PDF icon Download PDF
Semin Liver Dis 2025; 45(01): 052-065
DOI: 10.1055/a-2516-2361
Review Article

Role of Intestinal Barrier Disruption to Acute-on-Chronic Liver Failure

Julian Pohl
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
,
Dimitrios Aretakis
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
,
Frank Tacke
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
,
Cornelius Engelmann
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
2   Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
3   Institute for Liver and Digestive Health, University College London, London, United Kingdom
,
Michael Sigal
1   Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
4   Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
› Author Affiliations
Funding None.
› Further Information
   Permissions and Reprints


Preview

Abstract

Acute-on-chronic liver failure (ACLF) is a severe condition in patients with decompensated liver cirrhosis, marked by high short-term mortality. Recent experimental and clinical evidence has linked intestinal dysfunction to both the initiation of ACLF as well as disease outcome. This review discusses the significant role of the gut–liver axis in ACLF pathogenesis, highlighting recent advances. Gut mucosal barrier disruption, gut dysbiosis, and bacterial translocation emerge as key factors contributing to systemic inflammation in ACLF. Different approaches of therapeutically targeting the gut–liver axis via farnesoid X receptor agonists, nonselective beta receptor blockers, antibiotics, and probiotics are discussed as potential strategies mitigating ACLF progression. The importance of understanding the distinct pathophysiology of ACLF compared with other stages of liver cirrhosis is highlighted. In conclusion, research findings suggest that disruption of intestinal integrity may be an integral component of ACLF pathogenesis, paving the way for novel diagnostic and therapeutic approaches to manage this syndrome more effectively.

Keywords

liver cirrhosis - acute-on-chronic liver failure - gut - bacterial translocation - systemic inflammation


Publication History

Article published online:
13 March 2025

© 2025. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Arroyo V, Moreau R, Jalan R. Acute-on-chronic liver failure. N Engl J Med 2020; 382 (22) 2137-2145
    Search in Google Scholar
  • 2 European Association for the Study of the Liver. European Association for the Study of the L. EASL Clinical Practice Guidelines on acute-on-chronic liver failure. J Hepatol 2023; 79: 461-491
    Search in Google Scholar
  • 3 Trebicka J, Fernandez J, Papp M. et al; PREDICT STUDY group of the EASL-CLIF Consortium. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol 2020; 73 (04) 842-854
    Search in Google Scholar
  • 4 Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol 2021; 18 (03) 167-180
    Search in Google Scholar
  • 5 Trebicka J, Amoros A, Pitarch C. et al. Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis. Front Immunol 2019; 10: 476
    Search in Google Scholar
  • 6 Bajaj JS, Reddy KR, O'Leary JG. et al. 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. Gastroenterology 2020; 159 (05) 1715-1730.e12
    Search in Google Scholar
  • 7 Prado V, Hernández-Tejero M, Mücke MM. et al. Rectal colonization by resistant bacteria increases the risk of infection by the colonizing strain in critically ill patients with cirrhosis. J Hepatol 2022; 76 (05) 1079-1089
    Search in Google Scholar
  • 8 Fernández J, Clària J, Amorós A. et al. Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis. Gastroenterology 2019; 157 (01) 149-162
    Search in Google Scholar
  • 9 Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol 2021; 75 (Suppl. 01) S67-S81
    Search in Google Scholar
  • 10 D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44 (01) 217-231
    Search in Google Scholar
  • 11 European Association for the Study of the Liver. European Association for the Study of the L. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69: 406-460
    Search in Google Scholar
  • 12 Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002; 20 (03) 252-261
    Search in Google Scholar
  • 13 Moreau R, Jalan R, Gines P. et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (07) 1426-1437 , 1437.e1–1437.e9
    Search in Google Scholar
  • 14 Bajaj JS. Defining acute-on-chronic liver failure: will East and West ever meet?. Gastroenterology 2013; 144 (07) 1337-1339
    Search in Google Scholar
  • 15 Schierwagen R, Gu W, Brieger A. et al; ACLF-I Investigators. Pathogenetic mechanisms and therapeutic approaches of acute-to-chronic liver failure. Am J Physiol Cell Physiol 2023; 325 (01) C129-C140
    Search in Google Scholar
  • 16 Morales-Arráez D, Ventura-Cots M, Altamirano J. et al. The MELD score is superior to the Maddrey discriminant function score to predict short-term mortality in alcohol-associated hepatitis: a global study. Am J Gastroenterol 2022; 117 (02) 301-310
    Search in Google Scholar
  • 17 Gustot T, Fernandez J, Garcia E. et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 2015; 62 (01) 243-252
    Search in Google Scholar
  • 18 Putignano A, Gustot T. New concepts in acute-on-chronic liver failure: Implications for liver transplantation. Liver Transpl 2017; 23 (02) 234-243
    Search in Google Scholar
  • 19 Sundaram V, Jalan R, Wu T. et al. Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation. Gastroenterology 2019; 156 (05) 1381-1391.e3
    Search in Google Scholar
  • 20 Artru F, Louvet A, Ruiz I. et al. Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3. J Hepatol 2017; 67 (04) 708-715
    Search in Google Scholar
  • 21 Engelmann C, Thomsen KL, Zakeri N. et al. Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure. Crit Care 2018; 22 (01) 254
    Search in Google Scholar
  • 22 Lamatsch S, Sittner R, Tacke F, Engelmann C. Novel drug discovery strategies for the treatment of decompensated cirrhosis. Expert Opin Drug Discov 2022; 17 (03) 273-282
    Search in Google Scholar
  • 23 Agarwal B, Cañizares RB, Saliba F. et al. Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure. J Hepatol 2023; 79 (01) 79-92
    Search in Google Scholar
  • 24 Engelmann C, Herber A, Franke A. et al. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study). J Hepatol 2021; 75 (06) 1346-1354
    Search in Google Scholar
  • 25 Fernández J, Acevedo J, Castro M. et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012; 55 (05) 1551-1561
    Search in Google Scholar
  • 26 Arvaniti V, D'Amico G, Fede G. et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010; 139 (04) 1246-1256 , 1256.e1–1256.e5
    Search in Google Scholar
  • 27 Borzio M, Salerno F, Piantoni L. et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33 (01) 41-48
    Search in Google Scholar
  • 28 Bajaj JS, O'Leary JG, Reddy KR. et al; NACSELD. Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology 2012; 56 (06) 2328-2335
    Search in Google Scholar
  • 29 Arroyo V, Moreau R, Jalan R, Ginès P. EASL-CLIF Consortium CANONIC Study. Acute-on-chronic liver failure: A new syndrome that will re-classify cirrhosis. J Hepatol 2015; 62 (1, Suppl): S131-S143
    Search in Google Scholar
  • 30 Jalan R, Saliba F, Pavesi M. et al; CANONIC study investigators of the EASL-CLIF Consortium. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014; 61 (05) 1038-1047
    Search in Google Scholar
  • 31 Fernández J, Acevedo J, Wiest R. et al; European Foundation for the Study of Chronic Liver Failure. Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis. Gut 2018; 67 (10) 1870-1880
    Search in Google Scholar
  • 32 Wong F, Piano S, Angeli P. Reply to: correspondence on “clinical features and evolution of bacterial infection-related acute-on-chronic liver failure”. J Hepatol 2021; 75 (04) 1010-1012
    Search in Google Scholar
  • 33 Sigal M, Meyer TF. Coevolution between the human microbiota and the epithelial immune system. Dig Dis 2016; 34 (03) 190-193
    Search in Google Scholar
  • 34 Helander HF, Fändriks L. Surface area of the digestive tract - revisited. Scand J Gastroenterol 2014; 49 (06) 681-689
    Search in Google Scholar
  • 35 Allaire JM, Crowley SM, Law HT, Chang SY, Ko HJ, Vallance BA. The intestinal epithelium: central coordinator of mucosal immunity. Trends Immunol 2018; 39 (09) 677-696
    Search in Google Scholar
  • 36 Harnack C, Berger H, Liu L, Mollenkopf HJ, Strowig T, Sigal M. Short-term mucosal disruption enables colibactin-producing E. coli to cause long-term perturbation of colonic homeostasis. Gut Microbes 2023; 15 (01) 2233689
    Search in Google Scholar
  • 37 Earle KA, Billings G, Sigal M. et al. Quantitative imaging of gut microbiota spatial organization. Cell Host Microbe 2015; 18 (04) 478-488
    Search in Google Scholar
  • 38 Birchenough GM, Johansson ME, Gustafsson JK, Bergström JH, Hansson GC. New developments in goblet cell mucus secretion and function. Mucosal Immunol 2015; 8 (04) 712-719
    Search in Google Scholar
  • 39 Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 2010; 12 (05) 319-330
    Search in Google Scholar
  • 40 Iftekhar A, Sigal M. Defence and adaptation mechanisms of the intestinal epithelium upon infection. Int J Med Microbiol 2021; 311 (03) 151486
    Search in Google Scholar
  • 41 Marchiando AM, Graham WV, Turner JR. Epithelial barriers in homeostasis and disease. Annu Rev Pathol 2010; 5: 119-144
    Search in Google Scholar
  • 42 Barker N, van Es JH, Kuipers J. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449 (7165): 1003-1007
    Search in Google Scholar
  • 43 Harnack C, Berger H, Antanaviciute A. et al. R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nat Commun 2019; 10 (01) 4368
    Search in Google Scholar
  • 44 Gerbe F, Sidot E, Smyth DJ. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 2016; 529 (7585): 226-230
    Search in Google Scholar
  • 45 Stolfi C, Maresca C, Monteleone G, Laudisi F. Implication of intestinal barrier dysfunction in gut dysbiosis and diseases. Biomedicines 2022; 10 (02) 10
    Search in Google Scholar
  • 46 Lin M, Hartl K, Heuberger J. et al. Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche. Nat Commun 2023; 14 (01) 3025
    Search in Google Scholar
  • 47 Van der Merwe S, Chokshi S, Bernsmeier C, Albillos A. The multifactorial mechanisms of bacterial infection in decompensated cirrhosis. J Hepatol 2021; 75 (Suppl. 01) S82-S100
    Search in Google Scholar
  • 48 Wasmuth HE, Kunz D, Yagmur E. et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol 2005; 42 (02) 195-201
    Search in Google Scholar
  • 49 Mookerjee RP, Stadlbauer V, Lidder S. et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007; 46 (03) 831-840
    Search in Google Scholar
  • 50 Huang DQ, Mathurin P, Cortez-Pinto H, Loomba R. Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors. Nat Rev Gastroenterol Hepatol 2023; 20 (01) 37-49
    Search in Google Scholar
  • 51 Huang DQ, Terrault NA, Tacke F. et al. Global epidemiology of cirrhosis - aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol 2023; 20 (06) 388-398
    Search in Google Scholar
  • 52 Wang Y, Tong J, Chang B, Wang B, Zhang D, Wang B. Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins. Mol Med Rep 2014; 9 (06) 2352-2356
    Search in Google Scholar
  • 53 Tang Y, Banan A, Forsyth CB. et al. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease. Alcohol Clin Exp Res 2008; 32 (02) 355-364
    Search in Google Scholar
  • 54 Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 2009; 50 (02) 638-644
    Search in Google Scholar
  • 55 Basuroy S, Sheth P, Kuppuswamy D, Balasubramanian S, Ray RM, Rao RK. Expression of kinase-inactive c-Src delays oxidative stress-induced disassembly and accelerates calcium-mediated reassembly of tight junctions in the Caco-2 cell monolayer. J Biol Chem 2003; 278 (14) 11916-11924
    Search in Google Scholar
  • 56 Seth A, Sheth P, Elias BC, Rao R. Protein phosphatases 2A and 1 interact with occludin and negatively regulate the assembly of tight junctions in the CACO-2 cell monolayer. J Biol Chem 2007; 282 (15) 11487-11498
    Search in Google Scholar
  • 57 Rao RK, Li L, Baker RD, Baker SS, Gupta A. Glutathione oxidation and PTPase inhibition by hydrogen peroxide in Caco-2 cell monolayer. Am J Physiol Gastrointest Liver Physiol 2000; 279 (02) G332-G340
    Search in Google Scholar
  • 58 Reiberger T, Ferlitsch A, Payer BA. et al; Vienna Hepatic Hemodynamic Lab. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol 2013; 58 (05) 911-921
    Search in Google Scholar
  • 59 Trebicka J, Reiberger T, Laleman W. Gut-liver axis links portal hypertension to acute-on-chronic liver failure. Visc Med 2018; 34 (04) 270-275
    Search in Google Scholar
  • 60 Schierwagen R, Alvarez-Silva C, Madsen MSA. et al. Circulating microbiome in blood of different circulatory compartments. Gut 2019; 68 (03) 578-580
    Search in Google Scholar
  • 61 Lehmann JM, Claus K, Jansen C. et al. Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality. Liver Int 2018; 38 (05) 875-884
    Search in Google Scholar
  • 62 Berres ML, Lehmann J, Jansen C. et al. Chemokine (C-X-C motif) ligand 11 levels predict survival in cirrhotic patients with transjugular intrahepatic portosystemic shunt. Liver Int 2016; 36 (03) 386-394
    Search in Google Scholar
  • 63 Berres ML, Asmacher S, Lehmann J. et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Hepatol 2015; 62 (02) 332-339
    Search in Google Scholar
  • 64 Norman DA, Atkins JM, Seelig Jr LL, Gomez-Sanchez C, Krejs GJ. Water and electrolyte movement and mucosal morphology in the jejunum of patients with portal hypertension. Gastroenterology 1980; 79 (04) 707-715
    Search in Google Scholar
  • 65 Such J, Guardiola JV, de Juan J. et al. Ultrastructural characteristics of distal duodenum mucosa in patients with cirrhosis. Eur J Gastroenterol Hepatol 2002; 14 (04) 371-376
    Search in Google Scholar
  • 66 Haak BW, Wiersinga WJ. The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol 2017; 2 (02) 135-143
    Search in Google Scholar
  • 67 Cani PD. Gut microbiota - at the intersection of everything?. Nat Rev Gastroenterol Hepatol 2017; 14 (06) 321-322
    Search in Google Scholar
  • 68 Dikopoulos N, Weidenbach H, Adler G, Schmid RM. Lipopolysaccharide represses cholesterol 7-alpha hydroxylase and induces binding activity to the bile acid response element II. Eur J Clin Invest 2003; 33 (01) 58-64
    Search in Google Scholar
  • 69 Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes 2013; 4 (05) 382-387
    Search in Google Scholar
  • 70 Axelson M, Sjövall J. Potential bile acid precursors in plasma–possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man. J Steroid Biochem 1990; 36 (06) 631-640
    Search in Google Scholar
  • 71 Stenman LK, Holma R, Eggert A, Korpela R. A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids. Am J Physiol Gastrointest Liver Physiol 2013; 304 (03) G227-G234
    Search in Google Scholar
  • 72 Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science 2018; 362 (6418): 362
    Search in Google Scholar
  • 73 Gómez-Hurtado I, Santacruz A, Peiró G. et al. Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4-induced fibrosis. PLoS One 2011; 6 (07) e23037
    Search in Google Scholar
  • 74 Pandey A, Galeone A, Han SY. et al. Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila. Nat Commun 2023; 14 (01) 5667
    Search in Google Scholar
  • 75 Shemtov SJ, Emani R, Bielska O. et al. The intestinal immune system and gut barrier function in obesity and ageing. FEBS J 2023; 290 (17) 4163-4186
    Search in Google Scholar
  • 76 Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol 2023; 21 (11) 719-733
    Search in Google Scholar
  • 77 Lee JY, Tsolis RM, Bäumler AJ. The microbiome and gut homeostasis. Science 2022; 377 (6601): eabp9960
    Search in Google Scholar
  • 78 Zhu L, Baker SS, Gill C. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57 (02) 601-609
    Search in Google Scholar
  • 79 Bayoumy AB, Mulder CJJ, Mol JJ, Tushuizen ME. Gut fermentation syndrome: a systematic review of case reports. United European Gastroenterol J 2021; 9 (03) 332-342
    Search in Google Scholar
  • 80 Duan Y, Llorente C, Lang S. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019; 575 (7783): 505-511
    Search in Google Scholar
  • 81 Chen Y, Yang F, Lu H. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54 (02) 562-572
    Search in Google Scholar
  • 82 Chen Y, Guo J, Qian G. et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. J Gastroenterol Hepatol 2015; 30 (09) 1429-1437
    Search in Google Scholar
  • 83 Bajaj JS, Peña-Rodriguez M, La Reau A. et al. Longitudinal transkingdom gut microbial approach towards decompensation in outpatients with cirrhosis. Gut 2023; 72 (04) 759-771
    Search in Google Scholar
  • 84 Engelmann C, Adebayo D, Oria M. et al. Recombinant alkaline phosphatase prevents acute on chronic liver failure. Sci Rep 2020; 10 (01) 389
    Search in Google Scholar
  • 85 Kondo T, Macdonald S, Engelmann C. et al. The role of RIPK1 mediated cell death in acute on chronic liver failure. Cell Death Dis 2021; 13 (01) 5
    Search in Google Scholar
  • 86 Bajaj JS, Heuman DM, Hylemon PB. et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60 (05) 940-947
    Search in Google Scholar
  • 87 Bajaj JS, Ridlon JM, Hylemon PB. et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012; 302 (01) G168-G175
    Search in Google Scholar
  • 88 Benten D, Wiest R. Gut microbiome and intestinal barrier failure–the “Achilles heel” in hepatology?. J Hepatol 2012; 56 (06) 1221-1223
    Search in Google Scholar
  • 89 Berg RD, Garlington AW. Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun 1979; 23 (02) 403-411
    Search in Google Scholar
  • 90 Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63 (05) 1272-1284
    Search in Google Scholar
  • 91 Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021; 75 (Suppl. 01) S49-S66
    Search in Google Scholar
  • 92 Piano S, Fasolato S, Salinas F. et al. The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: results of a randomized, controlled clinical trial. Hepatology 2016; 63 (04) 1299-1309
    Search in Google Scholar
  • 93 Wiest R, Rath HC. Gastrointestinal disorders of the critically ill. Bacterial translocation in the gut. Best Pract Res Clin Gastroenterol 2003; 17 (03) 397-425
    Search in Google Scholar
  • 94 Worlicek M, Knebel K, Linde HJ. et al. Splanchnic sympathectomy prevents translocation and spreading of E. coli but not S. aureus in liver cirrhosis. Gut 2010; 59 (08) 1127-1134
    Search in Google Scholar
  • 95 Balmer ML, Slack E, de Gottardi A. et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci Transl Med 2014; 6 (237) 237ra66
    Search in Google Scholar
  • 96 Pose E, Coll M, Martínez-Sánchez C. et al. Programmed death ligand 1 is overexpressed in liver macrophages in chronic liver diseases, and its blockade improves the antibacterial activity against infections. Hepatology 2021; 74 (01) 296-311
    Search in Google Scholar
  • 97 Peiseler M, Araujo David B, Zindel J. et al. Kupffer cell-like syncytia replenish resident macrophage function in the fibrotic liver. Science 2023; 381 (6662): eabq5202
    Search in Google Scholar
  • 98 Clària J, Stauber RE, Coenraad MJ. et al; CANONIC Study Investigators of the EASL-CLIF Consortium and the European Foundation for the Study of Chronic Liver Failure (EF-CLIF). Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology 2016; 64 (04) 1249-1264
    Search in Google Scholar
  • 99 Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61 (06) 1385-1396
    Search in Google Scholar
  • 100 Albillos A, de la Hera A, González M. et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology 2003; 37 (01) 208-217
    Search in Google Scholar
  • 101 Albillos A, de-la-Hera A, Alvarez-Mon M. Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites. Lancet 2004; 363 (9421): 1608-1610
    Search in Google Scholar
  • 102 Papp M, Sipeki N, Vitalis Z. et al. High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. J Hepatol 2013; 59 (03) 457-466
    Search in Google Scholar
  • 103 Márquez M, Fernández-Gutiérrez C, Montes-de-Oca M. et al. Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis. Clin Exp Immunol 2009; 158 (02) 219-229
    Search in Google Scholar
  • 104 Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol 2017; 67 (05) 1084-1103
    Search in Google Scholar
  • 105 Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol 2019; 25 (39) 5897-5917
    Search in Google Scholar
  • 106 Verbeke L, Farre R, Trebicka J. et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59 (06) 2286-2298
    Search in Google Scholar
  • 107 Lutz P, Berger C, Langhans B. et al. A farnesoid X receptor polymorphism predisposes to spontaneous bacterial peritonitis. Dig Liver Dis 2014; 46 (11) 1047-1050
    Search in Google Scholar
  • 108 Van Mil SW, Milona A, Dixon PH. et al. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 2007; 133 (02) 507-516
    Search in Google Scholar
  • 109 Marzolini C, Tirona RG, Gervasini G. et al. A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression. Mol Endocrinol 2007; 21 (08) 1769-1780
    Search in Google Scholar
  • 110 Semmler G, Simbrunner B, Scheiner B. et al. Impact of farnesoid X receptor single nucleotide polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension. J Gastroenterol Hepatol 2019; 34 (12) 2164-2172
    Search in Google Scholar
  • 111 Úbeda M, Lario M, Muñoz L. et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol 2016; 64 (05) 1049-1057
    Search in Google Scholar
  • 112 Verbeke L, Farre R, Verbinnen B. et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol 2015; 185 (02) 409-419
    Search in Google Scholar
  • 113 Sanyal AJ, Ratziu V, Loomba R. et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2023; 79 (05) 1110-1120
    Search in Google Scholar
  • 114 Schwabl P, Hambruch E, Seeland BA. et al. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 2017; 66 (04) 724-733
    Search in Google Scholar
  • 115 Adorini L, Trauner M. FXR agonists in NASH treatment. J Hepatol 2023; 79 (05) 1317-1331
    Search in Google Scholar
  • 116 Pérez-Paramo M, Muñoz J, Albillos A. et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 2000; 31 (01) 43-48
    Search in Google Scholar
  • 117 Mookerjee RP, Pavesi M, Thomsen KL. et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol 2016; 64 (03) 574-582
    Search in Google Scholar
  • 118 Jachs M, Hartl L, Schaufler D. et al. Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes. Gut 2021; 70 (09) 1758-1767
    Search in Google Scholar
  • 119 Jensen MD, Watson H, Vilstrup H, Jepsen P. Non-selective beta-blockers and risk of sepsis in patients with cirrhosis and ascites: results from a large observational study. Clin Epidemiol 2023; 15: 775-783
    Search in Google Scholar
  • 120 Sersté T, Melot C, Francoz C. et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010; 52 (03) 1017-1022
    Search in Google Scholar
  • 121 Albillos A, Krag A. Beta-blockers in the era of precision medicine in patients with cirrhosis. J Hepatol 2023; 78 (04) 866-872
    Search in Google Scholar
  • 122 Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: evidence-based indications and limitations. JHEP Rep Innov Hepatol 2019; 2 (01) 100063
    Search in Google Scholar
  • 123 Madsen BS, Havelund T, Krag A. Targeting the gut-liver axis in cirrhosis: antibiotics and non-selective β-blockers. Adv Ther 2013; 30 (07) 659-670
    Search in Google Scholar
  • 124 Bajaj JS, Tandon P, OʼLeary JG. et al. Outcomes in patients with cirrhosis on primary compared to secondary prophylaxis for spontaneous bacterial peritonitis. Am J Gastroenterol 2019; 114 (04) 599-606
    Search in Google Scholar
  • 125 Bass NM, Mullen KD, Sanyal A. et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362 (12) 1071-1081
    Search in Google Scholar
  • 126 Yu X, Jin Y, Zhou W. et al. Rifaximin modulates the gut microbiota to prevent hepatic encephalopathy in liver cirrhosis without impacting the resistome. Front Cell Infect Microbiol 2022; 11: 761192
    Search in Google Scholar
  • 127 Israelsen M, Madsen BS, Torp N. et al; GALAXY, MicrobLiver Consortia. Rifaximin-α for liver fibrosis in patients with alcohol-related liver disease (GALA-RIF): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol 2023; 8 (06) 523-532
    Search in Google Scholar
  • 128 Kulkarni AV, Avadhanam M, Karandikar P. et al. Antibiotics with or without Rifaximin for acute hepatic Encephalopathy in critically ill patients with cirrhosis: a double-blind, randomized controlled (ARiE) trial. Am J Gastroenterol 2024; 119 (05) 864-874
    Search in Google Scholar
  • 129 Caraceni P, Vargas V, Solà E. et al; Liverhope Consortium. The use of rifaximin in patients with cirrhosis. Hepatology 2021; 74 (03) 1660-1673
    Search in Google Scholar
  • 130 Rimola A, García-Tsao G, Navasa M. et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000; 32 (01) 142-153
    Search in Google Scholar
  • 131 Philips CA, Pande A, Shasthry SM. et al. Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study. Clin Gastroenterol Hepatol 2017; 15 (04) 600-602
    Search in Google Scholar
  • 132 Philips CA, Phadke N, Ganesan K, Ranade S, Augustine P. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis. Indian J Gastroenterol 2018; 37 (03) 215-225
    Search in Google Scholar
  • 133 Sharma A, Roy A, Premkumar M. et al. Fecal microbiota transplantation in alcohol-associated acute-on-chronic liver failure: an open-label clinical trial. Hepatol Int 2022; 16 (02) 433-446
    Search in Google Scholar
  • 134 Bloom PP, Tapper EB. Lactulose in cirrhosis: current understanding of efficacy, mechanism, and practical considerations. Hepatol Commun 2023; 7 (11) 7
    Search in Google Scholar
  • 135 Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2016; 4: CD003044
    Search in Google Scholar
  • 136 Vince A, Dawson AM, Park N, O'Grady F. Ammonia production by intestinal bacteria. Gut 1973; 14 (03) 171-177
    Search in Google Scholar
  • 137 Vince A, Killingley M, Wrong OM. Effect of lactulose on ammonia production in a fecal incubation system. Gastroenterology 1978; 74 (03) 544-549
    Search in Google Scholar
  • 138 Vince AJ, Burridge SM. Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose. J Med Microbiol 1980; 13 (02) 177-191
    Search in Google Scholar
  • 139 Moratalla A, Ampuero J, Bellot P. et al. Lactulose reduces bacterial DNA translocation, which worsens neurocognitive shape in cirrhotic patients with minimal hepatic encephalopathy. Liver Int 2017; 37 (02) 212-223
    Search in Google Scholar
  • 140 Haase S, Wilck N, Haghikia A, Gold R, Mueller DN, Linker RA. The role of the gut microbiota and microbial metabolites in neuroinflammation. Eur J Immunol 2020; 50 (12) 1863-1870
    Search in Google Scholar
  • 141 Holle J, McParland V, Anandakumar H. et al. Gut dysbiosis contributes to TMAO accumulation in CKD. Nephrol Dial Transplant 2024; 39 (11) 1923-1926
    Search in Google Scholar