a method for the identification and simultaneous quantification of BMG, BDG and UCB by LC‒MS/MS. METHODS Liquid‒liquid extraction allows the separation of UCB, BMG and BDG from the serum of healthy subjects or patients with liver injury. Detection and quantification were performed using an LC‒MS/MS method. Compound separation was achieved with a BEH-C18 column at 40°C. The mobile phase was prepared with 5 mM ammonium acetate (pH 6) and acetonitrile, and a flow gradient was applied. RESULTS This is the first study to directly quantify BMG and UCB levels in human serum; no postcalculations or correction factors are needed. However, BDG quantification requires calculations and a correction factor. We identified the molecular species with ionic transitions m/z1+ 585.4 > 299.2 for UCB, 761.3 > 475.3 for BMG, 937.3 > 299.5 for BDG and mesobilirubin 589.4 > 301.3 (IS). CONCLUSION The procedures used in this study allowed the simultaneous identification and quantification of the molecular species of bilirubin, BDG, BMG and UCB. Analysis of the serum levels in patients with hyperbilirubinemia revealed that patients with acute-on-chronic liver failure had elevated levels of these species.
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Affiliation(s)
- Stephany M. Castillo-Castañeda
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
- Medical, Dental and Health Sciences Master and Doctorate Program, National Autonomous University of Mexico, Mexico City, Mexico
| | | | | | - Jacqueline Cordova-Gallardo
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Hepatology, General Surgery Department, General Hospital Dr. Manuel Gea González, Mexico City, Mexico
| | | | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
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Sule RO, Morisseau C, Yang J, Hammock BD, Gomes AV. Triazine herbicide prometryn alters epoxide hydrolase activity and increases cytochrome P450 metabolites in murine livers via lipidomic profiling. Sci Rep 2024; 14:19135. [PMID: 39160161 PMCID: PMC11333623 DOI: 10.1038/s41598-024-69557-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 08/06/2024] [Indexed: 08/21/2024] Open
Abstract
Oxylipins are a group of bioactive fatty acid metabolites generated via enzymatic oxygenation. They are notably involved in inflammation, pain, vascular tone, hemostasis, thrombosis, immunity, and coagulation. Oxylipins have become the focus of therapeutic intervention since they are implicated in many conditions, such as nonalcoholic fatty liver disease, cardiovascular disease, and aging. The liver plays a crucial role in lipid metabolism and distribution throughout the organism. Long-term exposure to pesticides is suspected to contribute to hepatic carcinogenesis via notable disruption of lipid metabolism. Prometryn is a methylthio-s-triazine herbicide used to control the growth of annual broadleaf and grass weeds in many cultivated plants. The amounts of prometryn documented in the environment, mainly waters, soil and plants used for human and domestic consumption are significantly high. Previous research revealed that prometryn decreased liver development during zebrafish embryogenesis. To understand the mechanisms by which prometryn could induce hepatotoxicity, the effect of prometryn (185 mg/kg every 48 h for seven days) was investigated on hepatic and plasma oxylipin levels in mice. Using an unbiased LC-MS/MS-based lipidomics approach, prometryn was found to alter oxylipins metabolites that are mainly derived from cytochrome P450 (CYP) and lipoxygenase (LOX) in both mice liver and plasma. Lipidomic analysis revealed that the hepatotoxic effects of prometryn are associated with increased epoxide hydrolase (EH) products, increased sEH and mEH enzymatic activities, and induction of oxidative stress. Furthermore, 9-HODE and 13-HODE levels were significantly increased in prometryn treated mice liver, suggesting increased levels of oxidation products. Together, these results support that sEH may be an important component of pesticide-induced liver toxicity.
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Affiliation(s)
- Rasheed O Sule
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA
- Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Christophe Morisseau
- Department of Entomology and Nematology, University of California, Davis, Davis, CA, 95616, USA
- Comprehensive Cancer Center, University of California, Davis, Davis, CA, 95616, USA
| | - Jun Yang
- Department of Entomology and Nematology, University of California, Davis, Davis, CA, 95616, USA
- Comprehensive Cancer Center, University of California, Davis, Davis, CA, 95616, USA
| | - Bruce D Hammock
- Department of Entomology and Nematology, University of California, Davis, Davis, CA, 95616, USA
- Comprehensive Cancer Center, University of California, Davis, Davis, CA, 95616, USA
| | - Aldrin V Gomes
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA.
- Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, 95616, USA.
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Liu X, Tu P, Zhang Y, Xu W, Shan J, Gao B. Aldicarb disturbed bile acid, steroid hormone and oxylipin homeostasis in C57BL/6 J mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 275:116285. [PMID: 38564866 DOI: 10.1016/j.ecoenv.2024.116285] [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: 12/06/2023] [Revised: 03/26/2024] [Accepted: 03/31/2024] [Indexed: 04/04/2024]
Abstract
Mounting evidence has shown that the gut microbiota plays a key role in human health. The homeostasis of the gut microbiota could be affected by many factors, including environmental chemicals. Aldicarb is a carbamate insecticide used to control a variety of insects and nematode pests in agriculture. Aldicarb is highly toxic and its wide existence has become a global public health concern. In our previous study, we have demonstrated that aldicarb disturbed the gut microbial community structure and composition. However, the impacts of aldicarb on gut microbiota-derived metabolites, bile acids, remain elusive. In present study, we performed targeted metabolomics analysis to explore the effects of aldicarb exposure on bile acids, as well as steroid hormones and oxylipins in the serum, feces and liver of C57BL/6 J mice. Our results showed that aldicarb exposure disturbed the level of various bile acids, steroid hormones and oxylipins in the serum and feces of C57BL/6 J mice. In the liver, the level of cortisol was decreased, meanwhile 15,16-dihydroxyoctadeca-9,12-dienoic acid was increased in aldicarb-treated mice. Metagenomic sequencing analysis showed that the relative abundance of a bile salt hydrolase, choloylglycine hydrolase (EC:3.5.1.24) and a sulfatase enzyme involved in steroid hormone metabolism, arylsulfatase, was significantly increased by aldicarb exposure. Furthermore, correlations were found between gut microbiota and various serum metabolites. The results from this study are helpful to improve the understanding of the impact of carbamate insecticides on host and microbial metabolism.
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Affiliation(s)
- Xin Liu
- Changwang School of Honors, Nanjing University of Information Science and Technology, Nanjing 210044, China.
| | - Pengcheng Tu
- Department of Environmental Health, Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Hangzhou 310051, China.
| | - Ying Zhang
- West Coast Metabolomics Center, University of California Davis, Davis, CA 95616, USA.
| | - Weichen Xu
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Pediatric Respiratory Disease, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Jinjun Shan
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Pediatric Respiratory Disease, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Bei Gao
- School of Marine Sciences, Nanjing University of Information Science and Technology, Nanjing 210044, China; Key Laboratory of Hydrometeorological Disaster Mechanism and Warning of Ministry of Water Resources, Nanjing University of Information Science and Technology, Nanjing 210044, China.
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Gutierrez V, Kim-Vasquez D, Shum M, Yang Q, Dikeman D, Louie SG, Shirihai OS, Tsukamoto H, Liesa M. The mitochondrial biliverdin exporter ABCB10 in hepatocytes mitigates neutrophilic inflammation in alcoholic hepatitis. Redox Biol 2024; 70:103052. [PMID: 38290384 PMCID: PMC10844117 DOI: 10.1016/j.redox.2024.103052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/19/2024] [Indexed: 02/01/2024] Open
Abstract
Acute liver failure caused by alcoholic hepatitis (AH) is only effectively treated with liver transplantation. Livers of patients with AH show a unique molecular signature characterized by defective hepatocellular redox metabolism, concurrent to hepatic infiltration of neutrophils that express myeloperoxidase (MPO) and form neutrophil extracellular traps (NETs). Exacerbated NET formation and MPO activity contribute to liver damage in mice with AH and predicts poor prognosis in AH patients. The identification of pathways that maladaptively exacerbate neutrophilic activity in liver could inform of novel therapeutic approaches to treat AH. Whether the redox defects of hepatocytes in AH directly exacerbate neutrophilic inflammation and NET formation is unclear. Here we identify that the protein content of the mitochondrial biliverdin exporter ABCB10, which increases hepatocyte-autonomous synthesis of the ROS-scavenger bilirubin, is decreased in livers from humans and mice with AH. Increasing ABCB10 expression selectively in hepatocytes of mice with AH is sufficient to decrease MPO gene expression and histone H3 citrullination, a specific marker of NET formation. These anti-inflammatory effects can be explained by ABCB10 function reducing ROS-mediated actions in liver. Accordingly, ABCB10 gain-of-function selectively increased the mitochondrial GSH/GSSG ratio and decreased hepatic 4-HNE protein adducts, without elevating mitochondrial fat expenditure capacity, nor mitigating steatosis and hepatocyte death. Thus, our study supports that ABCB10 function regulating ROS-mediated actions within surviving hepatocytes mitigates the maladaptive activation of infiltrated neutrophils in AH. Consequently, ABCB10 gain-of-function in human hepatocytes could potentially decrease acute liver failure by decreasing the inflammatory flare caused by excessive neutrophil activity.
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Affiliation(s)
- Vincent Gutierrez
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Molecular and Cellular Integrative Physiology, Interdepartmental Program, University of California, Los Angeles, CA, USA
| | - Doyeon Kim-Vasquez
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Michael Shum
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Qihong Yang
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Dante Dikeman
- Department of Clinical Pharmacy, School of Pharmacy, The University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90089, USA
| | - Stan G Louie
- Department of Clinical Pharmacy, School of Pharmacy, The University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90089, USA
| | - Orian S Shirihai
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Molecular and Cellular Integrative Physiology, Interdepartmental Program, University of California, Los Angeles, CA, USA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Marc Liesa
- Institut de Biologia Molecular de Barcelona, IBMB, CSIC, Barcelona, Catalonia, Spain.
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Wang J, Wang X, Peng H, Dong Z, Liangpunsakul S, Zuo L, Wang H. Platelets in Alcohol-Associated Liver Disease: Interaction With Neutrophils. Cell Mol Gastroenterol Hepatol 2024; 18:41-52. [PMID: 38461963 PMCID: PMC11127035 DOI: 10.1016/j.jcmgh.2024.03.001] [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: 11/03/2023] [Revised: 02/29/2024] [Accepted: 03/01/2024] [Indexed: 03/12/2024]
Abstract
Alcohol-associated liver disease (ALD) is a major contributor to liver-related mortality globally. An increasing body of evidence underscores the pivotal role of platelets throughout the spectrum of liver injury and recovery, offering unique insights into liver homeostasis and pathobiology. Alcoholic-associated steatohepatitis is characterized by the infiltration of hepatic neutrophils. Recent studies have highlighted the extensive distance neutrophils travel through sinusoids to reach the liver injury site, relying on a platelet-paved endothelium for efficient crawling. The adherence of platelets to neutrophils is crucial for accurate migration from circulation to the inflammatory site. A gradual decline in platelet levels leads to diminished neutrophil recruitment. Platelets exhibit the ability to activate neutrophils. Platelet activation is heightened upon the release of platelet granule contents, which synergistically activate neutrophils through their respective receptors. The sequence culminates in the formation of platelet-neutrophil complexes and the release of neutrophil extracellular traps intensifies liver damage, fosters inflammatory immune responses, and triggers hepatotoxic processes. Neutrophil infiltration is a hallmark of alcohol-associated steatohepatitis, and the roles of neutrophils in ALD pathogenesis have been studied extensively, however, the involvement of platelets in ALD has received little attention. The current review consolidates recent findings on the intricate and diverse roles of platelets and neutrophils in liver pathophysiology and in ALD. Potential therapeutic strategies are highlighted, focusing on targeting platelet-neutrophil interactions and activation in ALD. The anticipation is that innovative methods for manipulating platelet and neutrophil functions will open promising avenues for future ALD therapy.
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Affiliation(s)
- Juan Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Xianda Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Haodong Peng
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; The First School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Zijian Dong
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China.
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China.
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Yang N, Zhang J, Guo J, Xiang Q, Huang Y, Wen J, Liu Q, Hu T, Chen Y, Rao C. Revealing the mechanism of Zanthoxylum armatum DC. extract-induced liver injury in mice based on lipidomics. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117086. [PMID: 37634752 DOI: 10.1016/j.jep.2023.117086] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/19/2023] [Accepted: 08/23/2023] [Indexed: 08/29/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Zanthoxylum armatum DC. (Z. armatum) is an herbal medicine with various active ingredients and pharmacological effects. However, modern studies found that Z. armatum is hepatotoxic. The liver is the target organ for toxic effects and an important site for lipid metabolism. The effects of Z. armatum on lipid level and metabolism in the liver are still unclear. AIM OF THE STUDY This study aimed to analyze hepatic lipid levels, lipid metabolites and metabolic pathways of action of Z. armatum based on lipidomics, to investigate the potential hepatotoxic mechanism of Z. armatum. MATERIALS AND METHODS Different doses (62, 96, and 150 mg/kg) of the methanolic extract of Z. armatum (MZADC) were administered to ICR mice by gavage. The hepatotoxicity of MZADC was assessed by the liver index, serum biochemical measurements, and histopathological examination. Lipid levels measured by the serum lipid index were evaluated in the mice. Lipidomics was used to screen for differential lipid metabolism markers and lipid metabolism pathways in the liver. Western blot analysis was performed to investigate the effects of MZADC on the liver. RESULTS Liver index values and serum alanine transaminase and aspartate transaminase levels were increased in the MZADC group. Histopathology examination revealed hepatocyte necrosis, watery degeneration of the hepatocytes, and hepatic cord rupture in the livers of mice. Serum levels of low-density lipoprotein cholesterol, cholesterol, and triglycerides were elevated, and high-density lipoprotein cholesterol levels were decreased. Lipidomics screening for markers of differential lipid metabolism in the liver, and altered profiles of differential metabolites indicated that glycerophospholipid metabolism, linoleic acid metabolism, alpha-linolenic acid metabolism, glycosylphosphatidylinositol-anchored biosynthesis, sphingolipid metabolism and arachidonic acid metabolic pathways were significantly associated with MZADC-induced liver injury. Western blots confirmed that the protein expression of LC3, Beclin-1, ATG5, ATG12 and ATG16L1 was decreased, and p62 was increased in the MZADC group. The proportion of p-PI3K/PI3K and p-AKT/AKT was increased. CONCLUSIONS The liver injury induced by MZADC involved many different lipid metabolites and lipid metabolic pathways, which may be related to autophagy. This study provides a new perspective on the hepatotoxicity study of Z. armatum and provides a reference for the safe application of Z. armatum in the medicine and food fields.
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Affiliation(s)
- Nannan Yang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Jian Zhang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Jiafu Guo
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Qiwen Xiang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Yan Huang
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Jiayu Wen
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Qiuyan Liu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Tingting Hu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Yan Chen
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China.
| | - Chaolong Rao
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China.
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9
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Kaffe E, Tisi A, Magkrioti C, Aidinis V, Mehal WZ, Flavell RA, Maccarrone M. Bioactive signalling lipids as drivers of chronic liver diseases. J Hepatol 2024; 80:140-154. [PMID: 37741346 DOI: 10.1016/j.jhep.2023.08.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 08/23/2023] [Accepted: 08/28/2023] [Indexed: 09/25/2023]
Abstract
Lipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases. In this review, we focus specifically on the roles of bioactive lipids derived from phospholipids (lyso-phospholipids) and poly-unsaturated fatty acids (eicosanoids, pro-resolving lipid mediators and endocannabinoids) in prevalent chronic liver diseases (alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma). We discuss the balance between pathogenic and beneficial bioactive lipids as well as potential therapeutic targets related to the agonism or antagonism of their receptors.
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Affiliation(s)
- Eleanna Kaffe
- Department of Immunobiology, Yale University School of Medicine, 06511, New Haven, CT, USA.
| | - Annamaria Tisi
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | | | - Vassilis Aidinis
- Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece
| | - Wajahat Z Mehal
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, 06520, USA; Veterans Affairs Medical Center, West Haven, CT, 06516, USA
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, 06511, New Haven, CT, USA; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, 06519, USA
| | - Mauro Maccarrone
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy; Laboratory of Lipid Neurochemistry, European Center for Brain Research (CERC), Santa Lucia Foundation IRCCS, 00143 Rome, Italy.
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10
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Li W, Xia Y, Yang J, Sanyal AJ, Shah VH, Chalasani NP, Yu Q. Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.12.15.23300034. [PMID: 38168393 PMCID: PMC10760266 DOI: 10.1101/2023.12.15.23300034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Background Chronic excessive alcohol consumption leads to a spectrum of alcohol-associated liver diseases (ALD), including alcoholic hepatitis (AH). AH is characterized by intense systemic and liver inflammation, posing significant risks of health complications and mortality. While inflammation is a crucial defense mechanism against injury and infection, its timely resolution is essential to prevent tissue damage and restore tissue homeostasis. The resolution of inflammation is an actively regulated process, primarily governed by specialized pro-resolving mediators (SPMs), lipid metabolites derived from ω-6 and ω-3 poly-unsaturated fatty acids (PUFAs). We investigated the balance between pro-inflammatory lipid mediators (PLMs) and SPMs in the ω-6 and ω-3 PUFA metabolic pathways and examined the impact of alcohol abstinence on rectifying the dysregulated biosynthesis of PLMs and SPMs in AH patients. Methods LC-MS/MS and ELISA were used to quantify levels of bioactive lipid mediators (LMs) and their precursors in the plasma samples from 58 AH patients, 29 heavy drinkers without overt liver diseases (HDCs), and 35 healthy controls (HCs). Subsequently, we assessed correlations of altered LMs with clinical parameters and various markers of inflammatory cascade andmicrobial translocation. Furthermore, we conducted a longitudinal study to track changes in levels of LMs over 6- and 12-month follow-ups in AH patients who underwent alcohol abstinence. Results AH patients exhibited significantly higher plasma levels of ω-6 PLMs (PGD 2 and LTB 4 ) and SPM RvE1 compared to HDCs and/or HCs. Conversely, key SPMs such as LXA4, RvD1, and several precursors in the ω-3 pathway were significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity, clinical parameters, and various inflammatory cytokines. In particular, the LTB4/LXA4 ratio was substantially elevated in AH patients relative to HDCs and HCs. This altered ratio displayed a positive correlation with the MELD score, suggesting its potential utility as an indicator of disease severity in AH patients. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence. Conclusion Our study reveals significant dysregulation in the levels of PLM metabolites and anti-inflammatory SPMs in both ω-6 and ω-3 PUFA pathways in AH patients. This disrupted biosynthesis, characterized by an overabundance of PLMs and a deficiency in SPMs, is linked to the heightened inflammation observed in AH patients. Importantly, our findings suggest an important role of alcohol abstinence in restoring the balance of these LMs and the potential therapeutic benefits of SPM supplements in alleviating the inflammatory cascade in AH patients.
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11
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Malladi N, Alam MJ, Maulik SK, Banerjee SK. The role of platelets in non-alcoholic fatty liver disease: From pathophysiology to therapeutics. Prostaglandins Other Lipid Mediat 2023; 169:106766. [PMID: 37479133 DOI: 10.1016/j.prostaglandins.2023.106766] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/29/2023] [Accepted: 07/17/2023] [Indexed: 07/23/2023]
Abstract
Platelets are one of the key mediators in thrombosis as well as in the progression of many diseases. An increase in platelet activation and a decrease in platelet count is associated with a plethora of liver diseases. In non-alcoholic fatty liver disease (NAFLD), platelets are highly activated and participate in the disease progression by enhancing the pro-thrombotic and pro-inflammatory state. Some altered platelet parameters such as mean platelet volume, plateletcrits, and platelet distribution width, aspartate transaminase to platelet ratio index, liver stiffness to platelet ratio and red cell distribution width to platelet ratio were found to be associated with NAFLD disease. Further, platelet contributes to the progression of cardiovascular complications in NAFLD is gaining the researcher's attention. An elevated mean platelet volume is known to enhance the risk of stroke, atherosclerosis, thrombosis, and myocardial infarction in NAFLD. Evidence also suggested that modulation in platelet function using aspirin, ticlopidine, and cilostazol help in controlling the NAFLD progression. Future research should focus on antiplatelet therapy as a treatment strategy that can control platelet activation in NAFLD as well as its cardiovascular risk. In the present review, we have detailed the role of platelets in NAFLD and its cardiovascular complications. We further aimed to highlight the growing need for antiplatelet therapy in NAFLD.
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Affiliation(s)
- Navya Malladi
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati 781101, Assam, India
| | - Md Jahangir Alam
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati 781101, Assam, India; Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Subir K Maulik
- Indian Council of Medical Research, Ministry of Health, New Delhi 110029, India
| | - Sanjay K Banerjee
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati 781101, Assam, India.
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12
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Kruchinina MV, Parulikova MV, Belkovets AV, Nikolaev KY, Ovsyannikova AK. Features of the fatty acid profile of erythrocyte membranes in patients with fatty liver disease of alcoholic genesis. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2023:84-96. [DOI: 10.21518/ms2023-391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Introduction. Alcoholic steatosis, which is a reversible condition, is currently considered a significant risk factor for the progression of diffuse liver pathology, therefore understanding of its mechanisms at the molecular level is essential.Aim. To study the features of the fatty acid profile of erythrocyte membranes in patients with fatty liver disease of alcoholic origin for possible use of fatty acids (FAs) as biomarkers and potential therapeutic targets.Materials and methods. A total of 31 men with alcoholic fatty liver disease (AFLD) (average age of 45.1 ± 17.1 years) and 28 men of comparable age without AFLD and symptomatic pathology of internal organs were examined. The FA composition and levels of erythrocyte membranes (ER) were studied using Agilent 7000B (USA) triple quadrupole gas chromatography/mass spectrometry.Results and discussion. A higher level of a range of saturated FAs (lauric, margaric, pentadecane), monounsaturated FAs (MUFAs), which are additional factors for the progression of AFLD (palmitoleic, total monounsaturated acids), n-6/n-3 polyun-saturated FAs ratio (PUFAs), alpha-linolenic FA was detected in patients with AFL vs the control group (p = 0.00002–0.05). In contrast, the levels of arachidic and docosahexaenoic acids, total eicosapentaenoic and docosahexaenoic n-3 PUFAs, and total n-3 PUFAs were lower in patients with AFLD than in healthy men (p = 0.003–0.01), which is associated with increased ethanol induced adipose tissue lipolysis via PDE3B-AMPK axis. The use of FAs panel (C16:1;9, sum MUFA, n-6/n-3 PUFA, C22:6n3, C20:0) to distinguish patients with AFLD from healthy ones ensured high levels of sensitivity (79%), and specificity (81%) (AUC 0.808). Multidirectional associations of FA levels in erythrocyte membranes with each other and liver tests and lipid profile results were revealed.Conclusion. Thus, the features of erythrocytes membrane FAs in patients with AFLD and the potential to use them as biomarkers for differentiation of people with AFLD from healthy individuals have been identified.
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Affiliation(s)
- M. V. Kruchinina
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences; Novosibirsk State Medical University
| | - M. V. Parulikova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
| | - A. V. Belkovets
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences; Novosibirsk State Medical University
| | - K. Yu. Nikolaev
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
| | - A. K. Ovsyannikova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
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13
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Chistyakov DV, Kovalenko LV, Donnikov MY, Sergeeva MG. Blood Oxylipin Profiles as Markers of Oncological Diseases. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:621-629. [PMID: 37331708 DOI: 10.1134/s000629792305005x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 03/03/2023] [Accepted: 03/11/2023] [Indexed: 06/20/2023]
Abstract
Oxylipins are signal lipid molecules formed from polyunsaturated fatty acids (PUFAs) in several multienzymatic metabolic pathways, such as cyclooxygenase (COX), lipoxygenase (LOX), epoxygenase (CYP), and anandamide pathways, as well as non-enzymatically. The pathways of PUFA transformation are activated in parallel, yielding a mixture of physiologically active substances. Although the association of oxylipins with carcinogenesis had been established a long time ago, only recently analytical methods have advanced to a degree allowing detection and quantification of oxylipins from different classes (oxylipin profiles). The review describes current approaches to the HPLC-MS/MS analysis of oxylipin profiles and compares oxylipin profiles from patients with oncological diseases (breast cancer, colorectal cancer, ovarian cancer, lung cancer, prostate cancer, liver cancer). The possibility of using blood oxylipin profiles as biomarkers in oncological diseases is discussed. Understanding the patterns of PUFA metabolism and physiological activity of combinations of oxylipins will improve early diagnostics of oncological diseases and evaluation of disease prognosis.
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Affiliation(s)
- Dmitry V Chistyakov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia.
| | | | - Maxim Y Donnikov
- Medical Institute, Surgut State University, Surgut, 628416, Russia
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14
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Anton PE, Rutt LN, Capper C, Orlicky DJ, McCullough RL. Profiling the oxylipidome in aged mice after chronic ethanol feeding: Identifying lipid metabolites as drivers of hepatocyte stress. Alcohol 2023; 107:119-135. [PMID: 36150611 DOI: 10.1016/j.alcohol.2022.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 08/10/2022] [Accepted: 08/25/2022] [Indexed: 02/08/2023]
Abstract
The global population of people over the age of 65 is increasing and expected to reach 1.5 billion by 2050. While aging is associated with a number of chronic illnesses including dementia, the underlying contribution of alcohol misuse in the elderly is understudied. Long-term chronic alcohol misuse can lead to alcohol-associated liver disease, consisting of a spectrum of pathologies, including steatosis and cirrhosis; liver disease can be rapidly accelerated by non-resolving inflammation. Despite this knowledge, the mechanistic underpinnings of dysregulated host immunity and accelerated liver disease progression in the aged by alcohol is unknown. Alcohol misuse in the elderly is on the rise and aging is associated with progressive increases in pro-inflammatory cytokine production. The goals of the current study are to characterize bioactive lipid mediators of inflammation by making use of a murine model of ethanol-induced liver disease in 3-month-old and 20-month-old mice by quantitatively profiling selected oxylipins in liver, brain and plasma. Following chronic ethanol exposure, liver injury, steatosis, and senescence markers were robustly increased in aged mice compared to young adult mice. Expression of proinflammatory cytokines and lipid metabolizing enzymes were increased in liver by both age and ethanol feeding. Lipoxygenase-derived lipid metabolites 9- and 13-hydroxy-octadecadienoic acid and 15-hydroxyeicosatetraenoic acid were increased in liver and plasma in ethanol-fed aged mice and positively correlated with liver injury. In plasma, 9,10-dihydroxy-octadecenoic acid/epoxy-octadecenoic acid plasma ratios correlated with liver injury in ethanol-fed aged mice. Finally, 15-hydroxyeicosatetraenoic acid and 9,10-dihydroxy-octadecenoic acid positively correlated between liver and plasma. Importantly, leukotriene E4, 9,10-dihydroxy-octadecenoic acid and 15-hydroxyeicosatetraenoic acid increased lipid accumulation and ER stress in cultured AML12 hepatocytes. These data highlight the complexity of lipid metabolite networks but identify key mediators that may be used for diagnostic and prognostic markers in early stages of alcohol-related liver disease in patients of all ages.
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Affiliation(s)
- Paige E Anton
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Lauren N Rutt
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Courtney Capper
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - David J Orlicky
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Rebecca L McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; Colorado University Alcohol Research Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; GI and Liver Innate Immune Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
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15
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Alba MM, Ebright B, Hua B, Slarve I, Zhou Y, Jia Y, Louie SG, Stiles BL. Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development. Front Physiol 2023; 14:1098467. [PMID: 36818443 PMCID: PMC9932286 DOI: 10.3389/fphys.2023.1098467] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Liver cancer is a malignancy developed from underlying liver disease that encompasses liver injury and metabolic disorders. The progression from these underlying liver disease to cancer is accompanied by chronic inflammatory conditions in which liver macrophages play important roles in orchestrating the inflammatory response. During this process, bioactive lipids produced by hepatocytes and macrophages mediate the inflammatory responses by acting as pro-inflammatory factors, as well as, playing roles in the resolution of inflammation conditions. Here, we review the literature discussing the roles of bioactive lipids in acute and chronic hepatic inflammation and progression to cancer.
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Affiliation(s)
- Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Brandon Ebright
- Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Stan G. Louie
- Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
- Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, Unites States
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16
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Osna NA, Rasineni K, Ganesan M, Donohue TM, Kharbanda KK. Pathogenesis of Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:1492-1513. [PMID: 36340300 PMCID: PMC9630031 DOI: 10.1016/j.jceh.2022.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.
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Key Words
- AA, Arachidonic acid
- ADH, Alcohol dehydrogenase
- AH, Alcoholic hepatitis
- ALD, Alcohol-associated liver disease
- ALDH, Aldehyde dehydrogenase
- ALT, Alanine transaminase
- ASH, Alcohol-associated steatohepatitis
- AST, Aspartate transaminase
- AUD, Alcohol use disorder
- BHMT, Betaine-homocysteine-methyltransferase
- CD, Cluster of differentiation
- COX, Cycloxygenase
- CTLs, Cytotoxic T-lymphocytes
- CYP, Cytochrome P450
- CYP2E1, Cytochrome P450 2E1
- Cu/Zn SOD, Copper/zinc superoxide dismutase
- DAMPs, Damage-associated molecular patterns
- DC, Dendritic cells
- EDN1, Endothelin 1
- ER, Endoplasmic reticulum
- ETOH, Ethanol
- EVs, Extracellular vesicles
- FABP4, Fatty acid-binding protein 4
- FAF2, Fas-associated factor family member 2
- FMT, Fecal microbiota transplant
- Fn14, Fibroblast growth factor-inducible 14
- GHS-R1a, Growth hormone secretagogue receptor type 1a
- GI, GOsteopontinastrointestinal tract
- GSH Px, Glutathione peroxidase
- GSSG Rdx, Glutathione reductase
- GST, Glutathione-S-transferase
- GWAS, Genome-wide association studies
- H2O2, Hydrogen peroxide
- HA, Hyaluronan
- HCC, Hepatocellular carcinoma
- HNE, 4-hydroxynonenal
- HPMA, 3-hydroxypropylmercapturic acid
- HSC, Hepatic stellate cells
- HSD17B13, 17 beta hydroxy steroid dehydrogenase 13
- HSP 90, Heat shock protein 90
- IFN, Interferon
- IL, Interleukin
- IRF3, Interferon regulatory factor 3
- JAK, Janus kinase
- KC, Kupffer cells
- LCN2, Lipocalin 2
- M-D, Mallory–Denk
- MAA, Malondialdehyde-acetaldehyde protein adducts
- MAT, Methionine adenosyltransferase
- MCP, Macrophage chemotactic protein
- MDA, Malondialdehyde
- MIF, Macrophage migration inhibitory factor
- Mn SOD, Manganese superoxide dismutase
- Mt, Mitochondrial
- NK, Natural killer
- NKT, Natural killer T-lymphocytes
- OPN, Osteopontin
- PAMP, Pathogen-associated molecular patterns
- PNPLA3, Patatin-like phospholipase domain containing 3
- PUFA, Polyunsaturated fatty acid
- RIG1, Retinoic acid inducible gene 1
- SAH, S-adenosylhomocysteine
- SAM, S-adenosylmethionine
- SCD, Stearoyl-CoA desaturase
- STAT, Signal transduction and activator of transcription
- TIMP1, Tissue inhibitor matrix metalloproteinase 1
- TLR, Toll-like receptor
- TNF, Tumor necrosis factor-α
- alcohol
- alcohol-associated liver disease
- ethanol metabolism
- liver
- miRNA, MicroRNA
- p90RSK, 90 kDa ribosomal S6 kinase
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Affiliation(s)
- Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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17
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Artru F, McPhail MJW, Triantafyllou E, Trovato FM. Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids. Front Immunol 2022; 13:867261. [PMID: 35432367 PMCID: PMC9008479 DOI: 10.3389/fimmu.2022.867261] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/08/2022] [Indexed: 12/30/2022] Open
Abstract
Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.
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Affiliation(s)
- Florent Artru
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Mark J W McPhail
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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18
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Zeng S, Schnabl B. Roles for the mycobiome in liver disease. Liver Int 2022; 42:729-741. [PMID: 34995410 PMCID: PMC8930708 DOI: 10.1111/liv.15160] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/17/2021] [Accepted: 12/30/2021] [Indexed: 12/14/2022]
Abstract
Liver disease, a major cause of global mortality, has been associated with dysbiosis of the intestinal microbiota (bacteria, fungi, viruses, and other microbes). Studies have associated changes in gut bacteria with pathogenesis and severity of liver disease, but the contributions of the mycobiome (the fungal populations of the gut) to health and disease have not been well studied. We review recent findings of alterations in the composition of the mycobiota in patients with liver disease and discuss the mechanisms by which these might affect pathogenesis and disease progression. Strategies to manipulate the gut mycobiota might be developed to treat or prevent liver disease.
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Affiliation(s)
- Suling Zeng
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
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19
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Helsley RN, Miyata T, Kadam A, Varadharajan V, Sangwan N, Huang EC, Banerjee R, Brown AL, Fung KK, Massey WJ, Neumann C, Orabi D, Osborn LJ, Schugar RC, McMullen MR, Bellar A, Poulsen KL, Kim A, Pathak V, Mrdjen M, Anderson JT, Willard B, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton B, Szabo G, Dasarathy S, Garcia-Garcia JC, Rotroff DM, Allende DS, Wang Z, Hazen SL, Nagy LE, Brown JM. Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice. eLife 2022; 11:e76554. [PMID: 35084335 PMCID: PMC8853661 DOI: 10.7554/elife.76554] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 12/31/2021] [Indexed: 11/13/2022] Open
Abstract
There is mounting evidence that microbes residing in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. We show the gut microbial choline metabolite TMA is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. The microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury.
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Affiliation(s)
- Robert N Helsley
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, College of Medicine, University of KentuckyLexingtonUnited States
| | - Tatsunori Miyata
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Anagha Kadam
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Venkateshwari Varadharajan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Naseer Sangwan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Emily C Huang
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Rakhee Banerjee
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Amanda L Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Kevin K Fung
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - William J Massey
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Chase Neumann
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Danny Orabi
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Lucas J Osborn
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Rebecca C Schugar
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Megan R McMullen
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Annette Bellar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Kyle L Poulsen
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Adam Kim
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Vai Pathak
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Marko Mrdjen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - James T Anderson
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Belinda Willard
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Craig J McClain
- Department of Medicine, University of LouisvilleLouisvilleUnited States
| | - Mack Mitchell
- Department of Internal Medicine, University of Texas Southwestern Medical CenterDallasUnited States
| | - Arthur J McCullough
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and AlcoholismBethesdaUnited States
| | - Bruce Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical SchoolWorcesterUnited States
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUnited States
| | - Srinivasan Dasarathy
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | | | - Daniel M Rotroff
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Daniela S Allende
- Department of Anatomical Pathology, Cleveland ClinicClevelandUnited States
| | - Zeneng Wang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Stanley L Hazen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
- Department of Cardiovascular Medicine, Heart and Vascular and Thoracic Institute, Cleveland ClinicClevelandUnited States
| | - Laura E Nagy
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland ClinicClevelandUnited States
| | - Jonathan Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland ClinicClevelandUnited States
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland ClinicClevelandUnited States
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20
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Gao B, Wu TC, Lang S, Jiang L, Duan Y, Fouts DE, Zhang X, Tu XM, Schnabl B. Machine Learning Applied to Omics Datasets Predicts Mortality in Patients with Alcoholic Hepatitis. Metabolites 2022; 12:41. [PMID: 35050163 PMCID: PMC8781791 DOI: 10.3390/metabo12010041] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/31/2021] [Accepted: 01/01/2022] [Indexed: 12/14/2022] Open
Abstract
Alcoholic hepatitis is a major health care burden in the United States due to significant morbidity and mortality. Early identification of patients with alcoholic hepatitis at greatest risk of death is extremely important for proper treatments and interventions to be instituted. In this study, we used gradient boosting, random forest, support vector machine and logistic regression analysis of laboratory parameters, fecal bacterial microbiota, fecal mycobiota, fecal virome, serum metabolome and serum lipidome to predict mortality in patients with alcoholic hepatitis. Gradient boosting achieved the highest AUC of 0.87 for both 30-day mortality prediction using the bacteria and metabolic pathways dataset and 90-day mortality prediction using the fungi dataset, which showed better performance than the currently used model for end-stage liver disease (MELD) score.
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Affiliation(s)
- Bei Gao
- School of Marine Sciences, Nanjing University of Information Science and Technology, Nanjing 210044, China;
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.L.); (L.J.); (Y.D.)
| | - Tsung-Chin Wu
- Department of Mathematics, University of California San Diego, San Diego, CA 92093, USA;
- Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health, University of California San Diego, San Diego, CA 92093, USA; (X.Z.); (X.-M.T.)
| | - Sonja Lang
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.L.); (L.J.); (Y.D.)
| | - Lu Jiang
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.L.); (L.J.); (Y.D.)
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA
| | - Yi Duan
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.L.); (L.J.); (Y.D.)
| | | | - Xinlian Zhang
- Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health, University of California San Diego, San Diego, CA 92093, USA; (X.Z.); (X.-M.T.)
| | - Xin-Ming Tu
- Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health, University of California San Diego, San Diego, CA 92093, USA; (X.Z.); (X.-M.T.)
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (S.L.); (L.J.); (Y.D.)
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA
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21
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Kuracha MR, Thomas P, Tobi M, McVicker BL. Role of cell-free network communication in alcohol-associated disorders and liver metastasis. World J Gastroenterol 2021; 27:7080-7099. [PMID: 34887629 PMCID: PMC8613644 DOI: 10.3748/wjg.v27.i41.7080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/02/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The aberrant use of alcohol is a major factor in cancer progression and metastasis. Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-cancerous cells along the brain-gut-liver axis. Such interplay leads to changes in molecular, cellular, and biological functions resulting in cancer progression. Recent investigations have examined the role of extracellular vesicles (EVs) in cancer mechanisms in addition to their contribution as diagnostic biomarkers. Also, EVs are emerging as novel cell-free mediators in pathophysiological scenarios including alcohol-mediated gut microbiome dysbiosis and the release of nanosized EVs into the circulatory system. Interestingly, EVs in cancer patients are enriched with oncogenes, miRNA, lipids, and glycoproteins whose delivery into the hepatic microenvironment may be enhanced by the detrimental effects of alcohol. Proof-of-concept studies indicate that alcohol-associated liver disease is impacted by the effects of exosomes, including altered immune responses, reprogramming of stromal cells, and remodeling of the extracellular matrix. Moreover, the culmination of alcohol-related changes in the liver likely contributes to enhanced hepatic metastases and poor outcomes for cancer patients. This review summarizes the numerous aspects of exosome communications between organs with emphasis on the relationship of EVs in alcohol-associated diseases and cancer metastasis. The potential impact of EV cargo and release along a multi-organ axis is highly relevant to the promotion of tumorigenic mechanisms and metastatic disease. It is hypothesized that EVs target recipient tissues to initiate the formation of prometastatic niches and cancer progression. The study of alcohol-associated mechanisms in metastatic cancers is expected to reveal a better understanding of factors involved in the growth of secondary malignancies as well as novel approaches for therapeutic interventions.
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Affiliation(s)
- Murali R Kuracha
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Peter Thomas
- Department of Surgery, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Martin Tobi
- Research and Development Service, Detroit VAMC, Detroit, MI 48201, United States
- Department of Medicine, Central Michigan University College of Medicine, Detroit, MI 48201, United States
| | - Benita L McVicker
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
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22
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Warner J, Hardesty J, Song Y, Sun R, Deng Z, Xu R, Yin X, Zhang X, McClain C, Warner D, Kirpich I. Fat-1 Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration. Front Pharmacol 2021; 12:711590. [PMID: 34531743 PMCID: PMC8438569 DOI: 10.3389/fphar.2021.711590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol-associated liver disease (ALD) is the leading cause of liver disease worldwide, and alcohol-associated hepatitis (AH), a severe form of ALD, is a major contributor to the mortality and morbidity due to ALD. Many factors modulate susceptibility to ALD development and progression, including nutritional factors such as dietary fatty acids. Recent work from our group and others showed that modulation of dietary or endogenous levels of n6-and n3-polyunsaturated fatty acids (PUFAs) can exacerbate or attenuate experimental ALD, respectively. In the current study, we interrogated the effects of endogenous n3-PUFA enrichment in a mouse model which recapitulates features of early human AH using transgenic fat-1 mice which endogenously convert n6-PUFAs to n3-PUFAs. Male wild type (WT) and fat-1 littermates were provided an ethanol (EtOH, 5% v/v)-containing liquid diet for 10 days, then administered a binge of EtOH (5 g/kg) by oral gavage on the 11th day, 9 h prior to sacrifice. In WT mice, EtOH treatment resulted in liver injury as determined by significantly elevated plasma ALT levels, whereas in fat-1 mice, EtOH caused no increase in this biomarker. Compared to their pair-fed controls, a significant EtOH-mediated increase in liver neutrophil infiltration was observed also in WT, but not fat-1 mice. The hepatic expression of several cytokines and chemokines, including Pai-1, was significantly lower in fat-1 vs WT EtOH-challenged mice. Cultured bone marrow-derived macrophages isolated from fat-1 mice expressed less Pai-1 and Cxcl2 (a canonical neutrophil chemoattractant) mRNA compared to WT when stimulated with lipopolysaccharide. Further, we observed decreased pro-inflammatory M1 liver tissue-resident macrophages (Kupffer cells, KCs), as well as increased liver T regulatory cells in fat-1 vs WT EtOH-fed mice. Taken together, our data demonstrated protective effects of endogenous n3-PUFA enrichment on liver injury caused by an acute-on-chronic EtOH exposure, a paradigm which recapitulates human AH, suggesting that n3-PUFAs may be a viable nutritional adjuvant therapy for this disease.
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Affiliation(s)
- Jeffrey Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United States
| | - Josiah Hardesty
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Ying Song
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Rui Sun
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
| | - Zhongbin Deng
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.,Department of Surgery, University of Louisville, Louisville, KY, United States.,University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, United States
| | - Raobo Xu
- University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, United States.,University of Louisville Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United States.,Department of Chemistry, University of Louisville, Louisville, KY, United States.,Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY, United States
| | - Xinmin Yin
- University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, United States.,University of Louisville Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United States.,Department of Chemistry, University of Louisville, Louisville, KY, United States.,Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY, United States
| | - Xiang Zhang
- University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, United States.,University of Louisville Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United States.,Department of Chemistry, University of Louisville, Louisville, KY, United States.,Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY, United States
| | - Craig McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United States.,University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, United States.,University of Louisville Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United States.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, United States
| | - Dennis Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Irina Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United States.,University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, United States.,University of Louisville Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United States
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23
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Effect of n-3 long-chain polyunsaturated fatty acid intake on the eicosanoid profile in individuals with obesity and overweight: a systematic review and meta-analysis of clinical trials. J Nutr Sci 2021; 10:e53. [PMID: 34367628 PMCID: PMC8327393 DOI: 10.1017/jns.2021.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 06/25/2021] [Indexed: 12/20/2022] Open
Abstract
Dietary n-3 polyunsaturated fatty acids (PUFAs) present beneficial effects on counteracting inflammation status, displaying a critical anti-inflammatory role and maintaining physiological homeostasis in obesity. The primary objective of this systematic review was to evaluate the effect of n-3 PUFAs intake on the eicosanoid profile of people with obesity and overweight. The search strategy on Embase, Scopus, PubMed, Web of Science, Cochrane Library, Google Scholar and ProQuest was undertaken until November 2019 and updated January 2021. The effect size of n-3 PUFAs on prostaglandins was estimated by Glass's, type 1 in a random-effect model for the meta-analysis. Seven clinical trials met the eligible criteria and a total of 610 subjects were included in this systematic review, and four of seven studies were included in meta-analysis. The intake of n-3 PUFAs promoted an overall reduction in serum pro-inflammatory eicosanoids. Additionally, n-3 PUFAs intake significantly decreased the arachidonic acid COX-derived PG eicosanoid group levels (Glass's Δ -0⋅35; CI -0⋅62, -0⋅07, I 2 31⋅48). Subgroup analyses showed a higher effect on periods up to 8 weeks (Glass's Δ -0⋅51; CI -0⋅76, -0⋅27) and doses higher than 0⋅5 g of n-3 PUFAs (Glass's Δ -0⋅46; CI -0⋅72, -0⋅27). Dietary n-3 PUFAs intake contributes to reduce pro-inflammatory eicosanoids of people with obesity and overweight. Subgroup's analysis showed that n-3 PUFAs can reduce the overall arachidonic acid COX-derived PG when adequate dose and period are matched.
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24
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Warner D, Vatsalya V, Zirnheld KH, Warner JB, Hardesty JE, Umhau JC, McClain CJ, Maddipati K, Kirpich IA. Linoleic Acid-Derived Oxylipins Differentiate Early Stage Alcoholic Hepatitis From Mild Alcohol-Associated Liver Injury. Hepatol Commun 2021; 5:947-960. [PMID: 34141982 PMCID: PMC8183177 DOI: 10.1002/hep4.1686] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/05/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol-associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)-derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA-derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End-Stage Liver Disease score <20). Lipoxygenase-derived LA metabolites (13-hydroxy-octadecadienoic acid [13-HODE] and 13-oxo-octadecadienoic acid) were markedly elevated only in patients with mAH. The cytochrome P450-derived LA epoxides 9,10-epoxy-octadecenoic acid (9,10-EpOME) and 12,13-EpOME were decreased in all patients regardless of the presence or absence of liver injury. LA-derived diols 9,10-dihydroxy-octadecenoic acid (9,10-DiHOME) and 12,13-DiHOME as well as the corresponding diol/epoxide ratio were elevated in the mAH group, specifically compared to patients with mild liver injury. We found that 13-HODE and 12,13-EpOME (elevated and decreased, respectively) in combination with elevated interleukin-1β as independent predictors can effectively predict altered liver function as defined by elevated bilirubin levels. Conclusion: Specific changes in LA metabolites in individuals who are heavy drinkers can distinguish individuals with mAH from those with mild ALD.
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Affiliation(s)
- Dennis Warner
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA
| | - Vatsalya Vatsalya
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Robley Rex Veterans Medical CenterLouisvilleKYUSA
| | - Kara H Zirnheld
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA
| | - Jeffrey B Warner
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineKYUSA
| | - Josiah E Hardesty
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineKYUSA
| | | | - Craig J McClain
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Robley Rex Veterans Medical CenterLouisvilleKYUSA.,Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineKYUSA.,University of Louisville Alcohol CenterLouisvilleKYUSA.,Hepatobiology and Toxicology CenterUniversity of Louisville School of MedicineLouisvilleKYUSA
| | | | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineKYUSA.,University of Louisville Alcohol CenterLouisvilleKYUSA.,Hepatobiology and Toxicology CenterUniversity of Louisville School of MedicineLouisvilleKYUSA
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25
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Serum Acylcarnitines Associated with High Short-Term Mortality in Patients with Alcoholic Hepatitis. Biomolecules 2021; 11:biom11020281. [PMID: 33672832 PMCID: PMC7917657 DOI: 10.3390/biom11020281] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 02/10/2021] [Indexed: 01/11/2023] Open
Abstract
Alcohol-related liver disease is one of the most prevalent liver diseases in the United States. Early stages of alcohol-related liver disease are characterized by accumulation of triglycerides in hepatocytes. Alcoholic hepatitis is a severe form of alcohol-related liver disease associated with significant morbidity and mortality. We sought to identify patients who are at greatest risk of death using serum lipids. First, we performed lipidomics analysis on serum samples collected from 118 patients with alcoholic hepatitis to identify lipid markers that are associated with high risk of death. Next, we performed gene set enrichment analysis on liver transcriptomics data to identify dysregulated lipid metabolism in patients who received liver transplantation. Finally, we built a random forest model to predict 30-day mortality using serum lipids. A total of 277 lipids were annotated in the serum of patients with alcoholic hepatitis, among which 25 were significantly different between patients in the deceased and alive groups. Five chemical clusters were significantly altered between the two groups. In particular, acylcarnitine cluster was enriched in the deceased group. Several hepatic lipid metabolism pathways were dysregulated in patients with alcoholic hepatitis who received liver transplantation. The mRNA expression of genes involved in the fatty acid transport into mitochondria and β-oxidation were also dysregulated. When predicting 30-day mortality in alcoholic hepatitis patients using serum lipids, we found that the area under the curve achieved 0.95. Serum lipids such as acylcarnitines may serve as biomarkers to identify alcoholic hepatitis patients at the greatest risk of death.
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26
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Jiang L, Lang S, Duan Y, Zhang X, Gao B, Chopyk J, Schwanemann LK, Ventura-Cots M, Bataller R, Bosques-Padilla F, Verna EC, Abraldes JG, Brown RS, Vargas V, Altamirano J, Caballería J, Shawcross DL, Ho SB, Louvet A, Lucey MR, Mathurin P, Garcia-Tsao G, Kisseleva T, Brenner DA, Tu XM, Stärkel P, Pride D, Fouts DE, Schnabl B. Intestinal Virome in Patients With Alcoholic Hepatitis. Hepatology 2020; 72:2182-2196. [PMID: 32654263 PMCID: PMC8159727 DOI: 10.1002/hep.31459] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.
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Affiliation(s)
- Lu Jiang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Sonja Lang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Yi Duan
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Xinlian Zhang
- Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
| | - Bei Gao
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jessica Chopyk
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | | | - Meritxell Ventura-Cots
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA
| | - Francisco Bosques-Padilla
- Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, México
| | - Elizabeth C. Verna
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Juan G. Abraldes
- Division of Gastroenterology (Liver Unit). Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Robert S. Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA
| | - Victor Vargas
- Liver Unit, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain,Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Jose Altamirano
- Liver Unit, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Juan Caballería
- Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain,Liver Unit, Hospital Clinic, Barcelona, Spain
| | - Debbie L. Shawcross
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, King’s College Hospital, London, UK
| | - Samuel B. Ho
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Alexandre Louvet
- Service des Maladies de L’appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France
| | - Michael R. Lucey
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, WI, USA
| | - Philippe Mathurin
- Service des Maladies de L’appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA, and Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT, USA
| | - Tatiana Kisseleva
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - David A. Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Xin M. Tu
- Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
| | - Peter Stärkel
- St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
| | - David Pride
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Pathology, University of California San Diego, La Jolla, CA, USA,Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA, USA
| | | | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA,Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA, USA
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Lang S, Fairfied B, Gao B, Duan Y, Zhang X, Fouts DE, Schnabl B. Changes in the fecal bacterial microbiota associated with disease severity in alcoholic hepatitis patients. Gut Microbes 2020; 12:1785251. [PMID: 32684075 PMCID: PMC7524371 DOI: 10.1080/19490976.2020.1785251] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/10/2020] [Accepted: 06/11/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND AND AIMS Alcoholic hepatitis is the most severe form of alcohol-related liver disease. While the gut microbiome is known to play a role in disease development and progression, less is known about specific compositional changes of the gut bacterial microbiome associated with disease severity. Therefore, the aim of our study was to correlate gut microbiota features with disease severity in alcoholic hepatitis patients. METHODS We used 16S rRNA gene sequencing on fecal samples from 74 alcoholic hepatitis patients, which were enrolled at 9 centers in Europe, the United States, and Mexico in a multi-center observational study. The relative abundance of gut bacterial taxa on genus level, as well as the microbiome diversity, was correlated to various clinical, laboratory, and histologic parameters. RESULTS We observed a negative correlation between the model for end-stage liver disease score and Shannon diversity, independent of potentially confounding factors (Padjust = 0.046). Alcoholic hepatitis patients with more severe disease had significantly decreased relative abundances of Akkermansia while the relative abundance of Veillonella was increased. We observed a reduction in the Bacteroides abundance (Padjust = 0.048) and Shannon diversity (Padjust = 0.018) in antibiotic-treated patients and patients receiving steroids had an increase in Veillonella abundance (Padjust = 0.005), which was both independent of potentially confounding factors. CONCLUSION We observed distinct changes in the gut bacterial microbiome of alcoholic hepatitis patients with more severe disease. The gut bacterial microbiome might be an attractive target to prevent and treat this deadly disease.
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Affiliation(s)
- Sonja Lang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Bradley Fairfied
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Bei Gao
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Yi Duan
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Xinlian Zhang
- Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
| | - Derrick E. Fouts
- J.Craig Venter Institute, Department for Genomic Medicine, Rockville, MD, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
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28
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Maccioni L, Gao B, Leclercq S, Pirlot B, Horsmans Y, De Timary P, Leclercq I, Fouts D, Schnabl B, Stärkel P. Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans. Gut Microbes 2020; 12:1782157. [PMID: 32588725 PMCID: PMC7524402 DOI: 10.1080/19490976.2020.1782157] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Animal data suggest a role of the gut-liver axis in progression of alcoholic liver disease (ALD), but human data are scarce especially for early disease stages. METHODS We included patients with alcohol use disorder (AUD) who follow a rehabilitation program and matched healthy controls. We determined intestinal epithelial and vascular permeability (IP) (using urinary excretion of 51Cr-EDTA, fecal albumin content, and immunohistochemistry in distal duodenal biopsies), epithelial damage (histology, serum iFABP, and intestinal gene expression), and microbial translocation (Gram - and Gram + serum markers by ELISA). Duodenal mucosa-associated microbiota and fecal microbiota were analyzed by 16 S rRNA sequencing. ALD was staged by Fibroscan® (liver stiffness, controlled attenuation parameter) in combination with serum AST, ALT, and CK18-M65. RESULTS Only a subset of AUD patients had increased 51Cr-EDTA and fecal albumin together with disrupted tight junctions and vasculature expression of plasmalemma Vesicle-Associated Protein-1. The so-defined increased intestinal permeability was not related to changes of the duodenal microbiota or alterations of the intestinal epithelium but associated with compositional changes of the fecal microbiota. Leaky gut alone did not explain increased microbial translocation in AUD patients. By contrast, duodenal dysbiosis with a dominance shift toward specific potential pathogenic bacteria genera (Streptococcus, Shuttleworthia, Rothia), increased IP and elevated markers of microbial translocation characterized AUD patients with progressive ALD (steato-hepatitis, steato-fibrosis). CONCLUSION Progressive ALD already at early disease stages is associated with duodenal mucosa-associated dysbiosis and elevated microbial translocation. Surprisingly, such modifications were not linked with increased IP. Rather, increased IP appears related to fecal microbiota dysbiosis.
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Affiliation(s)
- Luca Maccioni
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Bei Gao
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Sophie Leclercq
- Institute of Neuroscience and Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Boris Pirlot
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Yves Horsmans
- Department of Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Philippe De Timary
- Department of Adult Psychiatry, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Isabelle Leclercq
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | | | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Peter Stärkel
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain, Brussels, Belgium,Department of Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium,CONTACT Peter Stärkel Laboratory of Hepato-gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
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29
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Gao B, Duan Y, Lang S, Barupal D, Wu T, Valdiviez L, Roberts B, Choy YY, Shen T, Byram G, Zhang Y, Fan S, Wancewicz B, Shao Y, Vervier K, Wang Y, Zhou R, Jiang L, Nath S, Loomba R, Abraldes JG, Bataller R, Tu XM, Stärkel P, Lawley TD, Fiehn O, Schnabl B. Functional Microbiomics Reveals Alterations of the Gut Microbiome and Host Co-Metabolism in Patients With Alcoholic Hepatitis. Hepatol Commun 2020; 4:1168-1182. [PMID: 32766476 PMCID: PMC7395072 DOI: 10.1002/hep4.1537] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 04/19/2020] [Accepted: 04/26/2020] [Indexed: 12/17/2022] Open
Abstract
Alcohol-related liver disease is a major public health burden, and the gut microbiota is an important contributor to disease pathogenesis. The aim of the present study is to characterize functional alterations of the gut microbiota and test their performance for short-term mortality prediction in patients with alcoholic hepatitis. We integrated shotgun metagenomics with untargeted metabolomics to investigate functional alterations of the gut microbiota and host co-metabolism in a multicenter cohort of patients with alcoholic hepatitis. Profound changes were found in the gut microbial composition, functional metagenome, serum, and fecal metabolomes in patients with alcoholic hepatitis compared with nonalcoholic controls. We demonstrate that in comparison with single omics alone, the performance to predict 30-day mortality was improved when combining microbial pathways with respective serum metabolites in patients with alcoholic hepatitis. The area under the receiver operating curve was higher than 0.85 for the tryptophan, isoleucine, and methionine pathways as predictors for 30-day mortality, but achieved 0.989 for using the urea cycle pathway in combination with serum urea, with a bias-corrected prediction error of 0.083 when using leave-one-out cross validation. Conclusion: Our study reveals changes in key microbial metabolic pathways associated with disease severity that predict short-term mortality in our cohort of patients with alcoholic hepatitis.
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Affiliation(s)
- Bei Gao
- Department of MedicineUniversity of California San DiegoLa JollaCA
| | - Yi Duan
- Department of MedicineUniversity of California San DiegoLa JollaCA
- Department of MedicineVA San Diego Healthcare SystemSan DiegoCA
| | - Sonja Lang
- Department of MedicineUniversity of California San DiegoLa JollaCA
| | - Dinesh Barupal
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Tsung‐Chin Wu
- Division of MathematicsUniversity of California San DiegoSan DiegoCA
| | - Luis Valdiviez
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Bryan Roberts
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Ying Yng Choy
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Tong Shen
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Gregory Byram
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Ying Zhang
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Sili Fan
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Benjamin Wancewicz
- Department of Cell and Regenerative BiologyUniversity of Wisconsin‐MadisonMadisonWI
| | - Yan Shao
- Host‐Microbiota Interactions LaboratoryWellcome Sanger InstituteWellcome Genome CampusHinxtonUnited Kingdom
| | - Kevin Vervier
- Host‐Microbiota Interactions LaboratoryWellcome Sanger InstituteWellcome Genome CampusHinxtonUnited Kingdom
| | - Yanhan Wang
- Department of MedicineUniversity of California San DiegoLa JollaCA
- Department of MedicineVA San Diego Healthcare SystemSan DiegoCA
| | - Rongrong Zhou
- Department of MedicineUniversity of California San DiegoLa JollaCA
| | - Lu Jiang
- Department of MedicineUniversity of California San DiegoLa JollaCA
| | - Shilpa Nath
- Department of MedicineUniversity of California San DiegoLa JollaCA
| | - Rohit Loomba
- Department of MedicineUniversity of California San DiegoLa JollaCA
| | | | - Ramon Bataller
- Division of Gastroenterology, Hepatology and NutritionDepartment of MedicinePittsburgh Liver Research CenterUniversity of Pittsburgh Medical CenterPittsburghPA
| | - Xin M. Tu
- Department of Biostatistics and BioinformaticsDepartment of Family Medicine and Public HealthUniversity of California San DiegoSan DiegoCA
| | - Peter Stärkel
- St. Luc University HospitalUniversité Catholique de LouvainBrusselsBelgium
| | - Trevor D. Lawley
- Host‐Microbiota Interactions LaboratoryWellcome Sanger InstituteWellcome Genome CampusHinxtonUnited Kingdom
| | - Oliver Fiehn
- West Coast Metabolomics CenterUniversity of California DavisDavisCA
| | - Bernd Schnabl
- Department of MedicineUniversity of California San DiegoLa JollaCA
- Department of MedicineVA San Diego Healthcare SystemSan DiegoCA
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30
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Azbukina NV, Lopachev AV, Chistyakov DV, Goriainov SV, Astakhova AA, Poleshuk VV, Kazanskaya RB, Fedorova TN, Sergeeva MG. Oxylipin Profiles in Plasma of Patients with Wilson's Disease. Metabolites 2020; 10:metabo10060222. [PMID: 32485807 PMCID: PMC7345781 DOI: 10.3390/metabo10060222] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/17/2020] [Accepted: 05/25/2020] [Indexed: 12/31/2022] Open
Abstract
Wilson’s disease (WD) is a rare autosomal recessive metabolic disorder resulting from mutations in the copper-transporting, P-type ATPase gene ATP7B gene, but influences of epigenetics, environment, age, and sex-related factors on the WD phenotype complicate diagnosis and clinical manifestations. Oxylipins, derivatives of omega-3, and omega-6 polyunsaturated fatty acids (PUFAs) are signaling mediators that are deeply involved in innate immunity responses; the regulation of inflammatory responses, including acute and chronic inflammation; and other disturbances related to any system diseases. Therefore, oxylipin profile tests are attractive for the diagnosis of WD. With UPLC-MS/MS lipidomics analysis, we detected 43 oxylipins in the plasma profiles of 39 patients with various clinical manifestations of WD compared with 16 healthy controls (HCs). Analyzing the similarity matrix of oxylipin profiles allowed us to cluster patients into three groups. Analysis of the data by VolcanoPlot and partial least square discriminant analysis (PLS-DA) showed that eight oxylipins and lipids stand for the variance between WD and HCs: eicosapentaenoic acid EPA, oleoylethanolamide OEA, octadecadienoic acids 9-HODE, 9-KODE, 12-hydroxyheptadecatrenoic acid 12-HHT, prostaglandins PGD2, PGE2, and 14,15-dihydroxyeicosatrienoic acids 14,15-DHET. The compounds indicate the involvement of oxidative stress damage, inflammatory processes, and peroxisome proliferator-activated receptor (PPAR) signaling pathways in this disease. The data reveal novel possible therapeutic targets and intervention strategies for treating WD.
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Affiliation(s)
- Nadezhda V. Azbukina
- Faculty of Bioengineering and Bioinformatics, Moscow Lomonosov State University, Moscow 119234, Russia;
| | - Alexander V. Lopachev
- Laboratory of Clinical and Experimental neurochemistry, Research Center of Neurology, Moscow 125367, Russia;
| | - Dmitry V. Chistyakov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia;
- Correspondence: (D.V.C.); (T.N.F.); (M.G.S.)
| | - Sergei V. Goriainov
- SREC PFUR Peoples’ Friendship University of Russia (RUDN University), Moscow 117198, Russia;
| | - Alina A. Astakhova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia;
| | | | - Rogneda B. Kazanskaya
- Biological Department, Saint Petersburg State University, Universitetskaya Emb. 7/9, St Petersburg 199034, Russia;
| | - Tatiana N. Fedorova
- Laboratory of Clinical and Experimental neurochemistry, Research Center of Neurology, Moscow 125367, Russia;
- Correspondence: (D.V.C.); (T.N.F.); (M.G.S.)
| | - Marina G. Sergeeva
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia;
- Correspondence: (D.V.C.); (T.N.F.); (M.G.S.)
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31
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Gao B, Emami A, Zhou R, Lang S, Duan Y, Wang Y, Jiang L, Loomba R, Brenner DA, Stärkel P, Schnabl B. Functional Microbial Responses to Alcohol Abstinence in Patients With Alcohol Use Disorder. Front Physiol 2020; 11:370. [PMID: 32390870 PMCID: PMC7193112 DOI: 10.3389/fphys.2020.00370] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/30/2020] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is associated with hepatic steatosis and dysregulation of the gut microbiota in patients with alcohol use disorder (AUD). However, how gut microbiota responds when patients stop drinking has not been well studied. In this study, we use shotgun metagenomic sequencing to elucidate the alterations in the functional capacity of gut microbiota in patients with AUD when they stop drinking for 2-weeks. Sensitive microbial pathways to alcohol abstinence were identified in AUD patients. Further, we found the functional microbial responses to alcohol abstinence were different in AUD patients with different degree of hepatic steatosis. Our results provide insights into the link between functional alterations of the gut microbiota and steatosis associated with alcohol consumption.
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Affiliation(s)
- Bei Gao
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Atoosa Emami
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Rongrong Zhou
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Sonja Lang
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Yi Duan
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
| | - Yanhan Wang
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
| | - Lu Jiang
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
| | - Rohit Loomba
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - David A. Brenner
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Peter Stärkel
- St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
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32
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Koelmel JP, Napolitano MP, Ulmer CZ, Vasiliou V, Garrett TJ, Yost RA, Prasad MNV, Godri Pollitt KJ, Bowden JA. Environmental lipidomics: understanding the response of organisms and ecosystems to a changing world. Metabolomics 2020; 16:56. [PMID: 32307636 DOI: 10.1007/s11306-020-01665-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 03/13/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Understanding the interaction between organisms and the environment is important for predicting and mitigating the effects of global phenomena such as climate change, and the fate, transport, and health effects of anthropogenic pollutants. By understanding organism and ecosystem responses to environmental stressors at the molecular level, mechanisms of toxicity and adaptation can be determined. This information has important implications in human and environmental health, engineering biotechnologies, and understanding the interaction between anthropogenic induced changes and the biosphere. One class of molecules with unique promise for environmental science are lipids; lipids are highly abundant and ubiquitous across nearly all organisms, and lipid profiles often change drastically in response to external stimuli. These changes allow organisms to maintain essential biological functions, for example, membrane fluidity, as they adapt to a changing climate and chemical environment. Lipidomics can help scientists understand the historical and present biofeedback processes in climate change and the biogeochemical processes affecting nutrient cycles. Lipids can also be used to understand how ecosystems respond to historical environmental changes with lipid signatures dating back to hundreds of millions of years, which can help predict similar changes in the future. In addition, lipids are direct targets of environmental stressors, for example, lipids are easily prone to oxidative damage, which occurs during exposure to most toxins. AIM OF REVIEW This is the first review to summarize the current efforts to comprehensively measure lipids to better understand the interaction between organisms and their environment. This review focuses on lipidomic applications in the arenas of environmental toxicology and exposure assessment, xenobiotic exposures and health (e.g., obesity), global climate change, and nutrient cycles. Moreover, this review summarizes the use of and the potential for lipidomics in engineering biotechnologies for the remediation of persistent compounds and biofuel production. KEY SCIENTIFIC CONCEPT With the preservation of certain lipids across millions of years and our ever-increasing understanding of their diverse biological roles, lipidomic-based approaches provide a unique utility to increase our understanding of the contemporary and historical interactions between organisms, ecosystems, and anthropogenically-induced environmental changes.
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Affiliation(s)
- Jeremy P Koelmel
- Department of Chemistry, University of Florida, 125 Buckman Drive, Gainesville, FL, 32611, USA
- Department of Environmental Health Sciences, School of Public Health, Yale University, New Haven, CT, 06510, USA
| | - Michael P Napolitano
- CSS, Inc., under contract to National Oceanic and Atmospheric Administration, National Centers for Coastal Ocean Science, Hollings Marine Laboratory, 331 Fort Johnson Road, Charleston, SC, 29412, USA
| | - Candice Z Ulmer
- National Institute of Standards and Technology, Hollings Marine Laboratory, 331 Ft. Johnson Road, Charleston, SC, 29412, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, School of Public Health, Yale University, New Haven, CT, 06510, USA
| | - Timothy J Garrett
- Department of Chemistry, University of Florida, 125 Buckman Drive, Gainesville, FL, 32611, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Richard A Yost
- Department of Chemistry, University of Florida, 125 Buckman Drive, Gainesville, FL, 32611, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - M N V Prasad
- Department of Plant Sciences, University of Hyderabad, Hyderabad, Telangana, 500046, India
| | - Krystal J Godri Pollitt
- Department of Environmental Health Sciences, School of Public Health, Yale University, New Haven, CT, 06510, USA
| | - John A Bowden
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, USA.
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33
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Beyoğlu D, Idle JR. Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy. Metabolites 2020; 10:E50. [PMID: 32012846 PMCID: PMC7074571 DOI: 10.3390/metabo10020050] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 01/24/2020] [Accepted: 01/26/2020] [Indexed: 02/07/2023] Open
Abstract
In recent years, there has been a plethora of attempts to discover biomarkers that are more reliable than α-fetoprotein for the early prediction and prognosis of hepatocellular carcinoma (HCC). Efforts have involved such fields as genomics, transcriptomics, epigenetics, microRNA, exosomes, proteomics, glycoproteomics, and metabolomics. HCC arises against a background of inflammation, steatosis, and cirrhosis, due mainly to hepatic insults caused by alcohol abuse, hepatitis B and C virus infection, adiposity, and diabetes. Metabolomics offers an opportunity, without recourse to liver biopsy, to discover biomarkers for premalignant liver disease, thereby alerting the potential of impending HCC. We have reviewed metabolomic studies in alcoholic liver disease (ALD), cholestasis, fibrosis, cirrhosis, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH). Specificity was our major criterion in proposing clinical evaluation of indole-3-lactic acid, phenyllactic acid, N-lauroylglycine, decatrienoate, N-acetyltaurine for ALD, urinary sulfated bile acids for cholestasis, cervonoyl ethanolamide for fibrosis, 16α-hydroxyestrone for cirrhosis, and the pattern of acyl carnitines for NAFL and NASH. These examples derive from a large body of published metabolomic observations in various liver diseases in adults, adolescents, and children, together with animal models. Many other options have been tabulated. Metabolomic biomarkers for premalignant liver disease may help reduce the incidence of HCC.
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Affiliation(s)
| | - Jeffrey R. Idle
- Arthur G. Zupko’s Division of Systems Pharmacology and Pharmacogenomics, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn, NY 11201, USA;
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Zirnheld KH, Warner DR, Warner JB, Hardesty JE, McClain CJ, Kirpich IA. Dietary fatty acids and bioactive fatty acid metabolites in alcoholic liver disease. LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.10.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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35
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Duan Y, Llorente C, Lang S, Brandl K, Chu H, Jiang L, White RC, Clarke TH, Nguyen K, Torralba M, Shao Y, Liu J, Hernandez-Morales A, Lessor L, Rahman IR, Miyamoto Y, Ly M, Gao B, Sun W, Kiesel R, Hutmacher F, Lee S, Ventura-Cots M, Bosques-Padilla F, Verna EC, Abraldes JG, Brown RS, Vargas V, Altamirano J, Caballería J, Shawcross DL, Ho SB, Louvet A, Lucey MR, Mathurin P, Garcia-Tsao G, Bataller R, Tu XM, Eckmann L, van der Donk WA, Young R, Lawley TD, Stärkel P, Pride D, Fouts DE, Schnabl B. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019; 575:505-511. [PMID: 31723265 PMCID: PMC6872939 DOI: 10.1038/s41586-019-1742-x] [Citation(s) in RCA: 566] [Impact Index Per Article: 94.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 10/02/2019] [Indexed: 12/14/2022]
Abstract
Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.
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Affiliation(s)
- Yi Duan
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Sonja Lang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Katharina Brandl
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Huikuan Chu
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Lu Jiang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | | | | | | | | | - Yan Shao
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK
| | - Jinyuan Liu
- Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
| | | | - Lauren Lessor
- Center for Phage Technology, Texas A & M AgriLife Research and Texas A & M University, College Station, TX, USA
| | - Imran R Rahman
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Yukiko Miyamoto
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Melissa Ly
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Bei Gao
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Weizhong Sun
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Roman Kiesel
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Felix Hutmacher
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Suhan Lee
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Meritxell Ventura-Cots
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA
| | - Francisco Bosques-Padilla
- Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Elizabeth C Verna
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Juan G Abraldes
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA
| | - Victor Vargas
- Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Jose Altamirano
- Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Juan Caballería
- Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
- Liver Unit, Hospital Clinic, Barcelona, Spain
| | - Debbie L Shawcross
- Liver Sciences, Department of Inflammation Biology, School of Infectious Diseases and Microbial Sciences, King's College London, London, UK
| | - Samuel B Ho
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Alexandre Louvet
- Service des Maladies de L'appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France
| | - Michael R Lucey
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Philippe Mathurin
- Service des Maladies de L'appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
- Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, CT, USA
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA
| | - Xin M Tu
- Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
| | - Lars Eckmann
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Wilfred A van der Donk
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Ry Young
- Department of Biochemistry and Biophysics, Texas A & M University, College Station, TX, USA
- Center for Phage Technology, Texas A & M AgriLife Research and Texas A & M University, College Station, TX, USA
| | - Trevor D Lawley
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK
| | - Peter Stärkel
- St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
| | - David Pride
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA, USA
| | | | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA.
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
- Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA, USA.
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