Gyongyi Szabo1, Jan Petrasek2,3. 1. Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605,USA. 2. Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605, USA. 3. Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Abstract
BACKGROUND: Innate immunity plays a critical role in the development of alcohol-induced liver inflammation. Understanding the inter-relationship of signals from within and outside of the liver that trigger liver inflammation is pivotal for development of novel therapeutic targets of alcoholic liver disease (ALD). AIM: The aim of this paper is to review recent advances in the field of alcohol-induced liver inflammation. METHODS: A detailed literature review was performed using the PubMed database published between January 1980 and December 2016. RESULTS: We provide an update on the role of intestinal microbiome, metabolome and the gut-liver axis in ALD, discuss the growing body of evidence on the diversity of liver macrophages and their differential contribution to alcohol-induced liver inflammation, and highlight the crucial role of inflammasomes in integration of inflammatory signals in ALD. Studies to date have identified a multitude of new therapeutic targets, some of which are currently being tested in patients with severe alcoholic hepatitis. These treatments aim to strengthen the intestinal barrier, ameliorate liver inflammation and augment hepatocyte regeneration. CONCLUSION: Given the complexity of inflammation in ALD, multiple pathobiological mechanisms may need to be targeted at the same time as it seems unlikely that there is a single dominant pathogenic pathway in ALD that would be easily targeted using a single target drug approach. SHORT SUMMARY: Here, we focus on recent advances in immunopathogenesis of alcoholic liver disease (ALD), including gut-liver axis, hepatic macrophage activation, sterile inflammation and synergy between bacterial and sterile signals. We propose a multiple parallel hit model of inflammation in ALD and discuss its implications for clinical trials in alcoholic hepatitis.
BACKGROUND: Innate immunity plays a critical role in the development of alcohol-induced liver inflammation. Understanding the inter-relationship of signals from within and outside of the liver that trigger liver inflammation is pivotal for development of novel therapeutic targets of alcoholic liver disease (ALD). AIM: The aim of this paper is to review recent advances in the field of alcohol-induced liver inflammation. METHODS: A detailed literature review was performed using the PubMed database published between January 1980 and December 2016. RESULTS: We provide an update on the role of intestinal microbiome, metabolome and the gut-liver axis in ALD, discuss the growing body of evidence on the diversity of liver macrophages and their differential contribution to alcohol-induced liver inflammation, and highlight the crucial role of inflammasomes in integration of inflammatory signals in ALD. Studies to date have identified a multitude of new therapeutic targets, some of which are currently being tested in patients with severe alcoholic hepatitis. These treatments aim to strengthen the intestinal barrier, ameliorate liver inflammation and augment hepatocyte regeneration. CONCLUSION: Given the complexity of inflammation in ALD, multiple pathobiological mechanisms may need to be targeted at the same time as it seems unlikely that there is a single dominant pathogenic pathway in ALD that would be easily targeted using a single target drug approach. SHORT SUMMARY: Here, we focus on recent advances in immunopathogenesis of alcoholic liver disease (ALD), including gut-liver axis, hepatic macrophage activation, sterile inflammation and synergy between bacterial and sterile signals. We propose a multiple parallel hit model of inflammation in ALD and discuss its implications for clinical trials in alcoholic hepatitis.
Authors: Kendle M Maslowski; Angelica T Vieira; Aylwin Ng; Jan Kranich; Frederic Sierro; Di Yu; Heidi C Schilter; Michael S Rolph; Fabienne Mackay; David Artis; Ramnik J Xavier; Mauro M Teixeira; Charles R Mackay Journal: Nature Date: 2009-10-29 Impact factor: 49.962
Authors: Sophie Leclercq; Sébastien Matamoros; Patrice D Cani; Audrey M Neyrinck; François Jamar; Peter Stärkel; Karen Windey; Valentina Tremaroli; Fredrik Bäckhed; Kristin Verbeke; Philippe de Timary; Nathalie M Delzenne Journal: Proc Natl Acad Sci U S A Date: 2014-10-06 Impact factor: 11.205
Authors: Jennifer T Wolstenholme; Justin M Saunders; Maren Smith; Jason D Kang; Phillip B Hylemon; Javier González-Maeso; Andrew Fagan; Derrick Zhao; Masoumeh Sikaroodi; Jeremy Herzog; Amirhossein Shamsaddini; Marcela Peña-Rodríguez; Lianyong Su; Yun-Ling Tai; Jing Zheng; Po-Cheng Cheng; R Balfour Sartor; Patrick M Gillevet; Huiping Zhou; Jasmohan S Bajaj Journal: Nat Commun Date: 2022-10-19 Impact factor: 17.694
Authors: Matias A Avila; Jean-François Dufour; Alexander L Gerbes; Fabien Zoulim; Ramon Bataller; Patrizia Burra; Helena Cortez-Pinto; Bin Gao; Ian Gilmore; Philippe Mathurin; Christophe Moreno; Vladimir Poznyak; Bernd Schnabl; Gyongyi Szabo; Maja Thiele; Mark R Thursz Journal: Gut Date: 2019-12-26 Impact factor: 23.059