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Yakut A. Gut microbiota in the development and progression of chronic liver diseases: Gut microbiota-liver axis. World J Hepatol 2025; 17:104167. [PMID: 40177197 PMCID: PMC11959663 DOI: 10.4254/wjh.v17.i3.104167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
The gut microbiota (GM) is a highly dynamic ecology whose density and composition can be influenced by a wide range of internal and external factors. Thus, "How do GM, which can have commensal, pathological, and mutualistic relationships with us, affect human health?" has become the most popular research issue in recent years. Numerous studies have demonstrated that the trillions of microorganisms that inhabit the human body can alter host physiology in a variety of systems, such as metabolism, immunology, cardiovascular health, and neurons. The GM may have a role in the development of a number of clinical disorders by producing bioactive peptides, including neurotransmitters, short-chain fatty acids, branched-chain amino acids, intestinal hormones, and secondary bile acid conversion. These bioactive peptides enter the portal circulatory system through the gut-liver axis and play a role in the development of chronic liver diseases, cirrhosis, and hepatic encephalopathy. This procedure is still unclear and quite complex. In this study, we aim to discuss the contribution of GM to the development of liver diseases, its effects on the progression of existing chronic liver disease, and to address the basic mechanisms of the intestinal microbiota-liver axis in the light of recent publications that may inspire the future.
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Affiliation(s)
- Aysun Yakut
- Department of Gastroenterology, İstanbul Medipol University Sefakoy Health Practice Research Center, İstanbul 38000, Türkiye.
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2
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Rondanelli M, Borromeo S, Cavioni A, Gasparri C, Gattone I, Genovese E, Lazzarotti A, Minonne L, Moroni A, Patelli Z, Razza C, Sivieri C, Valentini EM, Barrile GC. Therapeutic Strategies to Modulate Gut Microbial Health: Approaches for Chronic Metabolic Disorder Management. Metabolites 2025; 15:127. [PMID: 39997751 PMCID: PMC11857149 DOI: 10.3390/metabo15020127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/17/2025] [Accepted: 01/28/2025] [Indexed: 02/26/2025] Open
Abstract
Numerous recent studies have suggested that the composition of the intestinal microbiota can trigger metabolic disorders, such as diabetes, prediabetes, obesity, metabolic syndrome, sarcopenia, dyslipidemia, hyperhomocysteinemia, and non-alcoholic fatty liver disease. Since then, considerable effort has been made to understand the link between the composition of intestinal microbiota and metabolic disorders, as well as the role of probiotics in the modulation of the intestinal microbiota. The aim of this review was to summarize the reviews and individual articles on the state of the art regarding ideal therapy with probiotics and prebiotics in order to obtain the reversion of dysbiosis (alteration in microbiota) to eubiosis during metabolic diseases, such as diabetes, prediabetes, obesity, hyperhomocysteinemia, dyslipidemia, sarcopenia, and non-alcoholic fatty liver diseases. This review includes 245 eligible studies. In conclusion, a condition of dysbiosis, or in general, alteration of the intestinal microbiota, could be implicated in the development of metabolic disorders through different mechanisms, mainly linked to the release of pro-inflammatory factors. Several studies have already demonstrated the potential of using probiotics and prebiotics in the treatment of this condition, detecting significant improvements in the specific symptoms of metabolic diseases. These findings reinforce the hypothesis that a condition of dysbiosis can lead to a generalized inflammatory picture with negative consequences on different organs and systems. Moreover, this review confirms that the beneficial effects of probiotics on metabolic diseases are promising, but more research is needed to determine the optimal probiotic strains, doses, and administration forms for specific metabolic conditions.
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Affiliation(s)
- Mariangela Rondanelli
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy;
| | - Sara Borromeo
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Alessandro Cavioni
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Clara Gasparri
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Ilaria Gattone
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Elisa Genovese
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Alessandro Lazzarotti
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Leonardo Minonne
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Alessia Moroni
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Zaira Patelli
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Claudia Razza
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Claudia Sivieri
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Eugenio Marzio Valentini
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
| | - Gaetan Claude Barrile
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, 27100 Pavia, Italy; (S.B.); (A.C.); (C.G.); (I.G.); (E.G.); (A.L.); (L.M.); (A.M.); (Z.P.); (C.R.); (C.S.); (E.M.V.)
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Termite F, Archilei S, D’Ambrosio F, Petrucci L, Viceconti N, Iaccarino R, Liguori A, Gasbarrini A, Miele L. Gut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD. Antioxidants (Basel) 2025; 14:56. [PMID: 39857390 PMCID: PMC11759774 DOI: 10.3390/antiox14010056] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition marked by excessive lipid accumulation in hepatic tissue. This disorder can lead to a range of pathological outcomes, including metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Despite extensive research, the molecular mechanisms driving MASLD initiation and progression remain incompletely understood. Oxidative stress and lipid peroxidation are pivotal in the "multiple parallel hit model", contributing to hepatic cell death and tissue damage. Gut microbiota plays a substantial role in modulating hepatic oxidative stress through multiple pathways: impairing the intestinal barrier, which results in bacterial translocation and chronic hepatic inflammation; modifying bile acid structure, which impacts signaling cascades involved in lipidic metabolism; influencing hepatocytes' ferroptosis, a form of programmed cell death; regulating trimethylamine N-oxide (TMAO) metabolism; and activating platelet function, both recently identified as pathogenetic factors in MASH progression. Moreover, various exogenous factors impact gut microbiota and its involvement in MASLD-related oxidative stress, such as air pollution, physical activity, cigarette smoke, alcohol, and dietary patterns. This manuscript aims to provide a state-of-the-art overview focused on the intricate interplay between gut microbiota, lipid peroxidation, and MASLD pathogenesis, offering insights into potential strategies to prevent disease progression and its associated complications.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Luca Miele
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy (S.A.)
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Rochoń J, Kalinowski P, Szymanek-Majchrzak K, Grąt M. Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease. World J Gastroenterol 2024; 30:2964-2980. [PMID: 38946874 PMCID: PMC11212696 DOI: 10.3748/wjg.v30.i23.2964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.
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Affiliation(s)
- Jakub Rochoń
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
| | - Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
| | | | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
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Rodrigues SG, van der Merwe S, Krag A, Wiest R. Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases. Semin Immunol 2024; 71:101859. [PMID: 38219459 DOI: 10.1016/j.smim.2023.101859] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Schalk van der Merwe
- Department of Gastroenterology and Hepatology, University hospital Gasthuisberg, University of Leuven, Belgium
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark, University of Southern Denmark, Odense, Denmark
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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6
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Soppert J, Brandt EF, Heussen NM, Barzakova E, Blank LM, Kuepfer L, Hornef MW, Trebicka J, Jankowski J, Berres ML, Noels H. Blood Endotoxin Levels as Biomarker of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2023; 21:2746-2758. [PMID: 36470528 DOI: 10.1016/j.cgh.2022.11.030] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 01/02/2023]
Abstract
BACKGROUND & AIMS Growing evidence supports a role of gut-derived metabolites in nonalcoholic fatty liver disease (NAFLD), but the relation of endotoxin levels with gut permeability and NAFLD stage remains unclear. This systematic review with meta-analysis aims to provide further insights. METHODS PubMed, Embase, and Cochrane Library were searched for studies published until January 2022 assessing blood endotoxins in patients with NAFLD. Meta-analyses and univariate/multivariate meta-regression, as well as correlation analyses, were performed for endotoxin values and potential relationships to disease stage, age, sex, parameters of systemic inflammation, and metabolic syndrome, as well as liver function and histology. RESULTS Forty-three studies were included, of which 34 were used for meta-analyses. Blood endotoxin levels were higher in patients with simple steatosis vs liver-healthy controls (standardized mean difference, 0.86; 95% confidence interval, 0.62-1.11) as well as in patients with nonalcoholic steatohepatitis vs patients with nonalcoholic fatty liver/non-nonalcoholic steatohepatitis (standardized mean difference, 0.81; 95% confidence interval, 0.27-1.35; P = .0078). Consistently, higher endotoxin levels were observed in patients with more advanced histopathological gradings of liver steatosis and fibrosis. An increase of blood endotoxin levels was partially attributed to a body mass index rise in patients with NAFLD compared with controls. Nevertheless, significant increases of blood endotoxin levels in NAFLD retained after compensation for differences in body mass index, metabolic condition, or liver enzymes. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations, and in most cases, paralleled a rise in markers for intestinal permeability. CONCLUSION Our results support blood endotoxin levels as relevant diagnostic biomarker for NAFLD, both for disease detection as well as staging during disease progression, and might serve as surrogate marker of enhanced intestinal permeability in NAFLD. Registration number in Prospero: CRD42022311166.
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Affiliation(s)
- Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Elisa Fabiana Brandt
- Department of Internal Medicine III, University Hospital of Aachen, Aachen, Germany
| | - Nicole Maria Heussen
- Department of Medical Statistics, RWTH Aachen University, Aachen, Germany; Center of Biostatistics and Epidemiology, Medical School, Sigmund Freud University, Vienna, Austria
| | - Emona Barzakova
- Department of Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Lars Mathias Blank
- Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
| | - Lars Kuepfer
- Institute for Systems Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | | | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Marie-Luise Berres
- Department of Internal Medicine III, University Hospital of Aachen, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Site Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
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Stojic J, Kukla M, Grgurevic I. The Intestinal Microbiota in the Development of Chronic Liver Disease: Current Status. Diagnostics (Basel) 2023; 13:2960. [PMID: 37761327 PMCID: PMC10528663 DOI: 10.3390/diagnostics13182960] [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: 08/08/2023] [Revised: 09/06/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic liver disease (CLD) is a significant global health burden, leading to millions of deaths annually. The gut-liver axis plays a pivotal role in this context, allowing the transport of gut-derived products directly to the liver, as well as biological compounds from the liver to the intestine. The gut microbiota plays a significant role in maintaining the health of the digestive system. A change in gut microbiome composition as seen in dysbiosis is associated with immune dysregulation, altered energy and gut hormone regulation, and increased intestinal permeability, contributing to inflammatory mechanisms and damage to the liver, irrespective of the underlying etiology of CLD. The aim of this review is to present the current knowledge about the composition of the intestinal microbiome in healthy individuals and those with CLD, including the factors that affect this composition, the impact of the altered microbiome on the liver, and the mechanisms by which it occurs. Furthermore, this review analyzes the effects of gut microbiome modulation on the course of CLD, by using pharmacotherapy, nutrition, fecal microbiota transplantation, supplements, and probiotics. This review opens avenues for the translation of knowledge about gut-liver interplay into clinical practice as an additional tool to fight CLD and its complications.
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Affiliation(s)
- Josip Stojic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
| | - Michał Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagellonian University Medical College, 31-688 Kraków, Poland;
- Department of Endoscopy, University Hospital, 30-688 Kraków, Poland
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
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Gao Y, Lin J, Ye C, Guo S, Jiang C. Microbial transformations of bile acids and their receptors in the regulation of metabolic dysfunction-associated steatotic liver disease. LIVER RESEARCH 2023; 7:165-176. [PMID: 39958385 PMCID: PMC11792070 DOI: 10.1016/j.livres.2023.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/02/2023] [Accepted: 09/08/2023] [Indexed: 01/03/2025]
Abstract
Bile acids (BAs) play important roles in the digestion of dietary fats and molecular signal transduction, and modulation of the BA composition usually affects the progression of metabolic diseases. While the liver produces primary BAs, the gut microbiota modifies these products into various forms that greatly increase their diversity and biological functions. Mechanistically, BAs can regulate their own metabolism and transport as well as other key aspects of metabolic processes via dedicated BA receptors. Disruption of BA transport and homeostasis leads to the progression of liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Here, we summarize the microbial transformations of BAs and their downstream signaling in the development of metabolic diseases and present new insights into novel therapeutic strategies targeting BA pathways that may contribute to these diseases.
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Affiliation(s)
- Yuhua Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jun Lin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Chuan Ye
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Siqi Guo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
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9
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Shalaby N, Samocha-Bonet D, Kaakoush NO, Danta M. The Role of the Gastrointestinal Microbiome in Liver Disease. Pathogens 2023; 12:1087. [PMID: 37764895 PMCID: PMC10536540 DOI: 10.3390/pathogens12091087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.
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Affiliation(s)
- Nicholas Shalaby
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
| | - Dorit Samocha-Bonet
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
- Clinical Insulin Resistance Group, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Nadeem O. Kaakoush
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW 2033, Australia
| | - Mark Danta
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
- Department of Gastroenterology and Hepatology, St Vincent’s Hospital, Darlinghurst, NSW 2010, Australia
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10
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Elghannam MT, Hassanien MH, Ameen YA, Turky EA, Elattar GM, ElRay AA, Eltalkawy MD. Oral microbiota and liver diseases. Clin Nutr ESPEN 2023; 54:68-72. [PMID: 36963900 DOI: 10.1016/j.clnesp.2022.12.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/25/2022] [Accepted: 12/30/2022] [Indexed: 01/07/2023]
Abstract
Gut microbiota plays a crucial role in our health and particularly liver diseases, including NAFLD, cirrhosis, and HCC. Oral microbiome and its role in health and disease represent an active field of research. Several lines of evidence have suggested that oral microbiota dysbiosis represents a major factor contributing to the occurrence and progression of many liver diseases. The human microbiome is valuable to the diagnosis of cancer and provides a novel strategy for targeted therapy of HCC. The most studied liver disease in relation to oral-gut-liver axis dysbiosis includes MAFLD; however, other diseases include Precancerous liver disease as viral liver diseases, liver cirrhosis, AIH and liver carcinoma (HCC). It seems that restoring populations of beneficial organisms and correcting dysbiosis appears to improve outcomes in liver disorders. We discuss the possible role of oral microbiota in these diseases.
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Affiliation(s)
- Maged Tharwat Elghannam
- TBRI, Warak ALHadar, P.O. Box 30 Imbaba, Cairo, Egypt; Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt.
| | | | | | | | | | - Ahmed Aly ElRay
- Hepatogastroenterology Department, Theodor Bilharz Research Institute, Giza, Egypt.
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Yang S, Yu D, Liu J, Qiao Y, Gu S, Yang R, Chai X, Wang W. Global publication trends and research hotspots of the gut-liver axis in NAFLD: A bibliometric analysis. Front Endocrinol (Lausanne) 2023; 14:1121540. [PMID: 36967792 PMCID: PMC10034112 DOI: 10.3389/fendo.2023.1121540] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/21/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND Nonalcoholic Fatty Liver Disease(NAFLD)refers to a spectrum of diseases ranging from simple liver steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Bidirectional cross-talk between the gut-liver axis plays an important role in the pathogenesis of NAFLD. To learn more about the gut-liver axis in NAFLD, this study aims to provide a comprehensive analysis from a bibliometric perspective. METHOD Literature related to the gut-liver axis in NAFLD from 1989 to 2022 was extracted from the Web of Science Core Collection. Based on Microsoft Excel, CiteSpace and Vosviewer, we conducted to analyze the number of publications, countries/regions, institutions, authors, journals, references, and keywords. RESULTS A total of 1,891 literature since 2004 was included, with the rapid growth of the number of papers on the gut-liver axis in NAFLD annually. These publications were mainly from 66 countries and 442 institutions. Of the 638 authors analyzed, Bernd Schnabl was the one with the most publications, and Patrice D. Cani was the one with the most co-citations. International Journal of Molecular Sciences is the journal with the most articles published, and Hepatology is the journal with the most citations. The most common keywords are gut microbiota, inflammation, and insulin instance, which are current research hotspots. Short-chain fatty acid, in vitro, randomized controlled trial in clinical, and diabetes mellitus represent the research frontiers in this field and are in a stage of rapid development. CONCLUSION This is the first study to conduct a comprehensive bibliometric analysis of publications related to the gut-liver axis in NAFLD. This study reveals that gut microbiota, inflammation, insulin resistance, short-chain fatty acids, and randomized controlled trial will be the hotspots and new trends in the gut-liver axis in NAFLD research, which could provide researchers with key research information in this field and is helpful for further exploration of new research directions.
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Affiliation(s)
- Shuangjie Yang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Deshuai Yu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Junjie Liu
- Department of Cardiology, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Yanfang Qiao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shuxiao Gu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Ran Yang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Ran Yang, ; Xinlou Chai, ; Wei Wang,
| | - Xinlou Chai
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Ran Yang, ; Xinlou Chai, ; Wei Wang,
| | - Wei Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Ran Yang, ; Xinlou Chai, ; Wei Wang,
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12
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Perng W, Friedman JE, Janssen RC, Glueck DH, Dabelea D. Endotoxin Biomarkers Are Associated With Adiposity and Cardiometabolic Risk Across 6 Years of Follow-up in Youth. J Clin Endocrinol Metab 2022; 107:e3018-e3028. [PMID: 35276001 PMCID: PMC9202713 DOI: 10.1210/clinem/dgac149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Metabolic endotoxemia may be a shared mechanism underlying childhood obesity and early-onset metabolic diseases (eg, type 2 diabetes, nonalcoholic fatty liver disease). OBJECTIVE Examine prospective associations of serum endotoxin biomarkers lipopolysaccharide (LPS) and its binding protein, LPS binding protein (LBP), and anti-endotoxin core immunoglobulin G (EndoCab IgG) with adiposity and cardiometabolic risk in youth. DESIGN/SETTING This prospective study included 393 youth in the Exploring Perinatal Outcomes Among Children cohort in Colorado. Participants were recruited from 2006 to 2009 at age 10 years (baseline) and followed for 6 years (follow-up). We examined associations of endotoxin biomarkers at baseline with adiposity [body mass index (BMI) z-score, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skinfolds, waist circumference] and cardiometabolic risk (insulin, glucose, adipokines, lipid profile, blood pressure) across both visits using mixed-effects regression, and with hepatic fat fraction (HFF) at follow-up using linear regression. RESULTS Higher LPS and LBP predicted greater adiposity across follow-up. Each 1-unit log-transformed LPS corresponded with 0.23 (95% CI 0.03, 0.43) units BMI z-score, 5.66 (95% CI 1.99, 9.33) mm3 VAT, 30.7 (95% CI 8.0, 53.3) mm3 SAT, and 8.26 (95% CI 4.13, 12.40) mm skinfold sum. EndoCab IgG was associated with VAT only [3.03 (95% CI 0.34, 5.71) mm3]. LPS was associated with higher insulin [1.93 (95% CI 0.08, 3.70) µU/mL] and leptin [2.28 (95% CI 0.66, 3.90) ng/mL] and an adverse lipid profile. No association was observed with HFF. Accounting for pubertal status and lifestyle behaviors did not change findings. However, adjustment for prepregnancy BMI and gestational diabetes attenuated most associations. CONCLUSIONS Serum endotoxin may be a marker of pathophysiological processes underlying development of childhood obesity and cardiometabolic conditions associated with exposure to fetal overnutrition.
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Affiliation(s)
- Wei Perng
- Correspondence: Wei Perng, University of Colorado Denver, Anschutz Medical Campus, 12474 E. 19th Ave, Room 208, Aurora, CO 80045, USA.
| | - Jacob E Friedman
- Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, School of Medicine, Oklahoma City, OK, USA
| | - Rachel C Janssen
- Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, School of Medicine, Oklahoma City, OK, USA
| | - Deborah H Glueck
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora CO, USA
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora CO, USA
| | - Dana Dabelea
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora CO, USA
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, CO, USA
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora CO, USA
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Bacillus subtilis Supplementation in a High-Fat Diet Modulates the Gut Microbiota and Ameliorates Hepatic Lipid Accumulation in Grass Carp (Ctenopharyngodon idella). FISHES 2022. [DOI: 10.3390/fishes7030094] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
To study the effects of Bacillus subtilis supplementation in a high-fat diet on the gut microbiota and nonalcoholic fatty liver disease in grass carp (Ctenopharyngodon idella), juveniles (60 ± 5 g) were fed three diets: (a) a control diet (CON), (b) a high-fat diet (HFD) and (c) a high-fat diet supplemented with B. subtilis (HFD + BS). After 8 weeks of feeding, fish growth, serum biochemical indices and total liver lipid content were measured, and gut microbiota analysis was performed using the MiSeq250 high-throughput sequencing platform. The results of this study showed that B. subtilis could improve growth and blood serum indices and reduce lipid deposition in the fish liver, preventing fatty liver disease. A grass carp model of fatty liver induced by a high-fat diet was successfully established. Moreover, B. subtilis altered the intestinal microbiota of HFD-fed grass carp, making it more similar to that of the control group. This study revealed the important effects of B. subtilis on grass carp with fatty liver induced by a high-fat diet and provides the foundation for the application of probiotics in grass carp farming.
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14
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Dalbeni A, Castelli M, Zoncapè M, Minuz P, Sacerdoti D. Platelets in Non-alcoholic Fatty Liver Disease. Front Pharmacol 2022; 13:842636. [PMID: 35250588 PMCID: PMC8895200 DOI: 10.3389/fphar.2022.842636] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/03/2022] [Indexed: 12/17/2022] Open
Abstract
Non alcoholic steatohepatitis (NASH) is the inflammatory reaction of the liver to excessive accumulation of lipids in the hepatocytes. NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Fatty liver is the hepatic manifestation of metabolic syndrome. A subclinical inflammatory state is present in patients with metabolic alterations like insulin resistance, type-2 diabetes, obesity, hyperlipidemia, and hypertension. Platelets participate in immune cells recruitment and cytokines-induced liver damage. It is hypothesized that lipid toxicity cause accumulation of platelets in the liver, platelet adhesion and activation, which primes the immunoinflammatory reaction and activation of stellate cells. Recent data suggest that antiplatelet drugs may interrupt this cascade and prevent/improve NASH. They may also improve some metabolic alterations. The pathophysiology of inflammatory liver disease and the implication of platelets are discussed in details.
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Affiliation(s)
- Andrea Dalbeni
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Marco Castelli
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Mirko Zoncapè
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Pietro Minuz
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- *Correspondence: Pietro Minuz,
| | - David Sacerdoti
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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15
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Zhuang YP, Zhang YT, Zhang RX, Zhong HJ, He XX. The Gut-Liver Axis in Nonalcoholic Fatty Liver Disease: Association of Intestinal Permeability with Disease Severity and Treatment Outcomes. Int J Clin Pract 2022; 2022:4797453. [PMID: 35685554 PMCID: PMC9159210 DOI: 10.1155/2022/4797453] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 01/05/2022] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE To investigate the association between intestinal permeability and severity of nonalcoholic fatty liver disease (NAFLD) and the value of intestinal permeability in predicting the efficacy of metabolic therapy for NAFLD. METHODS Disease severity was compared between patients with normal and elevated intestinal permeability; correlations between D-lactate and different NAFLD parameters were analyzed; and the effects of metabolic therapy on NAFLD patients with normal and elevated intestinal permeability were evaluated. RESULTS A total of 190 patients with NAFLD were enrolled. NAFLD patients with elevated intestinal permeability had significantly higher levels of liver test parameters, liver ultrasonographic fat attenuation parameter, triglyceride, homeostasis model assessment of insulin resistance value, and diamine oxidase (all P˂0.05) than NAFLD patients with normal intestinal permeability. Furthermore, serum D-lactate levels were positively correlated with alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, total bilirubin, indirect bilirubin, fat attenuation parameter, triglyceride, and diamine oxidase (all P ˂ 0.05). Moreover, NAFLD patients with elevated intestinal permeability showed less improvement in TG levels (P = 0.014) after metabolic therapy. CONCLUSION Intestinal permeability correlates with the disease severity in patients with NAFLD. Moreover, intestinal permeability may have value for predicting the efficacy of metabolic therapy for NAFLD patients.
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Affiliation(s)
- Yu-Pei Zhuang
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
| | - Yi-Ting Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
| | - Ruo-Xin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
| | - Hao-Jie Zhong
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
- South China University of Technology, Guangzhou, China
| | - Xing-Xiang He
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, China
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Jiang Y, Chowdhury S, Xu BH, Meybodi MA, Damiris K, Devalaraju S, Pyrsopoulos N. Nonalcoholic fatty liver disease is associated with worse intestinal complications in patients hospitalized for Clostridioides difficile infection. World J Hepatol 2021; 13:1777-1790. [PMID: 34904045 PMCID: PMC8637681 DOI: 10.4254/wjh.v13.i11.1777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/08/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease with increasing prevalence worldwide. Clostridioides difficile infection (CDI) remains the most common cause of nosocomial diarrhea in developed countries. AIM To assess the impact of NAFLD on the outcomes of hospitalized patients with CDI. METHODS This study was a retrospective cohort study. The Nationwide Inpatient Sample database was used to identify a total of 7239 adults admitted as inpatients with a primary diagnosis of CDI and coexisting NAFLD diagnosis from 2010 to 2014 using ICD-9 codes. Patients with CDI and coexisting NAFLD were compared to those with CDI and coexisting alcoholic liver disease (ALD) and viral liver disease (VLD), individually. Primary outcomes included mortality, length of stay, and total hospitalization charges. Secondary outcomes were in-hospital complications. Multivariate regression was used for outcome analysis after adjusting for possible confounders. RESULTS CDI with NAFLD was independently associated with lower rates of acute respiratory failure (2.7% vs 4.2%, P < 0.01; 2.7% vs 4.2%, P < 0.05), shorter length of stay (days) (5.75 ± 0.16 vs 6.77 ± 0.15, P < 0.001; 5.75 ± 0.16 vs 6.84 ± 0.23, P <0.001), and lower hospitalization charges (dollars) (38150.34 ± 1757.01 vs 46326.72 ± 1809.82, P < 0.001; 38150.34 ± 1757.01 vs 44641.74 ± 1660.66, P < 0.001) when compared to CDI with VLD and CDI with ALD, respectively. CDI with NAFLD was associated with a lower rate of acute kidney injury (13.0% vs 17.2%, P < 0.01), but a higher rate of intestinal perforation (P < 0.01) when compared to VLD. A lower rate of mortality (0.8% vs 2.7%, P < 0.05) but a higher rate of intestinal obstruction (4.6% vs 2.2%, P = 0.001) was also observed when comparing CDI with NAFLD to ALD. CONCLUSION Hospitalized CDI patients with NAFLD had more intestinal complications compared to CDI patients with VLD and ALD. Gut microbiota dysbiosis may contribute to the pathogenesis of intestinal complications.
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Affiliation(s)
- Yi Jiang
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States
| | - Salil Chowdhury
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States
| | - Bing-Hong Xu
- Liver Center and Center for Asian Health, RWJBH-Saint Barnabas Medical Center, Florham Park, NJ 07932, United States
| | - Mohamad Aghaie Meybodi
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States
| | - Konstantinos Damiris
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States
| | - Samanthika Devalaraju
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States
| | - Nikolaos Pyrsopoulos
- Department of Medicine, Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07101, United States.
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17
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Jacob JS, Ahmed A, Cholankeril G. The impact of alteration in gut microbiome in the pathogenesis of nonalcoholic fatty liver disease. Curr Opin Infect Dis 2021; 34:477-482. [PMID: 34267042 DOI: 10.1097/qco.0000000000000759] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW We have increasing evidence that alterations of the intestinal microbiome have a strong influence on human health. Previous work has demonstrated the association between changes in the microbiome and metabolic risk factors. One related area of interest is the relationship between dysbiosis and nonalcoholic fatty liver disease (NAFLD), as the global prevalence of NAFLD, and its resultant complications, increases. RECENT FINDINGS In this review, we summarize the hypothesized pathophysiology of dysbiosis-mediated progression of NAFLD, including promotion of an inflammatory intestinal environment, increased intestinal permeability, endogenous ethanol production, short-chain fatty acid production, secondary bile acid metabolism, and choline depletion. We also review potential therapeutic interventions of the microbiome to slow or prevent NAFLD progression, including antibiotics, probiotics, prebiotics, fecal microbiota transplant, and farnesoid × receptor agonism. SUMMARY Much of the evidence supporting dysbiosis-mediated NAFLD progression has been gathered in high-quality animal trials. There remains a need for additional observational and randomized controlled trials in humans to establish causality between the suspected factors and pathogenesis of NAFLD.
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Affiliation(s)
- Jake S Jacob
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford, California
| | - George Cholankeril
- Liver Center, Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
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Kordy K, Li F, Lee DJ, Kinchen JM, Jew MH, La Rocque ME, Zabih S, Saavedra M, Woodward C, Cunningham NJ, Tobin NH, Aldrovandi GM. Metabolomic Predictors of Non-alcoholic Steatohepatitis and Advanced Fibrosis in Children. Front Microbiol 2021; 12:713234. [PMID: 34475864 PMCID: PMC8406633 DOI: 10.3389/fmicb.2021.713234] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in western countries both in children and adults. Metabolic dysregulation associated with gut microbial dysbiosis may influence disease progression from hepatic steatosis to inflammation and subsequent fibrosis. Using a multi-omics approach, we profiled the oral and fecal microbiome and plasma metabolites from 241 predominantly Latino children with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), and controls. Children with more severe liver pathology were dysbiotic and had increased gene content associated with lipopolysaccharide biosynthesis and lipid, amino acid and carbohydrate metabolism. These changes were driven by increases in Bacteroides and concomitant decreases of Akkermansia, Anaerococcus, Corynebacterium, and Finegoldia. Non-targeted mass spectrometry revealed perturbations in one-carbon metabolism, mitochondrial dysfunction, and increased oxidative stress in children with steatohepatitis and fibrosis. Random forests modeling of plasma metabolites was highly predictive of non-alcoholic steatohepatitis (NASH) (97% accuracy) and hepatic fibrosis, steatosis and lobular inflammation (93.8% accuracy), and can differentiate steatohepatitis from simple steatosis (90.0% accuracy). Multi-omics predictive models for disease and histology findings revealed perturbations in one-carbon metabolism, mitochondrial dysfunction, and increased oxidative stress in children with steatohepatitis and fibrosis. These results highlight the promise of non-invasive biomarkers for the growing epidemic of fatty liver disease.
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Affiliation(s)
- Kattayoun Kordy
- Pediatric Gastroenterology, Children’s Hospital of Los Angeles, Los Angeles, CA, United States
- Department of Pediatrics, University of Southern California, Los Angeles, CA, United States
| | - Fan Li
- Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
| | - David J. Lee
- Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
| | | | - Michael H. Jew
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | | | - Sara Zabih
- Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Monica Saavedra
- Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Cora Woodward
- Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Nicole J. Cunningham
- Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Nicole H. Tobin
- Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Grace M. Aldrovandi
- Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
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Kessoku T, Kobayashi T, Tanaka K, Yamamoto A, Takahashi K, Iwaki M, Ozaki A, Kasai Y, Nogami A, Honda Y, Ogawa Y, Kato S, Imajo K, Higurashi T, Hosono K, Yoneda M, Usuda H, Wada K, Saito S, Nakajima A. The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target. Int J Mol Sci 2021; 22:ijms22158161. [PMID: 34360923 PMCID: PMC8347478 DOI: 10.3390/ijms22158161] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression.
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Affiliation(s)
- Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Correspondence: ; Tel.: +81-45-787-2640; Fax: +81-45-784-3546
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kosuke Tanaka
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Atsushi Yamamoto
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kota Takahashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Yuki Kasai
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Shingo Kato
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Takuma Higurashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kunihiro Hosono
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Haruki Usuda
- Department of Pharmacology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan; (H.U.); (K.W.)
| | - Koichiro Wada
- Department of Pharmacology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan; (H.U.); (K.W.)
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
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Hussain M, Umair Ijaz M, Ahmad MI, Khan IA, Bukhary SUF, Khan W, Hussain S, Hashmi MS, Li C. Gut inflammation exacerbates hepatic injury in C57BL/6J mice via gut-vascular barrier dysfunction with high-fat-incorporated meat protein diets. Food Funct 2021; 11:9168-9176. [PMID: 33026380 DOI: 10.1039/d0fo02153a] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM Meat and its derivatives provide nutrients essential for human health. However, meat consumption, along with excessive fat intake, has been associated with gut inflammation, intestinal barrier dysfunction and alterations in gut microbiota. Herein, we investigated whether and how these changes in the intestinal barrier system affect the gut liver axis and hepatic injury and eventually lead to the progression of liver syndrome such as NAFLD. METHODS Mice were fed with high fat (60% kcal) or low fat (12% kcal) along with soybean (control), chicken and pork proteins (HFCH, HFP, LFCH, and LFP) for 12 weeks. The biomarkers for liver injury were investigated after meat protein intake along with the high fat. FINDINGS Greater amount of fat vacuoles visible in the H&E staining increased the inflammatory cell infiltration and disorganized liver structures were observed in the HFP-fed mice. Oil Red O staining revealed that the HFP-fed and HFCH-fed mice showed more lipid droplets, confirming the increased hepatic lipid accumulation. Potential serum markers for NAFLD, ALT and AST were increased in the HF meat diet groups. Key genes responsible for hepatic inflammation and lipogenesis, such as MCP-1, IL1-β and TNF-α were upregulated. HF meat protein diet-fed mice exhibited signs of compromised liver with increased levels of endotoxin in the liver and its binding protein in serum, upregulation of TLRs in the liver, and significant increase in TG, TC, LDL-C and HDL-C concentrations. SIGNIFICANCE Intestinal inflammation and barrier dysfunction aggravate liver injury and fibrosis due to the intake of HF meat protein diets in mice, which may contribute to the progress of liver injury and associated complications. Gut inflammation may directly contribute to the development of NAFLD, especially of the gut vascular barricade dysfunction.
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Affiliation(s)
- Muzahir Hussain
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Centre of Meat Production and Processing, Quality and Safety Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, PR China. and Department of Horticulture, Abdul Wali Khan University Mardan, KPK, Pakistan and Department of Food Science and Technology, The University of Agriculture Peshawar, Peshawar, KPK 26000, Pakistan
| | - Muhammad Umair Ijaz
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Centre of Meat Production and Processing, Quality and Safety Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Muhammad Ijaz Ahmad
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Centre of Meat Production and Processing, Quality and Safety Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Iftikhar Ali Khan
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Centre of Meat Production and Processing, Quality and Safety Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Syed Umar Farooq Bukhary
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Centre of Meat Production and Processing, Quality and Safety Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Waqar Khan
- College of Life Sciences, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Sayed Hussain
- Department of Horticulture, Abdul Wali Khan University Mardan, KPK, Pakistan
| | - Majid Suhail Hashmi
- Department of Food Science and Technology, The University of Agriculture Peshawar, Peshawar, KPK 26000, Pakistan
| | - Chunbao Li
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Centre of Meat Production and Processing, Quality and Safety Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, PR China.
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21
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Ahmed O, Robinson MW, O'Farrelly C. Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol 2021; 18:1375-1386. [PMID: 33864004 PMCID: PMC8166849 DOI: 10.1038/s41423-021-00639-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
The hepatic immune system is designed to tolerate diverse harmless foreign moieties to maintain homeostasis in the healthy liver. Constant priming and regulation ensure that appropriate immune activation occurs when challenged by pathogens and tissue damage. Failure to accurately discriminate, regulate, or effectively resolve inflammation offsets this balance, jeopardizing overall tissue health resulting from an either overly tolerant or an overactive inflammatory response. Compelling scientific and clinical evidence links dysregulated hepatic immune and inflammatory responses upon sterile injury to several pathological conditions in the liver, particularly nonalcoholic steatohepatitis and ischemia-reperfusion injury. Murine and human studies have described interactions between diverse immune repertoires and nonhematopoietic cell populations in both physiological and pathological activities in the liver, although the molecular mechanisms driving these associations are not clearly understood. Here, we review the dynamic roles of inflammatory mediators in responses to sterile injury in the context of homeostasis and disease, the clinical implications of dysregulated hepatic immune activity and therapeutic developments to regulate liver-specific immunity.
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Affiliation(s)
- Ola Ahmed
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Mark W Robinson
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Cliona O'Farrelly
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
- School of Biochemistry & Immunology, Trinity College Dublin, Dublin 2, Ireland.
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22
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Bakhshimoghaddam F, Alizadeh M. Contribution of gut microbiota to nonalcoholic fatty liver disease: Pathways of mechanisms. Clin Nutr ESPEN 2021; 44:61-68. [PMID: 34330514 DOI: 10.1016/j.clnesp.2021.05.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/22/2021] [Accepted: 05/11/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is a common, multifactorial liver disease with rapidly increasing prevalence. During the past decade, several lines of evidence have suggested that gut microbiota dysbiosis represents a major factor contributing to NAFLD occurrence and its progression. METHOD We have performed a review of the published data on the relationship between gut microbiota and risk factors for NAFLD and the role that gut-liver axis plays in the pathogenesis of NAFLD. RESULTS Accumulated evidence has indicated that dysfunction of the gut-liver axis, including increased intestinal permeability, small intestinal bacterial overgrowth, microbiota-derived mediators, and intestinal dysbiosis contribute to the progression and development of NAFLD. CONCLUSIONS The findings of this review suggest that lifestyle modification and manipulation of gut microbiota can be considered as a therapeutic target for NAFLD management. However, important documents supporting the role of gut microbiota in NAFLD come from animal studies; therefore, information from studies on humans could lead to novel therapeutics for this highly common disorder.
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Affiliation(s)
- Farnush Bakhshimoghaddam
- Student Research Committee, Department of Nutrition, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Alizadeh
- Department of Nutrition, Food and Beverages Safety Research Center, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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Moreno-Gonzalez M, Beraza N. The Role of the Microbiome in Liver Cancer. Cancers (Basel) 2021; 13:2330. [PMID: 34066064 PMCID: PMC8150469 DOI: 10.3390/cancers13102330] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy occuring in the context of chronic liver disease and is one of the main causes of cancer-derived death worldwide. The lack of effective treatments, together with the poor prognosis, underlines the urge to develop novel and multidisciplinary therapeutics. An increasing body of evidence shows that HCC associates with changes in intestinal microbiota abundance and composition as well as with impaired barrier function, leading to the release of bacteria and their metabolites to the liver. These factors trigger a cascade of inflammatory responses contributing to liver cirrhosis and constituting an ideal environment for the progression of HCC. Interestingly, the use of bacteriotherapy in human and preclinical studies of chronic liver disease and HCC has been shown to successfully modify the microbiota composition, reducing overall inflammation and fibrosis. In this review, we explore the existing knowledge on the characterisation of the intestinal microbial composition in humans and experimental murine chronic liver disease and HCC, as well as the use of antibiotics and bacteriotherapy as therapeutic options.
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Affiliation(s)
- Mar Moreno-Gonzalez
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK;
| | - Naiara Beraza
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK;
- Food Innovation and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK
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24
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Kessoku T, Kobayashi T, Imajo K, Tanaka K, Yamamoto A, Takahashi K, Kasai Y, Ozaki A, Iwaki M, Nogami A, Honda Y, Ogawa Y, Kato S, Higurashi T, Hosono K, Yoneda M, Okamoto T, Usuda H, Wada K, Kobayashi N, Saito S, Nakajima A. Endotoxins and Non-Alcoholic Fatty Liver Disease. Front Endocrinol (Lausanne) 2021; 12:770986. [PMID: 34777261 PMCID: PMC8586459 DOI: 10.3389/fendo.2021.770986] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 10/18/2021] [Indexed: 01/18/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It occurs with a prevalence of up to 25%, of which 10-20% cases progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The histopathology of NASH is characterized by neutrophilic infiltration, and endotoxins from gram-negative rods have been postulated as a contributing factor. Elevations in endotoxin levels in the blood can be classified as intestinal and hepatic factors. In recent years, leaky gut syndrome, which is characterized by impaired intestinal barrier function, has become a significant issue. A leaky gut may prompt intestinal bacteria dysbiosis and increase the amount of endotoxin that enters the liver from the portal vein. These contribute to persistent chronic inflammation and progressive liver damage. In addition, hepatic factors suggest that liver damage can be induced by low-dose endotoxins, which does not occur in healthy individuals. In particular, increased expression of CD14, an endotoxin co-receptor in the liver, may result in leptin-induced endotoxin hyper-responsiveness in obese individuals. Thus, elevated blood endotoxin levels contribute to the progression of NASH. The current therapeutic targets for NASH treat steatosis and liver inflammation and fibrosis. While many clinical trials are underway, no studies have been performed on therapeutic agents that target the intestinal barrier. Recently, a randomized placebo-controlled trial examined the role of the intestinal barrier in patients with NAFLD. To our knowledge, this study was the first of its kind and study suggested that the intestinal barrier may be a novel target in the future treatment of NAFLD.
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Affiliation(s)
- Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Palliative Medicine, Yokohama City University Hospital, Yokohama, Japan
- *Correspondence: Takaomi Kessoku,
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kosuke Tanaka
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Palliative Medicine, Yokohama City University Hospital, Yokohama, Japan
| | - Atsushi Yamamoto
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kota Takahashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yuki Kasai
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Palliative Medicine, Yokohama City University Hospital, Yokohama, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Shingo Kato
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takuma Higurashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kunihiro Hosono
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takayuki Okamoto
- Department of Pharmacology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Haruki Usuda
- Department of Pharmacology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Koichiro Wada
- Department of Pharmacology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Noritoshi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Oncology, Yokohama City University Hospital, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Jennison E, Byrne CD. The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin Mol Hepatol 2020; 27:22-43. [PMID: 33291863 PMCID: PMC7820212 DOI: 10.3350/cmh.2020.0129] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with a prevalence that is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. The pathogenesis of NAFLD is complex and multifactorial, involving environmental, genetic and metabolic factors. The role of the diet and the gut microbiome is gaining interest as a significant factor in NAFLD pathogenesis. Dietary factors induce alterations in the composition of the gut microbiome (dysbiosis), commonly reflected by a reduction of the beneficial species and an increase in pathogenic microbiota. Due to the close relationship between the gut and liver, altering the gut microbiome can affect liver functions; promoting hepatic steatosis and inflammation. This review summarises the current evidence supporting an association between NAFLD and the gut microbiome and dietary factors. The review also explores potential underlying mechanisms underpinning these associations and whether manipulation of the gut microbiome is a potential therapeutic strategy to prevent or treat NAFLD.
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Affiliation(s)
- Erica Jennison
- Department of Chemical Pathology, Southampton General Hospital, University Hospital Southampton, Southampton, UK
| | - Christopher D Byrne
- Department of Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK.,Southampton National Institute for Health Research Biomedical Research Centre, Southampton General Hospital, University Hospital Southampton, Southampton, UK
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26
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Jensen ET, Bertoni AG, Crago OL, Hoffman KL, Wood AC, Arzumanyan Z, Lam LSK, Roll K, Sandow K, Wu M, Rich SS, Rotter JI, Chen YDI, Petrosino JF, Goodarzi MO. Rationale, design and baseline characteristics of the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Diabetes Obes Metab 2020; 22:1976-1984. [PMID: 32687239 PMCID: PMC8444996 DOI: 10.1111/dom.14145] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/06/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023]
Abstract
AIM To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D). MATERIALS AND METHODS The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline. RESULTS After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance. CONCLUSIONS The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.
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Affiliation(s)
- Elizabeth T. Jensen
- Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Alain G. Bertoni
- Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Osa L. Crago
- Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Kristi L. Hoffman
- Department of Molecular Virology and Microbiology, Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas
| | - Alexis C. Wood
- USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - Zorayr Arzumanyan
- Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation and Harbor-UCLA Medical Center, Torrance, California
| | - Lok-Sze Kelvin Lam
- Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation and Harbor-UCLA Medical Center, Torrance, California
| | - Kathryn Roll
- Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation and Harbor-UCLA Medical Center, Torrance, California
| | - Kevin Sandow
- Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation and Harbor-UCLA Medical Center, Torrance, California
| | - Martin Wu
- Department of Biology, University of Virginia, Charlottesville, Virginia
| | - Stephen S. Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
| | - Jerome I. Rotter
- Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation and Harbor-UCLA Medical Center, Torrance, California
| | - Yii-Der I. Chen
- Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation and Harbor-UCLA Medical Center, Torrance, California
| | - Joseph F. Petrosino
- Department of Molecular Virology and Microbiology, Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas
| | - Mark O. Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
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27
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Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review. Int J Mol Sci 2020; 21:ijms21175999. [PMID: 32825440 PMCID: PMC7504062 DOI: 10.3390/ijms21175999] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/14/2020] [Accepted: 08/19/2020] [Indexed: 12/24/2022] Open
Abstract
Even though advancement in medicine has contributed to the control of many diseases to date, cancer therapy continues to pose several challenges. Hepatocellular carcinoma (HCC) etiology is multifactorial. Recently, non-alcoholic fatty liver disease (NAFLD) has been considered as an important risk factor of HCC. NAFLD can be divided into non-alcoholic simple fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) based on histopathological features. Recently, studies have indicated that the gut microbiota is associated with NAFLD and HCC. Therefore, in this review, we have discussed the effects of gut microbiota-related mechanisms, including dysbiosis and gut barrier function, and gut microbiota-derived metabolites on NAFLD and HCC pathogenesis and the potential therapeutic strategies for NAFLD and HCC. With a better understanding of the gut microbiota composition and function, new and improved diagnostic, prognostic, and therapeutic strategies for common liver diseases can be developed.
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Mantovani A, Zusi C, Dalbeni A, Grani G, Buzzetti E. Risk of Kidney Dysfunction IN Nafld. Curr Pharm Des 2020; 26:1045-1061. [DOI: 10.2174/1381612825666191026113119] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/21/2019] [Indexed: 02/06/2023]
Abstract
Background:
The timely identification of traditional and non-traditional precursors and risk factors for
chronic kidney disease (CKD) (a common systemic disease defined as a decreased kidney function documented
by reduced glomerular filtration rate, or markers of kidney damage, or both) is relevant in clinical practice, as
CKD increases the risk of end-stage renal disease and other serious comorbidities. A possible relationship between
non-alcoholic fatty liver disease (NAFLD) (which is to date the most common chronic disease worldwide)
and CKD has recently gained significant attention of researchers.
Methods :
A systematic literature search using appropriate keywords was made in order to identify relevant articles
that have investigated the association between NAFLD and CKD.
Results:
Several observational studies and meta-analyses have reported the existence of an independent association
between NAFLD and risk of CKD in patients with and without diabetes. However, whilst the association
between NAFLD and risk of prevalent CKD is strong across various patient populations, whether NAFLD is
independently associated with the development and progression of CKD is still debatable. Moreover, emerging
evidence now suggests a potential association between patatin-like phospholipase domain-containing protein-3
(PNPLA3) rs738409 genotype (the most important genetic variant associated to NAFLD) and decreasing kidney
function, independent of NAFLD.
Conclusions :
Convincing evidence now indicates that CKD is increased among patients with NAFLD. For this
reason, patients with NAFLD should be regularly monitored for renal function and, on the other hand , NAFLD
should be considered in all patients with CKD, especially if they are obese or have type 2 diabetes.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Chiara Zusi
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Andrea Dalbeni
- Section of General Medicine, Hypertension and Liver Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Giorgio Grani
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Elena Buzzetti
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy
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Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol 2020; 72:558-577. [PMID: 31622696 DOI: 10.1016/j.jhep.2019.10.003] [Citation(s) in RCA: 1210] [Impact Index Per Article: 242.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/14/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023]
Abstract
The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new therapeutic approaches.
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Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, IRYCIS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - Andrea de Gottardi
- Hepatology, Inselspital and Department of Biomedical Research, University of Bern, Switzerland; Servizio di Gastroenterología e Epatologia, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, Lugano, Switzerland
| | - María Rescigno
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele (Mi), Italy; Humanitas Clinical and Research Center, IRCCS, 20089 Rozzano (Mi), Italy
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30
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Spalinger MR, Atrott K, Baebler K, Schwarzfischer M, Melhem H, Peres DR, Lalazar G, Rogler G, Scharl M, Frey-Wagner I. Administration of the Hyper-immune Bovine Colostrum Extract IMM-124E Ameliorates Experimental Murine Colitis. J Crohns Colitis 2019; 13:785-797. [PMID: 30590526 DOI: 10.1093/ecco-jcc/jjy213] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/18/2018] [Accepted: 12/10/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel disease [IBD] is accompanied by lesions in the epithelial barrier, which allow translocation of bacterial products from the gut lumen to the host's circulation. IMM-124E is a colostrum-based product containing high levels of anti-E.coli-LPS IgG, and might limit exposure to bacterial endotoxins. Here, we investigated whether IMM-124E can ameliorate intestinal inflammation. METHODS Acute colitis was induced in WT C57Bl/6J mice by administration of 2.5% dextran sodium sulphate [DSS] for 7 days. T cell transfer colitis was induced via transfer of 0.5 x 106 naïve T cells into RAG2-/- C57Bl/6J mice. IMM-124E was administered daily by oral gavage, either preventively or therapeutically. RESULTS Treatment with IMM-124E significantly ameliorated colitis in acute DSS colitis and in T cell transfer colitis. Maximum anti-inflammatory effects were detected at an IMM-124E concentration of 100 mg/kg body weight, whereas 25 mg/kg and 500 mg/kg were less effective. Histology revealed reduced levels of infiltrating immune cells and less pronounced mucosal damage. Flow cytometry revealed reduced numbers of effector T helper cells in the intestine, whereas levels of regulatory T cells were enhanced. IMM-124E treatment reduced the DSS-induced increase of serum levels of lipopolysaccharide [LPS]-binding protein, indicating reduced systemic LPS exposure. CONCLUSIONS Our results demonstrate that oral treatment with IMM-124E significantly reduces intestinal inflammation, via decreasing the accumulation of pathogenic T cells and concomitantly increasing the induction of regulatory T cells. Our study confirms the therapeutic efficacy of IMM-124E in acute colitis and suggests that administration of IMM-124E might represent a novel therapeutic strategy to induce or maintain remission in chronic colitis.
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Affiliation(s)
- Marianne R Spalinger
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Kirstin Atrott
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Katharina Baebler
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Marlene Schwarzfischer
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Hassan Melhem
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
| | | | - Gadi Lalazar
- Laboratory of Cellular Biophysics, Rockefeller University, New York, NY, USA
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Isabelle Frey-Wagner
- Division of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland
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31
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Duarte SMB, Stefano JT, Oliveira CP. Microbiota and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH). Ann Hepatol 2019; 18:416-421. [PMID: 31036494 DOI: 10.1016/j.aohep.2019.04.006] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 01/09/2019] [Indexed: 02/04/2023]
Abstract
Genetic predisposition, the intestinal microbiota (IM) and environmental factors, such as sedentary lifestyle and inadequate diet, should be considered as critical factors for the development of nonalcoholic fatty liver disease (NAFLD). Recently, some studies have demonstrated an association between dysbiosis and NAFLD; however, the exact mechanisms that lead to intestinal membrane damage, bacterial translocation and inflammation are not well elucidated. Due to the relevance of this theme, the IM and its metabolites have received special attention in recent years in an attempt to better understand the mechanisms related to the prevention, physiopathology, and treatment of NAFLD. In this paper, we provide a review of the human IM and its role in diet, obesity, and the development/progression of NAFLD/NASH, as well as the use of prebiotics and probiotics in the modulation of IM.
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Affiliation(s)
- Sebastião M B Duarte
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07) do Departamento de Gastroenterologia e Hepatologia do Hospital das Clínicas HCFMUSP da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Jose Tadeu Stefano
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07) do Departamento de Gastroenterologia e Hepatologia do Hospital das Clínicas HCFMUSP da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Claudia P Oliveira
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07) do Departamento de Gastroenterologia e Hepatologia do Hospital das Clínicas HCFMUSP da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
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32
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Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci 2019; 76:1541-1558. [PMID: 30683985 PMCID: PMC11105223 DOI: 10.1007/s00018-019-03011-w] [Citation(s) in RCA: 337] [Impact Index Per Article: 56.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 12/11/2018] [Accepted: 01/15/2019] [Indexed: 12/11/2022]
Abstract
NAFLD is currently the main cause of chronic liver disease in developed countries, and the number of NAFLD patients is growing worldwide. NAFLD often has similar symptoms to other metabolic disorders, including type 2 diabetes and obesity. Recently, the role of the gut microbiota in the pathophysiology of many diseases has been revealed. Regarding NAFLD, experiments using gut microbiota transplants to germ-free animal models showed that fatty liver disease development is determined by gut bacteria. Moreover, the perturbation of the composition of the gut microbiota has been observed in patients suffering from NAFLD. Numerous mechanisms relating the gut microbiome to NAFLD have been proposed, including the dysbiosis-induced dysregulation of gut endothelial barrier function that allows for the translocation of bacterial components and leads to hepatic inflammation. In addition, the various metabolites produced by the gut microbiota may impact the liver and thus modulate NAFLD susceptibility. Therefore, the manipulation of the gut microbiome by probiotics, prebiotics or synbiotics was shown to improve liver phenotype in NAFLD patients as well as in rodent models. Hence, further knowledge about the interactions among dysbiosis, environmental factors, and diet and their impacts on the gut-liver axis can improve the treatment of this life-threatening liver disease and its related disorders.
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Affiliation(s)
- Zahra Safari
- Micalis Institute, INRA, UMR1319, Equipe AMIPEM, AgroParisTech, Université Paris-Saclay, Building 442, Domaine de Vilvert, 78350, Jouy-en-Josas, France
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Philippe Gérard
- Micalis Institute, INRA, UMR1319, Equipe AMIPEM, AgroParisTech, Université Paris-Saclay, Building 442, Domaine de Vilvert, 78350, Jouy-en-Josas, France.
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33
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Gut Microbiota-Derived Mediators as Potential Markers in Nonalcoholic Fatty Liver Disease. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8507583. [PMID: 30719448 PMCID: PMC6334327 DOI: 10.1155/2019/8507583] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 12/20/2018] [Indexed: 12/17/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common, multifactorial, and poorly understood liver disease whose incidence is globally rising. During the past decade, several lines of evidence suggest that dysbiosis of intestinal microbiome represents an important factor contributing to NAFLD occurrence and its progression into NASH. The mechanisms that associate dysbiosis with NAFLD include changes in microbiota-derived mediators, deregulation of the gut endothelial barrier, translocation of mediators of dysbiosis, and hepatic inflammation. Changes in short chain fatty acids, bile acids, bacterial components, choline, and ethanol are the result of altered intestinal microbiota. We perform a narrative review of the previously published evidence and discuss the use of gut microbiota-derived mediators as potential markers in NAFLD.
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34
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Roles of Gut-Derived Secretory Factors in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Their Possible Clinical Applications. Int J Mol Sci 2018; 19:ijms19103064. [PMID: 30297626 PMCID: PMC6213237 DOI: 10.3390/ijms19103064] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/01/2018] [Accepted: 10/06/2018] [Indexed: 02/06/2023] Open
Abstract
The rising prevalence of non-alcoholic fatty liver disease (NAFLD) parallels the global increase in the number of people diagnosed with obesity and metabolic syndrome. The gut-liver axis (GLA) plays an important role in the pathogenesis of NAFLD/non-alcoholic steatohepatitis (NASH). In this review, we discuss the clinical significance and underlying mechanisms of action of gut-derived secretory factors in NAFLD/NASH, focusing on recent human studies. Several studies have identified potential causal associations between gut-derived secretory factors and NAFLD/NASH, as well as the underlying mechanisms. The effects of gut-derived hormone-associated drugs, such as glucagon-like peptide-1 analog and recombinant variant of fibroblast growth factor 19, and other new treatment strategies for NAFLD/NASH have also been reported. A growing body of evidence highlights the role of GLA in the pathogenesis of NAFLD/NASH. Larger and longitudinal studies as well as translational research are expected to provide additional insights into the role of gut-derived secretory factors in the pathogenesis of NAFLD/NASH, possibly providing novel markers and therapeutic targets in patients with NAFLD/NASH.
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35
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Glycine protects against high sucrose and high fat-induced non-alcoholic steatohepatitis in rats. Oncotarget 2018; 7:80223-80237. [PMID: 27784003 PMCID: PMC5348315 DOI: 10.18632/oncotarget.12831] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 10/12/2016] [Indexed: 12/15/2022] Open
Abstract
We set out to explore the hypothesis that glycine attenuates non-alcoholic steatohepatitis (NASH) in rats and the possible mechanism by which is it does. Male Sprague-Dawley (SD) rats were fed a diet containing high fat and high sucrose (HSHF) for 24 weeks to induce NASH. Blood and liver tissues were sampled at selected time points throughout the study. Compared with control animals, the content of alanine transaminase (ALT), triglycerides (TGs), and free fatty acids (FFAs) in plasma and the TG and FFA content in the liver was increased from week 4 to 24. The level of TNFα and MCP-1 in plasma, the content of TNFα in the liver, the insulin resistance index, inflammatory cell infiltration, hepatocyte apoptosis, reactive oxygen species (ROS) generation, and endoplasmic stress-associated protein expression were unaltered at 4 weeks. However, these levels were significantly elevated in HSHF fed rats at 12 weeks. At the same time, the level of endotoxin progressively increased from 0.08 ± 0.02 endotoxin EU/ml at week 4 to 0.7 ± 0.19 EU/ml at week 24. Moreover, these rats had elevated blood endotoxin levels, which were positively associated with their NASH indexes. Liver histology progressively worsened over the course of the study. However, we found that with concomitant treatment with glycine, the level of endotoxin decreased, while NASH indexes significantly decreased and liver status markedly improved,. These data support the hypothesis that glycine protects against NASH in rats by decreasing the levels of intestinal endotoxin, alleviating endoplasmic reticulum and oxidative stress.
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36
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Cassard AM, Gérard P, Perlemuter G. Microbiota, Liver Diseases, and Alcohol. BUGS AS DRUGS 2018:187-212. [DOI: 10.1128/9781555819705.ch8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Affiliation(s)
- Anne-Marie Cassard
- INSERM U996 Inflammation, Chemokines and Immunopathology, DHU Hepatinov, Univ Paris-Sud; Université Paris-Saclay; 92140 Clamart France
| | - Philippe Gérard
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay; 78350 Jouyen-Josas France
| | - Gabriel Perlemuter
- INSERM U996 Inflammation, Chemokines and Immunopathology, DHU Hepatinov, Univ Paris-Sud; Université Paris-Saclay; 92140 Clamart France
- AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère; Clamart France
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37
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Wattacheril J, Rose KL, Hill S, Lanciault C, Murray CR, Washington K, Williams B, English W, Spann M, Clements R, Abumrad N, Flynn CR. Non-alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle. Hepatol Res 2017; 47:1469-1483. [PMID: 28258704 PMCID: PMC5583035 DOI: 10.1111/hepr.12885] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 01/27/2017] [Accepted: 02/28/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND Molecular signaling events associated with the necroinflammatory changes in nonalcoholic steatohepatitis (NASH) are not well understood. AIMS To understand the molecular basis of NASH, we evaluated reversible phosphorylation events in hepatic tissue derived from Class III obese subjects by phosphoproteomic means with the aim of highlighting key regulatory pathways that distinguish NASH from non-alcoholic fatty liver disease (also known as simple steatosis; SS). MATERIALS & METHODS Class III obese subjects undergoing bariatric surgery underwent liver biopsy (eight normal patients, eight with simple steatosis, and eight NASH patients). Our strategy was unbiased, comparing global differences in liver protein reversible phosphorylation events across the 24 subjects. RESULTS Of the 3078 phosphorylation sites assigned (2465 phosphoserine, 445 phosphothreonine, 165 phosphotyrosine), 53 were altered by a factor of 2 among cohorts, and of those, 12 were significantly increased or decreased by ANOVA (P < 0.05). DISCUSSION Statistical analyses of canonical signaling pathways identified carbohydrate metabolism and RNA post-transcriptional modification among the most over-represented networks. CONCLUSION Collectively, these results raise the possibility of abnormalities in carbohydrate metabolism as an important trigger for the development of NASH, in parallel with already established abnormalities in lipid metabolism.
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Affiliation(s)
- Julia Wattacheril
- Center for Liver Disease and Transplantation, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, United States of America
| | - Kristie L. Rose
- Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Salisha Hill
- Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Christian Lanciault
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Clark R. Murray
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Brandon Williams
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Wayne English
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Matthew Spann
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Ronald Clements
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Naji Abumrad
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Charles Robb Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America,Corresponding author: Charles Flynn, PhD, Assistant Professor, Department of Surgery, Vanderbilt University, MRBIV Room 8465A, 2213 Garland Ave, Nashville, TN 37232,
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Nadeau BA, Conjeevaram H. The gut microbiome and nonalcoholic fatty liver disease. Clin Liver Dis (Hoboken) 2017; 10:116-119. [PMID: 30992769 PMCID: PMC6467119 DOI: 10.1002/cld.671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 09/14/2017] [Accepted: 09/23/2017] [Indexed: 02/04/2023] Open
Affiliation(s)
- Brian A. Nadeau
- Division of Gastroenterology & Hepatology, Department of Internal MedicineUniversity of MichiganAnn ArborMI
| | - Hari Conjeevaram
- Division of Gastroenterology & Hepatology, Department of Internal MedicineUniversity of MichiganAnn ArborMI
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39
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Gut-Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease. CHILDREN-BASEL 2017; 4:children4080066. [PMID: 28767077 PMCID: PMC5575588 DOI: 10.3390/children4080066] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/18/2017] [Accepted: 07/21/2017] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A “multiple-hit” hypothesis has been invoked to explain its pathogenesis. The “first hit” is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as “second hits” implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis. In this regard, the gut–liver axis (GLA) seems to play a central role. Principal players are the gut microbiota, its bacterial products, and the intestinal barrier. A derangement of GLA (namely, dysbiosis and altered intestinal permeability) may promote bacteria/bacterial product translocation into portal circulation, activation of inflammation via toll-like receptors signaling in hepatocytes, and progression from simple steatosis to non-alcoholic steato-hepatitis (NASH). Among other factors a relevant role has been attributed to the farnesoid X receptor, a nuclear transcriptional factor activated from bile acids chemically modified by gut microbiota (GM) enzymes. The individuation and elucidation of GLA derangement in NAFLD pathomechanisms is of interest at all ages and especially in pediatrics to identify new therapeutic approaches in patients recalcitrant to lifestyle changes. Specific targeting of gut microbiota via pre-/probiotic supplementation, feces transplantation, and farnesoid X receptor modulation appear promising.
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Bakker GJ, Nieuwdorp M. Fecal Microbiota Transplantation: Therapeutic Potential for a Multitude of Diseases beyond Clostridium difficile. Microbiol Spectr 2017; 5:10.1128/microbiolspec.bad-0008-2017. [PMID: 28840809 PMCID: PMC11687518 DOI: 10.1128/microbiolspec.bad-0008-2017] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Indexed: 02/07/2023] Open
Abstract
The human intestinal tract contains trillions of bacteria, collectively called the gut microbiota. Recent insights have linked the gut microbiota to a plethora of diseases, including Clostridium difficile infection (CDI), inflammatory bowel disease (IBD), and metabolic diseases such as obesity, type 2 diabetes (T2D), and nonalcoholic steatohepatitis (NASH). Fecal microbiota transplantation (FMT) is currently tested as a therapeutic option in various diseases and can also help to dissect association from causality with respect to gut microbiota and disease. In CDI, FMT has been shown to be superior to antibiotic treatment. For IBD, T2D, and NASH, several placebo-controlled randomized controlled trials are under way. Moreover, techniques and standardization are developing. With the extension of FMT as a treatment modality in diseases other than CDI, a whole new treatment option may be emerging. Moreover, correlating alterations in specific strains to disease outcome may prove pivotal in finding new bacterial targets. Thus, although causality of the gut microbiota in various diseases still needs to be proven, FMT may prove to be a powerful tool providing us with diagnostic and therapeutic leads.
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Affiliation(s)
- Guido J Bakker
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Internal Medicine, VU University Medical Center, Amsterdam, Netherlands
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41
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Cassard AM, Gérard P, Perlemuter G. Microbiota, Liver Diseases, and Alcohol. Microbiol Spectr 2017; 5:10.1128/microbiolspec.bad-0007-2016. [PMID: 28840806 PMCID: PMC11687517 DOI: 10.1128/microbiolspec.bad-0007-2016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Indexed: 02/08/2023] Open
Abstract
Being overweight and obesity are the leading causes of liver disease in Western countries. Liver damage induced by being overweight can range from steatosis, harmless in its simple form, to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol consumption is an additional major cause of liver disease. Not all individuals who are overweight or excessively consume alcohol develop nonalcoholic fatty liver diseases (NAFLD) or alcoholic liver disease (ALD) and advanced liver disease. The role of the intestinal microbiota (IM) in the susceptibility to liver disease in this context has been the subject of recent studies. ALD and NAFLD appear to be influenced by the composition of the IM, and dysbiosis is associated with ALD and NAFLD in rodent models and human patient cohorts. Several microbial metabolites, such as short-chain fatty acids and bile acids, are specifically associated with dysbiosis. Recent studies have highlighted the causal role of the IM in the development of liver diseases, and the use of probiotics or prebiotics improves some parameters associated with liver disease. Several studies have made progress in deciphering the mechanisms associated with the modulation of the IM. These data have demonstrated the intimate relationship between the IM and metabolic liver disease, suggesting that targeting the gut microbiota could be a new preventive or therapeutic strategy for these diseases.
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Affiliation(s)
- Anne-Marie Cassard
- INSERM U996 Inflammation, Chemokines and Immunopathology, DHU Hepatinov, Univ Paris-Sud, Université Paris-Saclay, 92140 Clamart, France
| | - Philippe Gérard
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - Gabriel Perlemuter
- INSERM U996 Inflammation, Chemokines and Immunopathology, DHU Hepatinov, Univ Paris-Sud, Université Paris-Saclay, 92140 Clamart, France
- AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère, Clamart, France
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Panasevich MR, Peppler WT, Oerther DB, Wright DC, Rector RS. Microbiome and NAFLD: potential influence of aerobic fitness and lifestyle modification. Physiol Genomics 2017; 49:385-399. [PMID: 28600319 DOI: 10.1152/physiolgenomics.00012.2017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with prevalence rates that are on the rise in the US and worldwide. NAFLD encompasses a spectrum of liver pathologies including simple steatosis to nonalcoholic steatohepatitis (NASH) with inflammation and fibrosis. The gut microbiome has emerged as a potential therapeutic target in combating metabolic diseases including obesity, Type 2 diabetes, and NAFLD/NASH. Diet-induced obesity/Western style diet feeding causes severe microbial dysbiosis initiating a microbiome signature that promotes metabolite production that directly impacts hepatic metabolism. Changes in lifestyle (i.e., diet, exercise, and aerobic fitness) improve NAFLD outcomes and can significantly influence the microbiome. However, directly linking lifestyle-induced remodeling of the microbiome to NAFLD pathogenesis is not well understood. Understanding the reshaping of the microbiome and the metabolites produced and their subsequent actions on hepatic metabolism are vital in understanding the gut-liver axis. In this review, we 1) discuss microbiome-derived metabolites that significantly contribute to the gut-liver axis and are directly linked to NAFLD/NASH and 2) present evidence on lifestyle modifications reshaping the microbiome and the potential therapeutic aspects in combating the disease.
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Affiliation(s)
- Matthew R Panasevich
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri.,Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri.,Department of Nutrition and Exercise Physiology; University of Missouri, Columbia, Missouri
| | - Willem T Peppler
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Daniel B Oerther
- Department of Civil, Architectural, and Environmental Engineering, Missouri University of Science and Technology, Rolla, Missouri; and
| | - David C Wright
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - R Scott Rector
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; .,Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri.,Department of Nutrition and Exercise Physiology; University of Missouri, Columbia, Missouri
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Fedirko V, Tran HQ, Gewirtz AT, Stepien M, Trichopoulou A, Aleksandrova K, Olsen A, Tjønneland A, Overvad K, Carbonnel F, Boutron-Ruault MC, Severi G, Kühn T, Kaaks R, Boeing H, Bamia C, Lagiou P, Grioni S, Panico S, Palli D, Tumino R, Naccarati A, Peeters PH, Bueno-de-Mesquita HB, Weiderpass E, Castaño JMH, Barricarte A, Sánchez MJ, Dorronsoro M, Quirós JR, Agudo A, Sjöberg K, Ohlsson B, Hemmingsson O, Werner M, Bradbury KE, Khaw KT, Wareham N, Tsilidis KK, Aune D, Scalbert A, Romieu I, Riboli E, Jenab M. Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study. BMC Med 2017; 15:72. [PMID: 28372583 PMCID: PMC5379669 DOI: 10.1186/s12916-017-0830-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 03/03/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking. METHODS We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression. RESULTS Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70-81.40; P trend = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses. CONCLUSIONS These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.
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Affiliation(s)
- Veronika Fedirko
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
- Winship Cancer Institute, Emory University, Atlanta, GA, USA.
| | - Hao Quang Tran
- Center for Inflammation, Immunity, and Infection Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Andrew T Gewirtz
- Center for Inflammation, Immunity, and Infection Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Magdalena Stepien
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Antonia Trichopoulou
- Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece
- Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, University of Athens Medical School, Athens, Greece
| | - Krasimira Aleksandrova
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nutrition, Immunity and Metabolism Start-up Lab, Nuthetal, Germany
| | - Anja Olsen
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | | | - Kim Overvad
- Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Franck Carbonnel
- Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France
- Gustave Roussy, Villejuif, F-94805, France
- Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), University hospitals Paris-Sud, Site de Bicêtre, Paris Sud University, Paris XI, Le Kremlin Bicêtre, Villejuif, France
| | - Marie-Christine Boutron-Ruault
- Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France
- Gustave Roussy, Villejuif, F-94805, France
| | - Gianluca Severi
- Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France
- Gustave Roussy, Villejuif, F-94805, France
- Human Genetics Foundation (HuGeF), Torino, Italy
- Cancer Council Victoria and University of Melbourne, Melbourne, Australia
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Christina Bamia
- Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece
- Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, University of Athens Medical School, Athens, Greece
| | - Pagona Lagiou
- Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece
- Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, University of Athens Medical School, Athens, Greece
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
| | - Sara Grioni
- Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian, 1 20133, Milano, Italy
| | - Salvatore Panico
- Dipartimento di Medicina Clinica Echirurgia Federico II University, Naples, Italy
| | - Domenico Palli
- Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy
| | - Rosario Tumino
- Cancer Registry and Histopathology Unit, "Civic -M.P. Arezzo" Hospital, ASP, Ragusa, Italy
| | - Alessio Naccarati
- Molecular and Genetic Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino, Italy
| | - Petra H Peeters
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - H B Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK
- Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
- Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland
| | - José María Huerta Castaño
- Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Aurelio Barricarte
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Navarra Public Health Institute, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - María-José Sánchez
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada, Universidad de Granada, Granada, Spain
| | - Miren Dorronsoro
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Basque Regional Health Department, San Sebastian, Spain
| | | | - Antonio Agudo
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Klas Sjöberg
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Department of Gastroenterology and Nutrition, Skåne University Hospital, Malmö, Sweden
| | - Bodil Ohlsson
- Department of Clinical Sciences, Division of Internal Medicine, Skåne University Hospital, Malmö, Lund University, Lund, Sweden
| | - Oskar Hemmingsson
- Department of Surgical and Perioperative Sciences, Kirurgcentrum, Norrlands Universitetssjukhus, Umeå, Sweden
| | - Mårten Werner
- Department of Medicine Sections for Hepatology and Gastroenterology, Umeå University Hospital, SE-90185, Umeå, Sweden
| | - Kathryn E Bradbury
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Kay-Tee Khaw
- Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK
| | - Nick Wareham
- MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Dagfinn Aune
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Augustin Scalbert
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Isabelle Romieu
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Mazda Jenab
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
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Kitabatake H, Tanaka N, Fujimori N, Komatsu M, Okubo A, Kakegawa K, Kimura T, Sugiura A, Yamazaki T, Shibata S, Ichikawa Y, Joshita S, Umemura T, Matsumoto A, Koinuma M, Sano K, Aoyama T, Tanaka E. Association between endotoxemia and histological features of nonalcoholic fatty liver disease. World J Gastroenterol 2017; 23:712-722. [PMID: 28216979 PMCID: PMC5292346 DOI: 10.3748/wjg.v23.i4.712] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 11/14/2016] [Accepted: 01/02/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess whether surrogate biomarkers of endotoxemia were correlated with the histological features of nonalcoholic fatty liver disease (NAFLD). METHODS One hundred twenty-six NAFLD patients who had undergone percutaneous liver biopsy were enrolled. Serum lipopolysaccharide (LPS)-binding protein (LBP) and anti-endotoxin core immunoglobulin G (EndoCab IgG) antibody concentrations at the time of liver biopsy were measured using the enzyme-linked immunosorbent assays to examine for relationships between biomarker levels and histological scores. RESULTS Serum LBP concentration was significantly increased in nonalcoholic steatohepatitis (NASH) patients as compared with nonalcoholic fatty liver (NAFL) subjects and was correlated with steatosis (r = 0.38, P < 0.0001) and ballooning scores (r = 0.23, P = 0.01), but not with the severity of lobular inflammation or fibrosis. Multivariate linear regression analysis revealed that LBP was associated with steatosis score and circulating C-reactive protein, aspartate aminotransferase, and fibrinogen levels. Serum EndoCab IgG concentration was comparable between NASH and NAFL patients. No meaningful correlations were detected between EndoCab IgG and histological findings. CONCLUSION LBP/EndoCab IgG were not correlated with lobular inflammation or fibrosis. More accurate LPS biomarkers are required to stringently assess the contribution of endotoxemia to conventional NASH.
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Nien HC, Hsu SJ, Su TH, Yang PJ, Sheu JC, Wang JT, Chow LP, Chen CL, Kao JH, Yang WS. High Serum Lipopolysaccharide-Binding Protein Level in Chronic Hepatitis C Viral Infection Is Reduced by Anti-Viral Treatments. PLoS One 2017; 12:e0170028. [PMID: 28107471 PMCID: PMC5249206 DOI: 10.1371/journal.pone.0170028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 12/26/2016] [Indexed: 12/22/2022] Open
Abstract
Background Lipopolysaccharide-binding protein (LBP) has been reported to associate with metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease. Since chronic hepatitis C virus (HCV) infection is associated with metabolic derangements, the relationship between LBP and HCV deserves additional studies. This study aimed to determine the serum LBP level in subjects with or without HCV infection and investigate the change of its level after anti-viral treatments with or without interferon. Methods and Findings We recruited 120 non-HCV subjects, 42 and 17 HCV-infected subjects respectively treated with peginterferon α-2a/ribavirin and direct-acting antiviral drugs. Basic information, clinical data, serum LBP level and abdominal ultrasonography were collected. All the subjects provided written informed consent before being enrolled approved by the Research Ethics Committee of the National Taiwan University Hospital. Serum LBP level was significantly higher in HCV-infected subjects than non-HCV subjects (31.0 ± 8.8 versus 20.0 ± 6.4 μg/mL; p-value < 0.001). After multivariate analyses, LBP at baseline was independently associated with body mass index, hemoglobin A1c, alanine aminotransferase (ALT) and HCV infection. Moreover, the baseline LBP was only significantly positively associated with ALT and inversely with fatty liver in HCV-infected subjects. The LBP level significantly decreased at sustained virologic response (27.4 ± 6.6 versus 34.6 ± 7.3 μg/mL, p-value < 0.001; 15.9 ± 4.4 versus 22.2 ± 5.7 μg/mL, p-value = 0.001), regardless of interferon-based or -free therapy. Conclusions LBP, an endotoxemia associated protein might be used as an inflammatory biomarker of both infectious and non-infectious origins in HCV-infected subjects.
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Affiliation(s)
- Hsiao-Ching Nien
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
- Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Jer Hsu
- Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Po-Jen Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Jin-Chuan Sheu
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jin-Town Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Lu-Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- * E-mail: (WSY); (JHK)
| | - Wei-Shiung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- * E-mail: (WSY); (JHK)
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du Plessis J, Korf H, van Pelt J, Windmolders P, Vander Elst I, Verrijken A, Hubens G, Van Gaal L, Cassiman D, Nevens F, Francque S, van der Merwe S. Pro-Inflammatory Cytokines but Not Endotoxin-Related Parameters Associate with Disease Severity in Patients with NAFLD. PLoS One 2016; 11:e0166048. [PMID: 27992443 PMCID: PMC5167229 DOI: 10.1371/journal.pone.0166048] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 10/22/2016] [Indexed: 12/30/2022] Open
Abstract
Intestinal dysbiosis and elevated lipopolysaccharides (LPS) levels have been implicated in the development of obesity, insulin resistance and non-alcoholic steatohepatitis (NASH). In order to determine if LPS levels are elevated in patients with NASH compared to patients with non-alcoholic fatty liver (NAFL) and, if elevated LPS levels correlated with histological severity of non-alcoholic fatty liver disease (NAFLD) we compared LPS, markers of LPS bioactivity and pro-inflammatory cytokines/chemokines in patients undergoing bariatric surgery. At the time of surgery a liver biopsy was taken allowing the stratification into well-delineated subgroups including: No NAFL/NAFL; NASH; NASH with fibrosis and NASH cirrhotics, using the NAFLD Activity Score (NAS). Anthropometric data and plasma were collected for assessment of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14), intestinal-type fatty acid binding protein (iFABP), Toll-like receptors 2 and 4 (TLR2, 4) and a panel of cytokines/chemokines. Similar analysis was performed on plasma from a cohort of healthy controls. Our data indicate elevated levels of LPS, LBP, sCD14, iFABP and TLR2,4 in obese patients compared to healthy controls, however, these parameters remained unaltered within patients with limited liver disease (NAFL) compared to NASH/NASH with fibrosis subgroups. Hierarchic cluster analysis using endotoxin-related parameters failed to discriminate between lean controls, NAFLD. While similar cluster analysis implementing inflammation-related parameters clearly distinguished lean controls, NALFD subgroups and NASH cirrhotics. In addition, LPS levels was not associated with disease severity while TNFα, IL8, and CCL3 featured a clear correlation with transaminase levels and the histological severity of NALFD. In conclusion our data indicate a stronger correlation for circulating inflammatory- rather than endotoxin-related parameters in progression of NAFLD and highlights the need for additional larger studies in unravelling further mechanistic insights.
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Affiliation(s)
- Johannie du Plessis
- Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Hannelie Korf
- Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Jos van Pelt
- Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Petra Windmolders
- Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Ingrid Vander Elst
- Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - An Verrijken
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Guy Hubens
- Department of Abdominal Surgery, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Luc Van Gaal
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - David Cassiman
- Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
- Department of Internal Medicine, Division of Liver and biliopancreatic disorders, KU Leuven, Leuven, Belgium
| | - Frederik Nevens
- Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
- Department of Internal Medicine, Division of Liver and biliopancreatic disorders, KU Leuven, Leuven, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Schalk van der Merwe
- Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
- Department of Internal Medicine, Division of Liver and biliopancreatic disorders, KU Leuven, Leuven, Belgium
- * E-mail:
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Chung GE, Yim JY, Kim D, Kwak MS, Yang JI, Chung SJ, Yang SY, Kim JS. Associations between White Blood Cell Count and the Development of Incidental Nonalcoholic Fatty Liver Disease. Gastroenterol Res Pract 2016; 2016:7653689. [PMID: 28070183 PMCID: PMC5187485 DOI: 10.1155/2016/7653689] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 11/10/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023] Open
Abstract
Aims. Chronic low-grade inflammation is thought to be associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). This study aimed to determine the association between serum white blood cell (WBC) counts and the development of incidental NAFLD. Methods. In this retrospective longitudinal cohort study, we recruited participants who underwent abdominal ultrasonography and blood samplings during medical checkups in both 2005 and 2010. A total of 2,216 subjects were included in our analyses. Results. The prevalence of NAFLD in 2010 increased steadily in conjunction with increasing WBC counts in 2005 after adjustment for body mass index (BMI) [odds ratio (OR) 2.44, 95% confidence interval (CI) = 1.49-4.00 for women and OR 2.42, 95% CI = 1.61-3.63 for men, lowest quartile versus highest quartile]. Multivariate regression analysis after adjusting for age, BMI, hypertension, smoking, triglycerides, HDL cholesterol, and glucose levels revealed that NAFLD was significantly associated with the highest WBC quartile compared to the lowest quartile [OR 1.85, 95% CI, 1.10-3.10 for women and OR 1.68, 95% CI, 1.08-2.61 for men]. Conclusions. We demonstrated that the risk of developing NAFLD was significantly associated with WBC counts independently of metabolic factors. This finding provides novel evidence indicating that serum WBC counts may be potential surrogate markers of NAFLD.
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Affiliation(s)
- Goh Eun Chung
- Department of Internal Medicine, Healthcare Research Institute, Gangnam Healthcare Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jeong Yoon Yim
- Department of Internal Medicine, Healthcare Research Institute, Gangnam Healthcare Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Min-Sun Kwak
- Department of Internal Medicine, Healthcare Research Institute, Gangnam Healthcare Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jong In Yang
- Department of Internal Medicine, Healthcare Research Institute, Gangnam Healthcare Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Su Jin Chung
- Department of Internal Medicine, Healthcare Research Institute, Gangnam Healthcare Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sun Young Yang
- Department of Internal Medicine, Healthcare Research Institute, Gangnam Healthcare Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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48
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Abstract
NAFLD is now the most common cause of liver disease in Western countries. This Review explores the links between NAFLD, the metabolic syndrome, dysbiosis, poor diet and gut health. Animal studies in which the gut microbiota are manipulated, and observational studies in patients with NAFLD, have provided considerable evidence that dysbiosis contributes to the pathogenesis of NAFLD. Dysbiosis increases gut permeability to bacterial products and increases hepatic exposure to injurious substances that increase hepatic inflammation and fibrosis. Dysbiosis, combined with poor diet, also changes luminal metabolism of food substrates, such as increased production of certain short-chain fatty acids and alcohol, and depletion of choline. Changes to the microbiome can also cause dysmotility, gut inflammation and other immunological changes in the gut that might contribute to liver injury. Evidence also suggests that certain food components and lifestyle factors, which are known to influence the severity of NAFLD, do so at least in part by changing the gut microbiota. Improved methods of analysis of the gut microbiome, and greater understanding of interactions between dysbiosis, diet, environmental factors and their effects on the gut-liver axis should improve the treatment of this common liver disease and its associated disorders.
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Affiliation(s)
- Christopher Leung
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Melbourne, VIC 3084, Australia.,Department of Gastroenterology and Hepatology, Austin Health, Austin Hospital, Heidelberg, Melbourne, VIC 3084, Australia
| | - Leni Rivera
- Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC 3216, Australia.,Department of Anatomy and Neuroscience, University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia
| | - John B Furness
- Department of Anatomy and Neuroscience, University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia
| | - Peter W Angus
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Melbourne, VIC 3084, Australia.,Department of Gastroenterology and Hepatology, Austin Health, Austin Hospital, Heidelberg, Melbourne, VIC 3084, Australia
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49
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Abdou RM, Zhu L, Baker RD, Baker SS. Gut Microbiota of Nonalcoholic Fatty Liver Disease. Dig Dis Sci 2016; 61:1268-81. [PMID: 26898658 DOI: 10.1007/s10620-016-4045-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/16/2016] [Indexed: 02/08/2023]
Abstract
The prevalence of nonalcoholic fatty liver disease has been rapidly increasing worldwide. It has become a leading cause of liver transplantation. Accumulating evidence suggests a significant role for gut microbiota in its development and progression. Here we review the effect of gut microbiota on developing hepatic fatty infiltration and its progression. Current literature supports a possible role for gut microbiota in the development of liver steatosis, inflammation and fibrosis. We also review the literature on possible interventions for NAFLD that target the gut microbiota.
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Affiliation(s)
- Reham M Abdou
- Digestive Diseases and Nutrition Center, Department of Pediatrics, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA.
| | - Lixin Zhu
- Digestive Diseases and Nutrition Center, Department of Pediatrics, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA.,, 3435 Main Street, 413 Biomedical Research Building, Buffalo, NY, 14214, USA
| | - Robert D Baker
- Digestive Diseases and Nutrition Center, Department of Pediatrics, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA
| | - Susan S Baker
- Digestive Diseases and Nutrition Center, Department of Pediatrics, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA
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50
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Machado MV, Cortez-Pinto H. Diet, Microbiota, Obesity, and NAFLD: A Dangerous Quartet. Int J Mol Sci 2016; 17:481. [PMID: 27043550 PMCID: PMC4848937 DOI: 10.3390/ijms17040481] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 03/21/2016] [Accepted: 03/28/2016] [Indexed: 02/07/2023] Open
Abstract
Recently, the importance of the gut-liver-adipose tissue axis has become evident. Nonalcoholic fatty liver disease (NAFLD) is the hepatic disease of a systemic metabolic disorder that radiates from energy-surplus induced adiposopathy. The gut microbiota has tremendous influences in our whole-body metabolism, and is crucial for our well-being and health. Microorganisms precede humans in more than 400 million years and our guest flora evolved with us in order to help us face aggressor microorganisms, to help us maximize the energy that can be extracted from nutrients, and to produce essential nutrients/vitamins that we are not equipped to produce. However, our gut microbiota can be disturbed, dysbiota, and become itself a source of stress and injury. Dysbiota may adversely impact metabolism and immune responses favoring obesity and obesity-related disorders such as insulin resistance/diabetes mellitus and NAFLD. In this review, we will summarize the latest evidence of the role of microbiota/dysbiota in diet-induced obesity and NAFLD, as well as the potential therapeutic role of targeting the microbiota in this set.
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Affiliation(s)
- Mariana Verdelho Machado
- Departamento de Gastrenterologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte (CHLN), 1649-035 Lisbon, Portugal.
- Laboratório de Nutrição, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Alameda da Universidade, 1649-004 Lisboa, Portugal.
| | - Helena Cortez-Pinto
- Departamento de Gastrenterologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte (CHLN), 1649-035 Lisbon, Portugal.
- Laboratório de Nutrição, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Alameda da Universidade, 1649-004 Lisboa, Portugal.
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