{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:46:21Z","timestamp":1789069581027,"version":"build-2803163510"},"reference-count":140,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hallym University Research Fund","award":["HURF-2015\u201356"],"award-info":[{"award-number":["HURF-2015\u201356"]}]},{"name":"the Basic Science Research Program, the National Research Foundation of Korea funded by the Ministry of Education","award":["2020R1A6A1A03043026"],"award-info":[{"award-number":["2020R1A6A1A03043026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute-on-chronic liver failure (ACLF) is an important syndrome of liver failure that has a high risk of short-term mortality in patients with chronic liver disease. The development of ACLF is associated with proinflammatory precipitating events, such as infection, alcoholic hepatitis, and intense systemic inflammation. Recently, the role of the gut microbiome has increasingly emerged in human health and disease. Additionally, the gut microbiome might have a major role in the development of liver disease. In this review, we examine evidence to support the role of gut dysbiosis in cirrhosis and ACLF. Additionally, we explore the mechanism by which the gut microbiome contributes to the development of ACLF, with a focus on alcohol-induced liver disease.<\/jats:p>","DOI":"10.3390\/ijms222111680","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T23:51:36Z","timestamp":1635465096000},"page":"11680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The Role of Gut Dysbiosis in Acute-on-Chronic Liver Failure"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6236-780X","authenticated-orcid":false,"given":"Sung-Eun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24252, Korea"},{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5884-9993","authenticated-orcid":false,"given":"Ji Won","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24252, Korea"},{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung Su","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24252, Korea"},{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myoung-Kuk","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24252, Korea"},{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9206-9245","authenticated-orcid":false,"given":"Ki Tae","family":"Suk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24252, Korea"},{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5792-1500","authenticated-orcid":false,"given":"Dong Joon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24252, Korea"},{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.cell.2016.01.013","article-title":"Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans","volume":"164","author":"Sender","year":"2016","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1237439","DOI":"10.1126\/science.1237439","article-title":"The long-term stability of the human gut microbiota","volume":"341","author":"Faith","year":"2013","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1177\/0884533615609899","article-title":"Gut Microbiome: What We Do and Don\u2019t Know","volume":"30","author":"Cresci","year":"2015","journal-title":"Nutr. Clin. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00394-017-1445-8","article-title":"Gut microbiota functions: Metabolism of nutrients and other food components","volume":"57","author":"Rowland","year":"2018","journal-title":"Eur. J. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1056\/NEJMra1600266","article-title":"The Human Intestinal Microbiome in Health and Disease","volume":"375","author":"Lynch","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1053\/j.gastro.2014.01.020","article-title":"Interactions between the intestinal microbiome and liver diseases","volume":"146","author":"Schnabl","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1111\/acer.12704","article-title":"Alcoholic liver disease: The gut microbiome and liver cross talk","volume":"39","author":"Hartmann","year":"2015","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1055\/s-0036-1593882","article-title":"Bidirectional Communication between Liver and Gut during Alcoholic Liver Disease","volume":"36","author":"Schnabl","year":"2016","journal-title":"Semin. Liver Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.bbi.2012.04.001","article-title":"Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects","volume":"26","author":"Leclercq","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10809","article-title":"Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity","volume":"482","author":"Elinav","year":"2012","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1136\/gutjnl-2011-301012","article-title":"Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota","volume":"61","author":"Serino","year":"2012","journal-title":"Gut"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1053\/j.gastro.2012.01.034","article-title":"A high-fat diet is associated with endotoxemia that originates from the gut","volume":"142","author":"Pendyala","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.3892\/mmr.2014.2126","article-title":"Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins","volume":"9","author":"Wang","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/0168-8278(91)90933-3","article-title":"Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: Reevaluation with an improved chromogenic assay","volume":"12","author":"Fukui","year":"1991","journal-title":"J. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/alcalc\/37.1.81","article-title":"Concentrations of lipopolysaccharide-binding protein, bactericidal\/permeability-increasing protein, soluble CD14 and plasma lipids in relation to endotoxaemia in patients with alcoholic liver disease","volume":"37","author":"Parlesak","year":"2002","journal-title":"Alcohol Alcohol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tulstrup, M.V., Christensen, E.G., Carvalho, V., Linninge, C., Ahrn\u00e9, S., H\u00f8jberg, O., Licht, T.R., and Bahl, M.I. (2015). Antibiotic Treatment Affects Intestinal Permeability and Gut Microbial Composition in Wistar Rats Dependent on Antibiotic Class. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144854"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.3389\/fmicb.2016.01081","article-title":"The Gut Microbiota in Immune-Mediated Inflammatory Diseases","volume":"7","author":"Forbes","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","author":"Asrani","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jhep.2018.05.011","article-title":"Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies","volume":"69","author":"Pimpin","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1053\/j.gastro.2014.11.039","article-title":"Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States","volume":"148","author":"Wong","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41575-018-0055-0","article-title":"The changing epidemiology of liver diseases in the Asia-Pacific region","volume":"16","author":"Wong","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mam.2018.09.002","article-title":"Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues","volume":"65","author":"Parola","year":"2019","journal-title":"Mol. Aspects Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/S0140-6736(14)60121-5","article-title":"Liver cirrhosis","volume":"383","author":"Tsochatzis","year":"2014","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1053\/j.gastro.2013.02.042","article-title":"Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis","volume":"144","author":"Moreau","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s12072-019-09946-3","article-title":"Acute-on-chronic liver failure: Consensus recommendations of the Asian Pacific association for the study of the liver (APASL): An update","volume":"13","author":"Sarin","year":"2019","journal-title":"Hepatol. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1159\/000047017","article-title":"Acute-on-chronic liver failure: Pathophysiological basis of therapeutic options","volume":"20","author":"Jalan","year":"2002","journal-title":"Blood Purif."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1002\/hep.29773","article-title":"NACSELD acute-on-chronic liver failure (NACSELD-ACLF) score predicts 30-day survival in hospitalized patients with cirrhosis","volume":"67","author":"Reddy","year":"2018","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1097\/MCG.0000000000000987","article-title":"Long-term Prognosis of Acute-on-Chronic Liver Failure Survivors","volume":"53","author":"Yoon","year":"2019","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1002\/hep.28740","article-title":"Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure","volume":"64","author":"Stauber","year":"2016","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1136\/gutjnl-2017-314240","article-title":"Bacterial and fungal infections in acute-on-chronic liver failure: Prevalence, characteristics and impact on prognosis","volume":"67","author":"Acevedo","year":"2018","journal-title":"Gut"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.1056\/NEJMra0805786","article-title":"Alcoholic hepatitis","volume":"360","author":"Lucey","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16041","DOI":"10.1038\/nrdp.2016.41","article-title":"Acute-on-chronic liver failure in cirrhosis","volume":"2","author":"Arroyo","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.jhep.2019.11.009","article-title":"Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF","volume":"72","author":"Moreau","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1159\/000371678","article-title":"Gut microbiota, cirrhosis, and alcohol regulate bile acid metabolism in the gut","volume":"33","author":"Ridlon","year":"2015","journal-title":"Dig. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1002\/hep.24423","article-title":"Characterization of fecal microbial communities in patients with liver cirrhosis","volume":"54","author":"Chen","year":"2011","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.jhep.2013.12.019","article-title":"Altered profile of human gut microbiome is associated with cirrhosis and its complications","volume":"60","author":"Bajaj","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"G168","DOI":"10.1152\/ajpgi.00190.2011","article-title":"Linkage of gut microbiome with cognition in hepatic encephalopathy","volume":"302","author":"Bajaj","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nature13568","article-title":"Alterations of the human gut microbiome in liver cirrhosis","volume":"513","author":"Qin","year":"2014","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e98019","DOI":"10.1172\/jci.insight.98019","article-title":"Gut microbial RNA and DNA analysis predicts hospitalizations in cirrhosis","volume":"3","author":"Bajaj","year":"2018","journal-title":"JCI Insight"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"G675","DOI":"10.1152\/ajpgi.00152.2012","article-title":"Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation","volume":"303","author":"Bajaj","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1111\/j.1572-0241.2002.05791.x","article-title":"Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia","volume":"97","author":"Bauer","year":"2002","journal-title":"Am. J. Gastroenterol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1136\/gutjnl-2016-312729","article-title":"Gut microbiome and liver diseases","volume":"65","author":"Tilg","year":"2016","journal-title":"Gut"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/j.1472-765X.2007.02129.x","article-title":"Cultivable bacterial diversity from the human colon","volume":"44","author":"Duncan","year":"2007","journal-title":"Lett. Appl. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1097\/00004836-200603000-00015","article-title":"Colonic health: Fermentation and short chain fatty acids","volume":"40","author":"Wong","year":"2006","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1038\/ismej.2011.212","article-title":"The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates","volume":"6","author":"Zoetendal","year":"2012","journal-title":"ISME J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.jhep.2019.10.003","article-title":"The gut-liver axis in liver disease: Pathophysiological basis for therapy","volume":"72","author":"Albillos","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/S0168-8278(98)80022-6","article-title":"The sympathetic nervous system in liver disease","volume":"29","author":"Henriksen","year":"1998","journal-title":"J. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/j.jhep.2017.05.007","article-title":"Targeting the gut-liver axis in liver disease","volume":"67","author":"Wiest","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1002\/hep.24789","article-title":"Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense","volume":"55","author":"Teltschik","year":"2012","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1002\/hep.30349","article-title":"Intestinal Immune Dysregulation Driven by Dysbiosis Promotes Barrier Disruption and Bacterial Translocation in Rats with Cirrhosis","volume":"70","author":"Borrero","year":"2019","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1002\/hep.23918","article-title":"Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis","volume":"52","author":"Bellot","year":"2010","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/0168-8278(95)80424-2","article-title":"Endotoxemia in patients with chronic liver diseases: Relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation","volume":"22","author":"Lin","year":"1995","journal-title":"J. Hepatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1136\/gutjnl-2018-316227","article-title":"Circulating microbiome in blood of different circulatory compartments","volume":"68","author":"Schierwagen","year":"2019","journal-title":"Gut"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"(2018). EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J. Hepatol., 69, 406\u2013460.","DOI":"10.1016\/j.jhep.2018.03.024"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1172\/JCI76304","article-title":"Gut\/brain axis and the microbiota","volume":"125","author":"Mayer","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.molmet.2016.05.011","article-title":"How gut microbes talk to organs: The role of endocrine and nervous routes","volume":"5","author":"Cani","year":"2016","journal-title":"Mol. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nrgastro.2015.121","article-title":"Towards a systems view of IBS","volume":"12","author":"Mayer","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/j.jceh.2014.12.003","article-title":"Gut microbiota: Its role in hepatic encephalopathy","volume":"5","author":"Rai","year":"2015","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.abb.2013.03.016","article-title":"Inflammation and hepatic encephalopathy","volume":"536","author":"Coltart","year":"2013","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.molcel.2014.03.030","article-title":"Stress, inflammation, and defense of homeostasis","volume":"54","author":"Chovatiya","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.cell.2010.03.006","article-title":"Inflammation 2010: New adventures of an old flame","volume":"140","author":"Medzhitov","year":"2010","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"26800","DOI":"10.1038\/srep26800","article-title":"Impaired Gut-Liver-Brain Axis in Patients with Cirrhosis","volume":"6","author":"Ahluwalia","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"476","DOI":"10.3389\/fimmu.2019.00476","article-title":"Addressing Profiles of Systemic Inflammation across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis","volume":"10","author":"Trebicka","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"25487","DOI":"10.1038\/srep25487","article-title":"Characteristics, Diagnosis and Prognosis of Acute-on-Chronic Liver Failure in Cirrhosis Associated to Hepatitis B","volume":"6","author":"Li","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/hep.27795","article-title":"Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults","volume":"62","author":"Shi","year":"2015","journal-title":"Hepatology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrgastro.2015.219","article-title":"Acute-on-chronic liver failure: Terminology, mechanisms and management","volume":"13","author":"Sarin","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1002\/hep.23264","article-title":"Severe sepsis in cirrhosis","volume":"50","author":"Gustot","year":"2009","journal-title":"Hepatology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.cell.2010.01.022","article-title":"Pattern recognition receptors and inflammation","volume":"140","author":"Takeuchi","year":"2010","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.cgh.2018.07.022","article-title":"Association between Intestinal Microbiota Collected at Hospital Admission and Outcomes of Patients with Cirrhosis","volume":"17","author":"Bajaj","year":"2019","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1053\/j.gastro.2020.07.019","article-title":"Serum Levels of Metabolites Produced by Intestinal Microbes and Lipid Moieties Independently Associated with Acute-on-Chronic Liver Failure and Death in Patients with Cirrhosis","volume":"159","author":"Bajaj","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.jhep.2020.06.013","article-title":"The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology","volume":"73","author":"Trebicka","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1002\/hep.25947","article-title":"Second infections independently increase mortality in hospitalized patients with cirrhosis: The North American consortium for the study of end-stage liver disease (NACSELD) experience","volume":"56","author":"Bajaj","year":"2012","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/s41467-017-00796-x","article-title":"Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus","volume":"8","author":"Llorente","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1080\/19490976.2015.1127483","article-title":"Consequences of bile salt biotransformations by intestinal bacteria","volume":"7","author":"Ridlon","year":"2016","journal-title":"Gut Microbes"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"99","DOI":"10.4161\/gmic.2.2.15416","article-title":"Diversity of the autochthonous colonic microbiota","volume":"2","author":"Nava","year":"2011","journal-title":"Gut Microbes"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1111\/liv.14097","article-title":"Characterization of the circulating microbiome in acute-on-chronic liver failure associated with hepatitis B","volume":"39","author":"Zhang","year":"2019","journal-title":"Liver Int."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1111\/jgh.12932","article-title":"Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality","volume":"30","author":"Chen","year":"2015","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1053\/j.gastro.2020.08.054","article-title":"Alterations in Gut Microbiome in Cirrhosis as Assessed by Quantitative Metagenomics: Relationship with Acute-on-Chronic Liver Failure and Prognosis","volume":"160","author":"Guilly","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"929","DOI":"10.14309\/ajg.0000000000000201","article-title":"Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients","volume":"114","author":"Devarbhavi","year":"2019","journal-title":"Am. J. Gastroenterol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/hep.30205","article-title":"Flare of Autoimmune Hepatitis Causing Acute on Chronic Liver Failure: Diagnosis and Response to Corticosteroid Therapy","volume":"70","author":"Anand","year":"2019","journal-title":"Hepatology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.jceh.2020.08.007","article-title":"Determinants of Outcomes in Autoimmune Hepatitis Presenting as Acute on Chronic Liver Failure without Extrahepatic Organ Dysfunction upon Treatment With Steroids","volume":"11","author":"Sharma","year":"2021","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.3748\/wjg.v20.i10.2542","article-title":"Risk factors and outcome of bacterial infections in cirrhosis","volume":"20","author":"Bruns","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/liv.13645","article-title":"Infections complicating cirrhosis","volume":"38","author":"Piano","year":"2018","journal-title":"Liver Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/hep.27077","article-title":"Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures","volume":"60","author":"Bajaj","year":"2014","journal-title":"Hepatology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1136\/gut.2007.122176","article-title":"Pathogenetic mechanisms of hepatic encephalopathy","volume":"57","author":"Schliess","year":"2008","journal-title":"Gut"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.jhep.2010.07.045","article-title":"Infection and systemic inflammation, not ammonia, are associated with Grade 3\/4 hepatic encephalopathy, but not mortality in cirrhosis","volume":"54","author":"Shawcross","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s11011-006-9042-1","article-title":"Role of ammonia and inflammation in minimal hepatic encephalopathy","volume":"22","author":"Shawcross","year":"2007","journal-title":"Metab. Brain Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/hep.21843","article-title":"Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora\u2019s box?","volume":"46","author":"Wright","year":"2007","journal-title":"Hepatology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1002\/lt.24754","article-title":"Liver transplant modulates gut microbial dysbiosis and cognitive function in cirrhosis","volume":"23","author":"Bajaj","year":"2017","journal-title":"Liver Transpl."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"7419","DOI":"10.1073\/pnas.1001061107","article-title":"Indigenous opportunistic bacteria inhabit mammalian gut-associated lymphoid tissues and share a mucosal antibody-mediated symbiosis","volume":"107","author":"Obata","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1002\/hep.29306","article-title":"Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial","volume":"66","author":"Bajaj","year":"2017","journal-title":"Hepatology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1002\/hep.30690","article-title":"Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial","volume":"70","author":"Bajaj","year":"2019","journal-title":"Hepatology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1056\/NEJMoa1910437","article-title":"Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant","volume":"381","author":"DeFilipp","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1056\/NEJMoa0907893","article-title":"Rifaximin treatment in hepatic encephalopathy","volume":"362","author":"Bass","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1111\/apt.15326","article-title":"Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list","volume":"50","author":"Salehi","year":"2019","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/jgh.12070","article-title":"Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis","volume":"28","author":"Vlachogiannakos","year":"2013","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/jgh.13852","article-title":"Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: A randomized trial","volume":"33","author":"Kimer","year":"2018","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1002\/hep.28898","article-title":"Rifaximin has no effect on hemodynamics in decompensated cirrhosis: A randomized, double-blind, placebo-controlled trial","volume":"65","author":"Kimer","year":"2017","journal-title":"Hepatology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1136\/gutjnl-2011-300779","article-title":"Spontaneous bacterial peritonitis: Recent guidelines and beyond","volume":"61","author":"Wiest","year":"2012","journal-title":"Gut"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.jhep.2018.10.027","article-title":"Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe","volume":"70","author":"Prado","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1111\/j.1872-034X.2012.01015.x","article-title":"Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy","volume":"42","author":"Holte","year":"2012","journal-title":"Hepatol. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"E4485","DOI":"10.1073\/pnas.1415174111","article-title":"Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity","volume":"111","author":"Leclercq","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1136\/gutjnl-2015-310585","article-title":"Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease","volume":"65","author":"Llopis","year":"2016","journal-title":"Gut"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.alcohol.2008.08.006","article-title":"Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: A pilot study","volume":"42","author":"Kirpich","year":"2008","journal-title":"Alcohol"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"694629","DOI":"10.1155\/2012\/694629","article-title":"Microbial translocation in chronic liver diseases","volume":"2012","author":"Pinzone","year":"2012","journal-title":"Int. J. Microbiol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41575-018-0011-z","article-title":"The gut-liver axis and the intersection with the microbiome","volume":"15","author":"Tripathi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41586-019-1742-x","article-title":"Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease","volume":"575","author":"Duan","year":"2019","journal-title":"Nature"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jhep.2019.09.029","article-title":"The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease","volume":"72","author":"Chu","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"G966","DOI":"10.1152\/ajpgi.00380.2011","article-title":"Colonic microbiome is altered in alcoholism","volume":"302","author":"Mutlu","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1111\/liv.14383","article-title":"Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol-associated liver disease","volume":"40","author":"Addolorato","year":"2020","journal-title":"Liver Int."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1002\/hep.29623","article-title":"The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis","volume":"67","author":"Puri","year":"2018","journal-title":"Hepatology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1136\/gutjnl-2016-313432","article-title":"Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease","volume":"67","author":"Grander","year":"2018","journal-title":"Gut"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1782157","DOI":"10.1080\/19490976.2020.1782157","article-title":"Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans","volume":"12","author":"Maccioni","year":"2020","journal-title":"Gut Microbes"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3920","DOI":"10.1073\/pnas.0509592103","article-title":"Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor","volume":"103","author":"Inagaki","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1136\/gutjnl-2015-310283","article-title":"Microbiota-induced obesity requires farnesoid X receptor","volume":"66","author":"Sommer","year":"2017","journal-title":"Gut"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1111\/acer.13498","article-title":"Continued Alcohol Misuse in Human Cirrhosis is Associated with an Impaired Gut-Liver Axis","volume":"41","author":"Bajaj","year":"2017","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"G929","DOI":"10.1152\/ajpgi.00315.2013","article-title":"Colonic inflammation and secondary bile acids in alcoholic cirrhosis","volume":"306","author":"Kakiyama","year":"2014","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/apt.12084","article-title":"Review article: The emerging interplay among the gastrointestinal tract, bile acids and incretins in the pathogenesis of diabetes and non-alcoholic fatty liver disease","volume":"36","author":"Zarrinpar","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.jhep.2018.03.031","article-title":"Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis","volume":"69","author":"Brandl","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s003940070020","article-title":"Rationale for the luminal provision of butyrate in intestinal diseases","volume":"39","author":"Stein","year":"2000","journal-title":"Eur. J. Nutr."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s40168-017-0359-2","article-title":"Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease","volume":"5","author":"Dubinkina","year":"2017","journal-title":"Microbiome"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.jhep.2013.01.003","article-title":"Modulation of the fecal bile acid profile by gut microbiota in cirrhosis","volume":"58","author":"Kakiyama","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/hep.31178","article-title":"Fecal Microbiome Distinguishes Alcohol Consumption from Alcoholic Hepatitis But Does Not Discriminate Disease Severity","volume":"72","author":"Smirnova","year":"2020","journal-title":"Hepatology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4822","DOI":"10.1038\/s41598-018-23146-3","article-title":"Characterization of intestinal microbiota in alcoholic patients with and without alcoholic hepatitis or chronic alcoholic pancreatitis","volume":"8","author":"Ciocan","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"S38","DOI":"10.1016\/j.jhep.2015.03.006","article-title":"Trends in the management and burden of alcoholic liver disease","volume":"62","author":"Mathurin","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/ajg.2017.469","article-title":"ACG Clinical Guideline: Alcoholic Liver Disease","volume":"113","author":"Singal","year":"2018","journal-title":"Am. J. Gastroenterol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.jhep.2016.04.029","article-title":"Treatment of alcohol use disorders in patients with alcoholic liver disease","volume":"65","author":"Addolorato","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1002\/lt.24163","article-title":"The etiology of cirrhosis is a strong determinant of brain reserve: A multimodal magnetic resonance imaging study","volume":"21","author":"Ahluwalia","year":"2015","journal-title":"Liver Transpl."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1111\/acer.13605","article-title":"Effects of Alcohol on the Brain in Cirrhosis: Beyond Hepatic Encephalopathy","volume":"42","author":"Davis","year":"2018","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1093\/alcalc\/agx024","article-title":"The Microbiota, the Gut and the Brain in Eating and Alcohol Use Disorders: A \u2018M\u00e9nage \u00e0 Trois\u2019?","volume":"52","author":"Temko","year":"2017","journal-title":"Alcohol Alcohol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"347","DOI":"10.15288\/jsad.2014.75.347","article-title":"Associations of cocaine use and HIV infection with the intestinal microbiota, microbial translocation, and inflammation","volume":"75","author":"Volpe","year":"2014","journal-title":"J. Stud. Alcohol Drugs"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s11011-008-9129-y","article-title":"Thiamine deficiency-related brain dysfunction in chronic liver failure","volume":"24","author":"Butterworth","year":"2009","journal-title":"Metab. Brain Dis."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1002\/hep.31496","article-title":"A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder","volume":"73","author":"Bajaj","year":"2021","journal-title":"Hepatology"},{"key":"ref_134","first-page":"30","article-title":"Jejunal microflora in patients with chronic alcohol abuse","volume":"31","author":"Bode","year":"1984","journal-title":"Hepatogastroenterology"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"297","DOI":"10.3109\/00365528009181473","article-title":"Hepatic and extrahepatic elimination of ethanol in cirrhosis. With estimates of intrahepatic shunts and Km for ethanol elimination","volume":"15","author":"Utne","year":"1980","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1136\/gut.44.3.347","article-title":"Ciprofloxacin decreases the rate of ethanol elimination in humans","volume":"44","author":"Tillonen","year":"1999","journal-title":"Gut"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1038\/nature14851","article-title":"Decompensated cirrhosis and microbiome interpretation","volume":"525","author":"Bajaj","year":"2015","journal-title":"Nature"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1002\/hep.27819","article-title":"Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy","volume":"62","author":"Bajaj","year":"2015","journal-title":"Hepatology"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"179","DOI":"10.5005\/jp-journals-10024-1296","article-title":"Evaluation of periodontal status in alcoholic liver cirrhosis patients: A comparative study","volume":"14","author":"Raghava","year":"2013","journal-title":"J. Contemp. Dent. Pract."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Tuomisto, S., Pessi, T., Collin, P., Vuento, R., Aittoniemi, J., and Karhunen, P.J. (2014). Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics. 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