Advertisement

The microbiota in cirrhosis and its role in hepatic decompensation

  • Jonel Trebicka
    Correspondence
    Corresponding author. Address: Department of Internal Medicine I, University of Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. Tel: +49 69 63010.
    Affiliations
    Translational Hepatology, Internal Medicine I, Goethe University Frankfurt, Germany

    European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain

    Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
    Search for articles by this author
  • Jane Macnaughtan
    Affiliations
    Institute for Liver and Digestive Health, Royal Free Campus, University College London, United Kingdom
    Search for articles by this author
  • Bernd Schnabl
    Affiliations
    Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
    Search for articles by this author
  • Debbie L. Shawcross
    Affiliations
    Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, Denmark Hill Campus, London, United Kingdom
    Search for articles by this author
  • Jasmohan S. Bajaj
    Affiliations
    Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, VA, USA
    Search for articles by this author

      Summary

      Cirrhosis – the common end-stage of chronic liver disease – is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.

      Keywords

      Introduction

      Cirrhosis is the result of many years of chronic liver disease (CLD).
      • Tsochatzis E.A.
      • Bosch J.
      • Burroughs A.K.
      Often silent, CLD slowly changes the liver by restructuring its architecture, combining wound-healing processes, such as remodelling and fibrosis, with a decrease in the functioning parenchymal mass, which eventually leads to cirrhosis.
      • Friedman S.L.
      Mechanisms of hepatic fibrogenesis.
      In cirrhosis, which is also silent for years, the whole organism (skin, brain, kidneys, gastrointestinal tract, immune system, bone marrow, heart, etc.) changes and adapts to the diseased liver.
      • Tsochatzis E.A.
      • Bosch J.
      • Burroughs A.K.
      These changes probably portend and prompt the final showdown in the patient´s life, namely the acute decompensating event.
      • Arroyo V.
      • Moreau R.
      • Jalan R.
      Acute-on-Chronic liver failure.
      The microbiota, including bacteria (bacteriome), but also fungi (fungome) and viruses (virome), are also known to change during the development and progression of cirrhosis.
      • Tilg H.
      • Cani P.D.
      • Mayer E.A.
      Gut microbiome and liver diseases.
      Several factors appear to affect the microbiota including the aetiology of liver disease, such as alcohol and diet (in the case of non-alcoholic fatty liver disease [NAFLD]).
      • Tripathi A.
      • Debelius J.
      • Brenner D.A.
      • Karin M.
      • Loomba R.
      • Schnabl B.
      • et al.
      The gut-liver axis and the intersection with the microbiome.
      CLD primarily reduces bile flow and causes cholestasis, which impairs the enterohepatic circulation and majorly affects the microbiota.
      • Tilg H.
      • Cani P.D.
      • Mayer E.A.
      Gut microbiome and liver diseases.
      ,
      • Tripathi A.
      • Debelius J.
      • Brenner D.A.
      • Karin M.
      • Loomba R.
      • Schnabl B.
      • et al.
      The gut-liver axis and the intersection with the microbiome.
      As CLD progresses, changes in microbiota (dysbiosis) are maintained and further exacerbated, probably by changes in intestinal motility, permeability, barrier function towards the lymphatic and blood compartment, portal hypertension and the immune system.
      • Albillos A.
      • de Gottardi A.
      • Rescigno M.
      The gut-liver axis in liver disease: pathophysiological basis for therapy.
      Yet the role of the microbiota seems to be pivotal in patients with decompensated cirrhosis, as many decompensating events are related to microbes or their interaction with the host.
      • Trebicka J.
      • Reiberger T.
      • Laleman W.
      Gut-liver Axis links portal hypertension to acute-on-chronic liver failure.
      To describe the role of microbiota in cirrhosis and its role in decompensation, we first need to introduce acute decompensation (AD) and its most severe form acute-on-chronic liver failure (ACLF). AD defines the acute development of ascites, hepatic encephalopathy, gastrointestinal haemorrhage or bacterial infections, or any combination of these.
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      PREDICT identifies precipitating events associated with clinical course of acutely decompensated cirrhosis.
      AD is a sudden and fast deterioration in health that is associated with dysfunction of the liver and extrahepatic organs, especially the kidneys and brain.
      • Arroyo V.
      • Moreau R.
      • Jalan R.
      Acute-on-Chronic liver failure.
      The most severe form of AD is termed ACLF, which is associated with extremely high mortality approaching 40% at 28 days.
      • Arroyo V.
      • Moreau R.
      • Jalan R.
      Acute-on-Chronic liver failure.
      ,
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Intestinal bacterial overgrowth and dysbiosis occur during progression of chronic liver disease and mutually drive and are aggravated by decompensation.
      Recently, the phenotype of patients with AD without ACLF, was characterised in the PREDICT study, which defined 3 separate groups of patients with AD: i) those with pre-ACLF, who present with high systemic inflammation, will develop ACLF in the following 90 days, and have very high mortality;
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      those with unstable decompensated cirrhosis, who will develop complications mainly due to severe portal hypertension (large ascites or bleeding requiring TIPS [transjugular intrahepatic portosystemic shunt]) and will be readmitted to the hospital <90 days after their index acute decompensation episode;
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      and the majority of patients with so-called stable decompensated cirrhosis. That said, 10% of patients with stable decompensated cirrhosis died within 1 year, having developed either ACLF or complications of portal hypertension. As highlighted above, different microbiota profiles may either benefit or exacerbate the liver phenotype and thereby precipitate decompensation and influence outcome in these patients. These effects support the rationale of targeting the microbiota using different tools (rifaximin, faecal microbiota transplantation [FMT]) to prevent and treat decompensation in cirrhosis. This is the topic of the current review, wherein we focus on the role of microbiota in the decompensation of patients with cirrhosis, as well as strategies targeting microbiota to prevent or treat decompensation.

      Alteration of the microbiome and its associated changes in cirrhosis

      The large observational prospective studies NACSELD, APASL-AARC, CANONIC and PREDICT identified several events deriving or possibly deriving from the gut microbiota or their products, which precipitate AD and ACLF.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      • Arroyo V.
      • Moreau R.
      • Kamath P.S.
      • Jalan R.
      • Gines P.
      • Nevens F.
      • et al.
      Acute-on-chronic liver failure in cirrhosis.
      • Sarin S.K.
      • Choudhury A.
      Acute-on-chronic liver failure: terminology, mechanisms and management.
      • O'Leary J.G.
      • Reddy K.R.
      • Garcia-Tsao G.
      • Biggins S.W.
      • Wong F.
      • Fallon M.B.
      • et al.
      NACSELD acute-on-chronic liver failure (NACSELD-ACLF) score predicts 30-day survival in hospitalized patients with cirrhosis.
      • Bajaj J.S.
      • Reddy K.R.
      • O'Leary J.G.
      • Vargas H.E.
      • Lai J.C.
      • Kamath P.S.
      • 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.
      Bacterial infection and alcoholic hepatitis are the precipitating events most commonly associated with acute decompensation, with recent data from the PREDICT study demonstrating that either of them (or their combination) account for 90% of identifiable precipitating events.
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      However, even in prospective, very detailed investigations, the precipitating event leading to acute decompensation cannot be determined in almost one-third of patients.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      The microbiota and its metabolites may play a role in these undetermined cases, as shown recently.
      • Bajaj J.S.
      • Reddy K.R.
      • O'Leary J.G.
      • Vargas H.E.
      • Lai J.C.
      • Kamath P.S.
      • 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.
      The question that arises is, which changes in the microbiota during cirrhosis development and progression are relevant for the development of decompensation.
      Changes in the microbiota occur early in the development of CLD, even before detectable liver damage, especially in alcohol-related CLD and NAFLD.
      • Schnabl B.
      • Brenner D.A.
      Interactions between the intestinal microbiome and liver diseases.
      Different studies have shown shifts in the composition of the gut microbiome in different CLDs.
      • Schnabl B.
      • Brenner D.A.
      Interactions between the intestinal microbiome and liver diseases.
      ,
      • Bajaj J.S.
      Alcohol, liver disease and the gut microbiota.
      Yet, one common property of these changes, which is easy to assess, is the massive reduction in microbial diversity upon the development of cirrhosis and the even greater reduction upon decompensation.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in cirrhosis.
      • Bajaj J.S.
      • Betrapally N.S.
      • Gillevet P.M.
      Decompensated cirrhosis and microbiome interpretation.
      In addition to reduced species diversity, bacterial overgrowth occurs in the small bowel, so-called small intestine bacterial overgrowth (SIBO),
      • Bauer T.M.
      • Steinbruckner B.
      • Brinkmann F.E.
      • Ditzen A.K.
      • Schwacha H.
      • Aponte J.J.
      • et al.
      Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis.
      which is partly due to decreased gut motility.
      • Chang C.S.
      • Chen G.H.
      • Lien H.C.
      • Yeh H.Z.
      Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis.
      It is suspected that because of the sympathetic activation required to regulate the tone of dilated splanchnic vessels in cirrhosis, the motility of the gut is decreased, which leads to an increase in contact time of bacteria and thereby to fermentation changes in the luminal content.
      • Fukui H.
      • Wiest R.
      Changes of intestinal functions in liver cirrhosis.
      This may lead to changes in the microbial metabolites, which may affect the epithelial cells and the liver itself. Specifically, formation of short-chain fatty acids (SCFAs) seems to be crucial in the homeostasis of the epithelial layer,
      • Peng L.
      • Li Z.R.
      • Green R.S.
      • Holzman I.R.
      • Lin J.
      Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers.
      while different SCFAs may play a pathogenetic role in inflammation
      • Park J.
      • Kim M.
      • Kang S.G.
      • Jannasch A.H.
      • Cooper B.
      • Patterson J.
      • et al.
      Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway.
      and the liver disease itself.
      • Chu H.
      • Duan Y.
      • Yang L.
      • Schnabl B.
      Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease.
      Despite SIBO and decreased richness, several studies have identified cirrhosis-specific profiles of the microbiota.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      ,
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in cirrhosis.
      ,
      • Chen Y.
      • Yang F.
      • Lu H.
      • Wang B.
      • Chen Y.
      • Lei D.
      • et al.
      Characterization of fecal microbial communities in patients with cirrhosis.
      ,
      • Oh T.G.
      • Kim S.M.
      • Caussy C.
      • Fu T.
      • Guo J.
      • Bassirian S.
      • et al.
      A universal gut-microbiome-derived signature predicts cirrhosis.
      These profiles seem to be predominated by Fusobacteria, Proteobacteria, Enterococcaceae and Streptococacceae with relative decreases of Bacteroidetes, Ruminococcus, Roseburia, Veillonellaceae and Lachnospiraceae independent of cirrhosis aetiology.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      ,
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in cirrhosis.
      ,
      • Chen Y.
      • Yang F.
      • Lu H.
      • Wang B.
      • Chen Y.
      • Lei D.
      • et al.
      Characterization of fecal microbial communities in patients with cirrhosis.
      ,
      • Oh T.G.
      • Kim S.M.
      • Caussy C.
      • Fu T.
      • Guo J.
      • Bassirian S.
      • et al.
      A universal gut-microbiome-derived signature predicts cirrhosis.
      The similarity of the microbiome changes in cirrhosis is quite important, since it demonstrates that the cirrhotic liver per se can impair the microbiota. This occurs when the aetiological agent has direct contact with the microbiome (alcohol-related or NASH-cirrhosis) and when the aetiology of the liver disease is not directly linked with the microbiome (hepatitis B and C). In addition to the increase in potential pathogenic taxa in cirrhosis, there is also a decrease in potential beneficial taxa, such as Akkermansia abundance, which was found to be decreased in patients with different liver disease aetiologies.
      • Addolorato G.
      • Ponziani F.R.
      • Dionisi T.
      • Mosoni C.
      • Vassallo G.A.
      • Sestito L.
      • et al.
      Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol-associated liver disease.
      • Ponziani F.R.
      • Putignani L.
      • Paroni Sterbini F.
      • Petito V.
      • Picca A.
      • Del Chierico F.
      • et al.
      Influence of hepatitis C virus eradication with direct-acting antivirals on the gut microbiota in patients with cirrhosis.
      • Ponziani F.R.
      • Bhoori S.
      • Castelli C.
      • Putignani L.
      • Rivoltini L.
      • Del Chierico F.
      • et al.
      Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease.
      As mentioned, these profound changes in the microbiome are at least partly related to the liver disease itself rather than the direct effects of the aetiologic factor. This was confirmed by at least partial restoration of the gut microbiota after liver transplantation.
      • Bajaj J.S.
      • Fagan A.
      • Sikaroodi M.
      • White M.B.
      • Sterling R.K.
      • Gilles H.
      • et al.
      Liver transplant modulates gut microbial dysbiosis and cognitive function in cirrhosis.
      Another reason for the dysbiotic composition of the cirrhotic microbiota is impaired enterohepatic circulation. Cirrhosis is associated with decreased secretion of primary bile acids into the gut lumen.
      • Kakiyama G.
      • Pandak W.M.
      • Gillevet P.M.
      • Hylemon P.B.
      • Heuman D.M.
      • Daita K.
      • et al.
      Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.
      The secondary bile acids produced by bacteria are in turn decreased.
      • Kakiyama G.
      • Pandak W.M.
      • Gillevet P.M.
      • Hylemon P.B.
      • Heuman D.M.
      • Daita K.
      • et al.
      Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.
      • Ridlon J.M.
      • Alves J.M.
      • Hylemon P.B.
      • Bajaj J.S.
      Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship.
      • Kakiyama G.
      • Hylemon P.B.
      • Zhou H.
      • Pandak W.M.
      • Heuman D.M.
      • Kang D.J.
      • et al.
      Colonic inflammation and secondary bile acids in alcoholic cirrhosis.
      Moreover, bile acids are involved in the uptake of fat and fat-soluble proteins, and thereby have a tremendous influence on metabolism and possibly coagulation (Vitamin K-dependent coagulation factors) as well. Therefore, signs of malnutrition, including increased international normalised ratio, may be at least partly mediated by decreased primary and secondary bile acid synthesis and uptake in cirrhosis. Bile acids are also strong modulators of the farnesoid X receptor (FXR)-axis, which is crucial in the homeostasis of the epithelial barrier and the gut-vascular barrier,
      • Wang Y.D.
      • Chen W.D.
      • Moore D.D.
      • Huang W.
      FXR: a metabolic regulator and cell protector.
      ,
      • Sorribas M.
      • Jakob M.O.
      • Yilmaz B.
      • Li H.
      • Stutz D.
      • Noser Y.
      • et al.
      FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.
      the impairment of which facilitates bacterial translocation. FXR has also been identified as a good target for treatment in cirrhosis, with decreased bacterial translocation following its agonism.
      • Verbeke L.
      • Farre R.
      • Verbinnen B.
      • Covens K.
      • Vanuytsel T.
      • Verhaegen J.
      • et al.
      The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.
      ,
      • Ubeda M.
      • Lario M.
      • Munoz L.
      • Borrero M.J.
      • Rodriguez-Serrano M.
      • Sanchez-Diaz A.M.
      • et al.
      Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats.
      Bacterial translocation is also increased by structural changes to the intestinal epithelial layer, resulting from an increase in portal pressure (reviewed elsewhere
      • Fukui H.
      • Wiest R.
      Changes of intestinal functions in liver cirrhosis.
      ) and the changes in the type of resident and infiltrating immune cells.
      • Ubeda M.
      • Lario M.
      • Munoz L.
      • Borrero M.J.
      • Rodriguez-Serrano M.
      • Sanchez-Diaz A.M.
      • et al.
      Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats.
      ,
      • Munoz L.
      • Borrero M.J.
      • Ubeda M.
      • Conde E.
      • Del Campo R.
      • Rodriguez-Serrano M.
      • et al.
      Intestinal immune dysregulation driven by dysbiosis promotes barrier disruption and bacterial translocation in rats with cirrhosis.
      The changes in the gut-associated immune system include decreased synthesis and release of antibacterial peptides, IgA, defensins and hypo- or achlorhydria.
      • Shindo K.
      • Machida M.
      • Miyakawa K.
      • Fukumura M.
      A syndrome of cirrhosis, achlorhydria, small intestinal bacterial overgrowth, and fat malabsorption.
      • Pelletier G.
      • Briantais M.J.
      • Buffet C.
      • Pillot J.
      • Etienne J.P.
      Serum and intestinal secretory IgA in alcoholic cirrhosis of the liver.
      • Teltschik Z.
      • Wiest R.
      • Beisner J.
      • Nuding S.
      • Hofmann C.
      • Schoelmerich J.
      • et al.
      Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense.
      Bacterial translocation, which is facilitated by the aforementioned changes to the microbiota and its functions, may then induce decompensation of cirrhosis (Fig. 1).
      Acute decompensation, and especially its most severe forms, pre-ACLF and ACLF, are mainly precipitated by proven bacterial infection and/or severe alcoholic hepatitis, but also by bacterial translocation due to impaired intestinal barrier.
      Figure thumbnail gr1
      Fig. 1Microbiome and decompensated cirrhosis. Changes during progression of cirrhosis affect to a large extent the microbiota. Especially alcohol and diet, decreased bile flow, portal hypertension and activation of sympathetic nervous system impair gut motility and permeability, lead to decreased diversity, but increased bacterial load and bacterial overgrowth, imbalance in bacterial species and finally increased bacterial translocation. SCFA, short-chain fatty acid.

      Microbiome changes and development of decompensation

      Cirrhosis is associated with systemic inflammation as evidenced by increased systemic levels of oxidative stress, inflammatory cytokines, and markers of activated neutrophils and macrophages.
      • 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.
      • Claria J.
      • Stauber R.E.
      • Coenraad M.J.
      • Moreau R.
      • Jalan R.
      • Pavesi M.
      • et al.
      Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
      • Sole C.
      • Sola E.
      • Morales-Ruiz M.
      • Fernandez G.
      • Huelin P.
      • Graupera I.
      • et al.
      Characterization of inflammatory response in acute-on-chronic liver failure and relationship with prognosis.
      • Gronbaek H.
      • Rodgaard-Hansen S.
      • Aagaard N.K.
      • Arroyo V.
      • Moestrup S.K.
      • Garcia E.
      • et al.
      Macrophage activation markers predict mortality in patients with cirrhosis without or with acute-on-chronic liver failure (ACLF).
      • Trebicka J.
      • Amoros A.
      • Pitarch C.
      • Titos E.
      • Alcaraz-Quiles J.
      • Schierwagen R.
      • et al.
      Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis.
      • Monteiro S.
      • Grandt J.
      • Uschner F.E.
      • Kimer N.
      • Madsen J.L.
      • Schierwagen R.
      • et al.
      Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.
      • Praktiknjo M.
      • Monteiro S.
      • Grandt J.
      • Kimer N.
      • Madsen J.L.
      • Werge M.P.
      • et al.
      Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure.
      The degree of systemic inflammation increases with liver disease severity, infections,
      • Michelena J.
      • Altamirano J.
      • Abraldes J.G.
      • Affo S.
      • Morales-Ibanez O.
      • Sancho-Bru P.
      • et al.
      Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.
      renal failure,
      • Navasa M.
      • Follo A.
      • Filella X.
      • Jimenez W.
      • Francitorra A.
      • Planas R.
      • et al.
      Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
      hepatic encephalopathy
      • Bajaj J.S.
      • Ridlon J.M.
      • Hylemon P.B.
      • Thacker L.R.
      • Heuman D.M.
      • Smith S.
      • et al.
      Linkage of gut microbiome with cognition in hepatic encephalopathy.
      and ACLF.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Gut-derived pathogen-associated molecular patterns are major inducers of systemic inflammation; they translocate through a disrupted gut barrier from the intestinal lumen via the portal vein to the liver and systemic circulation. Decompensation is characterised not only by worsening of this increased paracellular intestinal permeability, but also by translocation of viable bacteria. Bacteria likely translocate by transcytosis from the gut to the extraintestinal space and organs ,
      • Cirera I.
      • Bauer T.M.
      • Navasa M.
      • Vila J.
      • Grande L.
      • Taura P.
      • et al.
      Bacterial translocation of enteric organisms in patients with cirrhosis.
      where they cause infections (such as spontaneous bacterial peritonitis) and contribute to systemic inflammation, arterial vasodilation and organ failure.
      • 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.
      ,
      • Wiest R.
      • Lawson M.
      • Geuking M.
      Pathological bacterial translocation in cirrhosis.
      ,
      • Frances R.
      • Zapater P.
      • Gonzalez-Navajas J.M.
      • Munoz C.
      • Cano R.
      • Moreu R.
      • et al.
      Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis.
      Fungal infections in a cirrhotic inpatient cohort are associated with higher ACLF development rate and worse 30-day survival.
      • Bajaj J.S.
      • Reddy R.K.
      • Tandon P.
      • Wong F.
      • Kamath P.S.
      • Biggins S.W.
      • et al.
      Prediction of fungal infection development and their impact on survival using the NACSELD cohort.
      Several mechanisms contribute to this additional layer of gut barrier dysfunction, which are all closely connected to intestinal dysbiosis. While intestinal bacterial overgrowth and changes in microbiota composition are common in patients with cirrhosis,
      • Bauer T.M.
      • Steinbruckner B.
      • Brinkmann F.E.
      • Ditzen A.K.
      • Schwacha H.
      • Aponte J.J.
      • et al.
      Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis.
      dysbiosis worsens during decompensation. Faecal microbial gene richness, microbial richness and species diversity are decreased in patients with decompensated cirrhosis compared with compensated cirrhosis.
      • Shao L.
      • Ling Z.
      • Chen D.
      • Liu Y.
      • Yang F.
      • Li L.
      Disorganized gut microbiome contributed to liver cirrhosis progression: a meta-omics-based study.
      A significant reduction in faecal Clostridiales XIV, Ruminococcaceae and Lachnospiraceae with a significant increase in pathogenic taxa such as Enterococcaceae, Staphylococcaceae and Enterobacteriaceae at the family level was found in patients with cirrhosis and worsening liver disease.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      Using metagenomic sequencing, faecal Alistipes indistinctus, Bilophila wadsworthia, Bilophila sp. 4_1_30, Ruminococcus champanellensis, Tannerella sp. 6_1_58FAA_CT1, Clostridium botulinum, Clostridium leptum, Clostridium methylpentosum and Clostridium sp. MSTE9 were lower, while Veillonella atypica, Veillonella sp. ACP1, Veillonella dispar, and Veillonella sp. oral taxon 158 were higher at the species level in patients with decompensated cirrhosis compared with compensated cirrhosis.
      • Shao L.
      • Ling Z.
      • Chen D.
      • Liu Y.
      • Yang F.
      • Li L.
      Disorganized gut microbiome contributed to liver cirrhosis progression: a meta-omics-based study.
      Changes in microbiota translate into functional metabolic differences.
      • Shao L.
      • Ling Z.
      • Chen D.
      • Liu Y.
      • Yang F.
      • Li L.
      Disorganized gut microbiome contributed to liver cirrhosis progression: a meta-omics-based study.
      Bacterial pathogenicity can be mediated via virulence factors. The toxin cytolysin, secreted by Enterococcus faecalis in the intestinal microbiota, associates with worse clinical outcomes and mortality in patients with alcoholic hepatitis.
      • Duan Y.
      • Llorente C.
      • Lang S.
      • Brandl K.
      • Chu H.
      • Jiang L.
      • et al.
      Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.
      While fungal dysbiosis and decreased fungal diversity is similar between patients with early stages of alcohol-associated liver disease and alcoholic hepatitis, the systemic immune response to fungal products is associated with increased mortality in patients with alcoholic hepatitis, likely because of impaired gut barrier function.
      • Lang S.
      • Duan Y.
      • Liu J.
      • Torralba M.G.
      • Kuelbs C.
      • Ventura-Cots M.
      • et al.
      Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis.
      Candidalysin, a secreted exotoxin of Candida albicans, is associated with liver disease severity and mortality in patients with alcoholic hepatitis.
      • Chu H.
      • Duan Y.
      • Lang S.
      • Jiang L.
      • Wang Y.
      • Llorente C.
      • et al.
      The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease.
      Cytolysin and candidalysin can directly damage primary hepatocytes, which might directly contribute to worsening liver function. Increased viral diversity was observed in faecal samples from patients with alcohol-associated liver disease, with the most significant changes in samples from patients with alcoholic hepatitis. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity and 90-day mortality in patients with alcoholic hepatitis.
      • Jiang L.
      • Lang S.
      • Duan Y.
      • Zhang X.
      • Gao B.
      • Chopyk J.
      • et al.
      Intestinal virome in patients with alcoholic hepatitis.
      In a recent study of outpatients with cirrhosis, bacteriophages that differentially associated with bacteria over the course of disease were less likely than bacteria to predict 90-day hospitalisations. That said, phages focused on urease-producing Streptococcus were linked with the action of rifaximin in patients with cirrhosis and hepatic encephalopathy.
      • Bajaj J.
      • Sikaroodi M.
      • Shamsaddini A.
      • Henseler Z.
      • Santiago-Rodriguez T.
      • Acharya C.
      • et al.
      Interaction of bacterial metagenome and virome in patients with cirrhosis and hepatic encephalopathy.
      How changes in the intestinal virome contribute to hepatic decompensation is not known.
      Dysbiosis causes intestinal inflammation, which in turn contributes to gut barrier dysfunction and pathological bacterial translocation.
      • Chen P.
      • Starkel P.
      • Turner J.R.
      • Ho S.B.
      • Schnabl B.
      Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice.
      Impaired antimicrobial activity in the intestine is associated with translocation of viable bacteria to the mesenteric lymph nodes in rats with cirrhosis and ascites.
      • Teltschik Z.
      • Wiest R.
      • Beisner J.
      • Nuding S.
      • Hofmann C.
      • Schoelmerich J.
      • et al.
      Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense.
      Intestinal immune surveillance improves following intestinal decontamination with antibiotics in experimental cirrhosis, indicating that the bacterial microbiota contributes to exhausting the mucosal immune response during decompensation.
      • Munoz L.
      • Jose Borrero M.
      • Ubeda M.
      • Lario M.
      • Diaz D.
      • Frances R.
      • et al.
      Interaction between intestinal dendritic cells and bacteria translocated from the gut in rats with cirrhosis.
      Cholestasis causes a reflux of bile acids from the hepatocytes into the circulation and decreases bile flow into the biliary system and the intestine. Lower bile flow and less intestinal bile acids will further increase bacterial overgrowth and affect the composition of the gut microbiota during decompensation. Vice versa, dysbiosis changes intestinal bile acid metabolism and reduces the conversion of primary into secondary bile acids, which in turn can affect gut barrier function by modulating FXR activity.
      • Ubeda M.
      • Lario M.
      • Munoz L.
      • Borrero M.J.
      • Rodriguez-Serrano M.
      • Sanchez-Diaz A.M.
      • et al.
      Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats.
      ,
      • Hartmann P.
      • Hochrath K.
      • Horvath A.
      • Chen P.
      • Seebauer C.T.
      • Llorente C.
      • et al.
      Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice.
      Patients with advanced cirrhosis had the lowest total faecal bile acids, with a reduced ratio of secondary to primary bile acids compared to those with early cirrhosis and controls, while serum primary bile acids were higher in those with advanced cirrhosis than in those with early cirrhosis or controls.
      • Kakiyama G.
      • Pandak W.M.
      • Gillevet P.M.
      • Hylemon P.B.
      • Heuman D.M.
      • Daita K.
      • et al.
      Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.
      Total and conjugated serum bile acids were shown to correlate positively with disease severity (model for end-stage liver disease [MELD]) in patients with alcoholic hepatitis.
      • Brandl K.
      • Hartmann P.
      • Jih L.J.
      • Pizzo D.P.
      • Argemi J.
      • Ventura-Cots M.
      • et al.
      Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.
      In viral hepatitis, the mechanisms may be different. In these patients hepatic injury may lead to AD and ACLF via danger-associated molecular patterns.
      • Shi Y.
      • Yang Y.
      • Hu Y.
      • Wu W.
      • Yang Q.
      • Zheng M.
      • et al.
      Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.
      ,
      • Li H.
      • Chen L.Y.
      • Zhang N.N.
      • Li S.T.
      • Zeng B.
      • Pavesi M.
      • et al.
      Characteristics, diagnosis and prognosis of acute-on-chronic liver failure in cirrhosis associated to hepatitis B.
      Indeed, circulating bacterial DNA (a measure of bacterial translocation) was significantly increased in patients with HBV-related ACLF and correlated with inflammatory markers.
      • Zhang Y.
      • Zhao R.
      • Shi D.
      • Sun S.
      • Ren H.
      • Zhao H.
      • et al.
      Characterization of the circulating microbiome in acute-on-chronic liver failure associated with hepatitis B.
      Taken together, worsening liver disease initiates a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins can directly cause hepatocyte death and worsening of liver function. Dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and multi-organ failure. (Fig. 2).
      Bacteria and bacterial components are known to contribute to acute decompensation in cirrhosis both through direct hepatotoxicity and indirectly via increased systemic inflammation.
      Figure thumbnail gr2
      Fig. 2Microbiome and hepatic decompensation. Worsening of liver disease initiates a cascade of events with intestinal bacterial overgrowth and dysbiosis as central events. Intestinal dysbiosis contributes to gut barrier function via several mechanisms. Increases in bacterial translocation lead to upregulation of systemic inflammation and infections, vasodilation and contribute to hepatic decompensation and multi-organ failure. Toxins produced by the microbiota can directly cause hepatocyte death and worsening of liver function.

      Lactulose and nutrition as modulators of the gut microbiome

      There are no published data employing untargeted or global culture-independent methodologies to assess the faecal microbiome in healthy individuals receiving lactulose. Lactulose has been shown to increase alpha diversity in healthy mice
      • Zhai S.
      • Zhu L.
      • Qin S.
      • Li L.
      Effect of lactulose intervention on gut microbiota and short chain fatty acid composition of C57BL/6J mice.
      and pigs,
      • Chae J.P.
      • Pajarillo E.A.
      • Oh J.K.
      • Kim H.
      • Kang D.K.
      Revealing the combined effects of lactulose and probiotic enterococci on the swine faecal microbiota using 454 pyrosequencing.
      as well as to increase Veillonellacaeae and Bifidobacteriaceae and to reduce Bacteroidaceae and Fusobacteriaceae in dogs.
      • Ferreira M.D.F.
      • Salavati Schmitz S.
      • Schoenebeck J.J.
      • Clements D.N.
      • Campbell S.M.
      • Gaylor D.E.
      • et al.
      Lactulose drives a reversible reduction and qualitative modulation of the faecal microbiota diversity in healthy dogs.
      The impact of lactulose in ameliorating dysbiosis in patients with cirrhosis is not clear cut. Studies utilising culture-dependent methodologies in patients with cirrhosis and minimal hepatic encephalopathy (HE) show increased Bifidobacterium, Lactobacillus and Bacteriodaceae colonies and reduced Enterobacteriaceae, Enterococcus and yeasts accompanying plasma ammonia reduction, improved psychometric tests and reduced risk of developing overt HE.
      • Ziada D.H.
      • Soliman H.H.
      • El Yamany S.A.
      • Hamisa M.F.
      • Hasan A.M.
      Can Lactobacillus acidophilus improve minimal hepatic encephalopathy? A neurometabolite study using magnetic resonance spectroscopy.
      Furthermore, lactulose leads to a decreased faecal pH with increased aerobic and anaerobic bacterial counts and lactobacilli in patients with cirrhosis without HE.
      • Riggio O.
      • Varriale M.
      • Testore G.P.
      • Di Rosa R.
      • Di Rosa E.
      • Merli M.
      • et al.
      Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients.
      Studies utilising 16S rDNA gene sequencing have failed to substantiate any impact of lactulose on the microbiome of patients with cirrhosis without HE and have reported only subtle changes in patients with HE,
      • Sarangi A.N.
      • Goel A.
      • Singh A.
      • Sasi A.
      • Aggarwal R.
      Faecal bacterial microbiota in patients with cirrhosis and the effect of lactulose administration.
      including after lactulose withdrawal.
      • Bajaj J.S.
      • Gillevet P.M.
      • Patel N.R.
      • Ahluwalia V.
      • Ridlon J.M.
      • Kettenmann B.
      • et al.
      A longitudinal systems biology analysis of lactulose withdrawal in hepatic encephalopathy.
      The effects of dietary habits on clinical outcomes in patients with cirrhosis have been interrogated; for example, cirrhotic and control groups in the United States have been compared to groups from Turkey. The Turkish diet, rich in fermented milk products, coffee, tea, and chocolate, was associated with increased microbial diversity. Furthermore, it was shown that coffee, tea, vegetables, and cereals were protective against 90-day rehospitalisation rates.
      • Bajaj J.S.
      • Idilman R.
      • Mabudian L.
      • Hood M.
      • Fagan A.
      • Turan D.
      • et al.
      Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort.

      Potential therapeutic implications of new targets including

      Faecal transplantation as a promising tool

      The revolving door of hospitalisations, re-hospitalisations, antibiotic and proton pump inhibitor (PPI) use, multiple instrumentations and inadequate dietary intake contribute to continued dysbiosis in cirrhosis.
      • Bajaj J.S.
      • Vargas H.E.
      • Reddy K.R.
      • Lai J.C.
      • O'Leary J.G.
      • Tandon P.
      • et al.
      Association between intestinal microbiota collected at hospital admission and outcomes of patients with cirrhosis.
      Resetting this requires a major shift in the gut ecosystem through FMT. Studies in germ-free and specific-pathogen-free mice have shown that FMT from affected human donors can partly replicate microbial and brain-related injury even without continued exposure to the toxin(s) that caused the liver injury.
      • Kang D.J.
      • Hylemon P.B.
      • Gillevet P.M.
      • Sartor R.B.
      • Betrapally N.S.
      • Kakiyama G.
      • et al.
      Gut microbial composition can differentially regulate bile acid synthesis in humanized mice.
      • Liu R.
      • Kang J.D.
      • Sartor R.B.
      • Sikaroodi M.
      • Fagan A.
      • Gavis E.A.
      • et al.
      Neuroinflammation in murine cirrhosis is dependent on the gut microbiome and is attenuated by fecal transplant.
      • Llopis M.
      • Cassard A.M.
      • Wrzosek L.
      • Boschat L.
      • Bruneau A.
      • Ferrere G.
      • et al.
      Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease.
      FMT has been extensively used to treat Clostridium difficile infections, which are characterised by an acute, major reduction in microbial diversity, unlike cirrhosis where there is a consistent gut-liver axis alteration. After FMT, bile acid moieties recover, indicating functional benefit.
      • Weingarden A.
      • Gonzalez A.
      • Vazquez-Baeza Y.
      • Weiss S.
      • Humphry G.
      • Berg-Lyons D.
      • et al.
      Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection.
      Moreover, when exposed to liver injury, permissive microbiota were more likely to propagate liver damage
      • Llopis M.
      • Cassard A.M.
      • Wrzosek L.
      • Boschat L.
      • Bruneau A.
      • Ferrere G.
      • et al.
      Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease.
      but FMT alone did not lead to cirrhosis.
      The experience with FMT in humans with cirrhosis spans outpatients with compensated cirrhosis and alcohol use disorder (AUD), outpatients with HE on rifaximin and lactulose, and inpatients with alcoholic hepatitis
      • Bajaj J.S.
      • Khoruts A.
      Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis.
      (Table 1). Moreover, it has been successfully used to treat concomitant C. difficile.
      • Pringle P.L.
      • Soto M.T.
      • Chung R.T.
      • Hohmann E.
      Patients with cirrhosis require more fecal microbiota capsules to cure refractory and recurrent Clostridium difficile infections.
      • Meighani A.
      • Alimirah M.
      • Ramesh M.
      • Salgia R.
      Fecal microbiota transplantation for clostridioides difficile infection in patients with chronic liver disease.
      • Cheng Y.W.
      • Alhaffar D.
      • Saha S.
      • Khanna S.
      • Bohm M.
      • Phelps E.
      • et al.
      Fecal microbiota transplantation is safe and effective in patients with clostridioides difficile infection and cirrhosis.
      Several more studies are being planned or are in process to leverage this exciting approach.
      • Hatton G.B.
      • Ran S.
      • Tranah T.H.
      • Shawcross D.L.
      Lessons learned from faecal microbiota transplantation in cirrhosis.
      Most current studies are small-scale, illustrating the first important step of any investigation, i.e. safety. Of note, there are no data for patients with complications (e.g. variceal bleeding) or decompensated patients. All studies demonstrate that this approach is safe even long-term and does not result in a greater incidence of infections if donors are screened according to guidelines.
      • DeFilipp Z.
      • Bloom P.P.
      • Torres Soto M.
      • Mansour M.K.
      • Sater M.R.A.
      • Huntley M.H.
      • et al.
      Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant.
      When these protocols were not followed, donor-derived infections were easily transmitted to immunosuppressed patients.
      • DeFilipp Z.
      • Bloom P.P.
      • Torres Soto M.
      • Mansour M.K.
      • Sater M.R.A.
      • Huntley M.H.
      • et al.
      Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant.
      Therefore, it is critical to select donors appropriately and in the era of COVID-19, ensuring that FMT is safe is even more important
      • Ianiro G.
      • Mullish B.H.
      • Kelly C.R.
      • Kassam Z.
      • Kuijper E.J.
      • Ng S.C.
      • et al.
      Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic.
      ,
      • Kassam Z.
      • Dubois N.
      • Ramakrishna B.
      • Ling K.
      • Qazi T.
      • Smith M.
      • et al.
      Donor screening for fecal microbiota transplantation.
      (See Table 2).
      Table 1Studies analysing FMT in cirrhosis.
      Study and designSamples/groups comparedRoute and duration of FMTFindings and significanceLimitations
      Alcohol-related disorders
      Bajaj et al. Hepatology 2020
      • Bajaj J.S.
      • Gavis E.A.
      • Fagan A.
      • Wade J.B.
      • Thacker L.R.
      • Fuchs M.
      • et al.
      A randomized clinical trial of fecal microbiota transplant for alcohol use disorder.
      Men with AUD and cirrhosis who were not successful on abstinence using current therapies
      • One-time enema vs. placebo
      • Reduced short-term alcohol craving and consumption with higher SCFA in FMT
      • Lower AUD-related hospitalisations long-term in FMT vs. placebo
      Reduction of addictive behaviour resulting in long-term reduction in AUD-related hospitalisations over 6 months
      • Small-scale
      • All men
      Phillips et al. CGH 2017
      • Philips C.A.
      • Pande A.
      • Shasthry S.M.
      • Jamwal K.D.
      • Khillan V.
      • Chandel S.S.
      • et al.
      Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study.
      Men with steroid resistant alcohol-related hepatitis
      • One week of daily NJT FMT from many donors
      • One year open-label study with historical controls
      Higher survival vs. controls
      • Open-label
      • Historical controls
      • All men
      Phillips et al. Indian J Gastro 2018
      • Philips C.A.
      • Phadke N.
      • Ganesan K.
      • Ranade S.
      • Augustine P.
      Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis.
      Men with alcohol-related hepatitis
      • One week of daily NJT FMT from many donors vs. standard therapy
      • Three-month follow-up
      3-month survival higher in FMT group, while 1-month survival was similar
      • Open-label
      • Small numbers
      • All men
      Cirrhosis
      Kao et al. Hepatol 2016
      • Kao D.
      • Roach B.
      • Park H.
      • Hotte N.
      • Madsen K.
      • Bain V.
      • et al.
      Fecal microbiota transplantation in the management of hepatic encephalopathy.
      One patient with HE
      • 1 FMT via colonoscopy followed by 3 weekly enemas
      • Safe and well tolerated with improvement in cognitive function
      Case report of FMT in cirrhosis with brain function improvement
      • Case report
      Bajaj et al. Hepatol 2017 and 2018
      • Bajaj J.S.
      • Kakiyama G.
      • Savidge T.
      • Takei H.
      • Kassam Z.A.
      • Fagan A.
      • et al.
      Antibiotic-associated disruption of microbiota composition and function in cirrhosis is restored by fecal transplant.
      ,
      • Bajaj J.S.
      • Kassam Z.
      • Fagan A.
      • Gavis E.A.
      • Liu E.
      • Cox I.J.
      • et al.
      Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial.
      20 HE patients on lactulose and rifaximin
      • One 90 ml of enema after 5 days of broad-spectrum antibiotics
      • Safe and well tolerated, improvement in hospitalisations, dysbiosis and SCFAs post antibiotics after FMT
      First randomised trial to study this in cirrhosis and HE and under Investigational new drug under FDA
      • Small-scale
      • Antibiotics +FMT rather than FMT alone
      Mehta et al. Indian J Gastro 2018
      • Mehta R.
      • Kabrawala M.
      • Nandwani S.
      • Kalra P.
      • Patel C.
      • Desai P.
      • et al.
      Preliminary experience with single fecal microbiota transplant for treatment of recurrent overt hepatic encephalopathy-A case series.


      Case series
      10 HE patients open-label
      • One FMT via colonoscopy
      • Sustained clinical response at week 20 in 6 patients
      Further evidence about safety and potential efficacy
      • Open-label case series
      Bajaj et al. Hepatology and JCI Insight 2019
      • Bajaj J.S.
      • Salzman N.H.
      • Acharya C.
      • Sterling R.K.
      • White M.B.
      • Gavis E.A.
      • et al.
      Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial.
      ,
      • Bajaj J.S.
      • Salzman N.
      • Acharya C.
      • Takei H.
      • Kakiyama G.
      • Fagan A.
      • et al.
      Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis.
      20 HE patients on lactulose and rifaximin
      • 15 capsules of FMT vs. placebo once
      • Brain function improved and outcomes got better in those with secondary BA formation
      Oral capsular FMT is also safe in HE and success can be linked to secondary BA formation.
      • Small numbers
      AUD, alcohol use disorder; BA, bile acid; FMT, faecal microbiota transplantation; HE, hepatic encephalopathy; NJT, nasojejunal tube; SCFA, short-chain fatty acid.
      Table 2Selected studies of rifaximin to reduce hepatic decompensation and improve outcomes.
      Study and designSamples/groups comparedRoute and duration of therapyFindings and significanceLimitations
      Bass N et al. NEJM 2010;362(12):1071-81
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • Poordad F.
      • Neff G.
      • Leevy C.B.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      299 patients with cirrhosis with 2 or more overt HE episodes in the preceding 6-months.Rifaximin 550 mg twice daily vs. placebo for 6 months. 91% of patients were on concomitant lactulose.Rifaximin significantly reduced risk of HE, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% CI 0.28–0.64; p <0.001). A breakthrough episode of HE occurred in 22.1% of patients on rifaximin, as compared with 45.9% of patients on placebo. 13.6% of the patients on rifaximin group had a hospitalisation involving HE, as compared with 22.6% of patients on placebo, hazard ratio of 0.50 (95% CI 0.29–0.87; p = 0.01).MELD score 25 or less
      Bajaj JS et al. PLoS One 2013;8(4):e60042
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • Hylemon P.B.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      20 patients with cirrhosis and minimal HE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics and faecal microbiome assessment (16S rRNA) pre- and post-rifaximin.Rifaximin 550 mg twice daily for 8-weeksRifaximin improved cognitive function and endotoxemia accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance.-
      Orr JR et al. Liver Int. 2016;36(9):1295-303.
      • Orr J.G.
      • Currie C.J.
      • Berni E.
      • Goel A.
      • Moriarty K.J.
      • Sinha A.
      • et al.
      The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-alpha.
      326 patients in 10 UK centres.Patients treated with rifaximin 550 mg twice daily. Data on hospital resource utilisation collected 12-months pre- and post-rifaximin therapy.Initiation of treatment with rifaximin-α was associated with a marked reduction in the number of hospital admissions and hospital length of stay.Retrospective study
      Goel A et al. Aliment Pharmacol Ther. 2017;46(11-12):1029-36.
      • Goel A.
      • Rahim U.
      • Nguyen L.H.
      • Stave C.
      • Nguyen M.H.
      Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis.
      Five studies with 555 patients (295 rifaximin, 260 systemic antibiotics) compared rifaximin with systemic antibiotics.Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis.Rifaximin reduced the risk of SBP by 47% compared to no antibiotics for primary prophylaxis and by 74% compared to systemic antibiotics for secondary prophylaxis.Systematic review with meta-analysis
      Ibrahim ES et al. Eur J Gastroenterol Hepatol. 2017;29(11):1247-50
      • Ibrahim E.S.
      • Alsebaey A.
      • Zaghla H.
      • Moawad Abdelmageed S.
      • Gameel K.
      • Abdelsameea E.
      Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome.
      80 patients with cirrhosis and ascites.Randomised to rifaximin 550 mg twice daily for 12 weeks or standard of care.Hepatorenal syndrome developed more in the control group than the rifaximin group [9 (22.5%) vs. 2 (5%); p = 0.048]No placebo
      Salehi S et al. Aliment Pharmacol Ther. 2019;50(4):435-41.
      • Salehi S.
      • Tranah T.H.
      • Lim S.
      • Heaton N.
      • Heneghan M.
      • Aluvihare V.
      • et al.
      Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list.
      622 patients listed for transplantation; 101 had HEOutcomes of patients treated with rifaximin 550 mg twice daily vs. those who were naïve.Patients on transplant waiting list treated with rifaximin had reduced all-cause admissions, episodes of spontaneous bacterial peritonitis and variceal bleeding. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in average days to readmission (adjusted effect estimate 71, 95% CI 3-140 days).Retrospective study
      HE, hepatic encephalopathy; MELD, model for end-stage liver disease; SBP, spontaneous bacterial peritonitis.
      As found in trials for C. difficile, FMT did not dramatically change the recipient’s microbial composition or diversity.
      • Weingarden A.R.
      • Chen C.
      • Bobr A.
      • Yao D.
      • Lu Y.
      • Nelson V.M.
      • et al.
      Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.
      Rather functional changes focused on bile acids, SCFAs and other metabolites were found.
      • Bajaj J.S.
      • Kakiyama G.
      • Savidge T.
      • Takei H.
      • Kassam Z.A.
      • Fagan A.
      • et al.
      Antibiotic-associated disruption of microbiota composition and function in cirrhosis is restored by fecal transplant.
      ,
      • Bajaj J.S.
      • Salzman N.H.
      • Acharya C.
      • Sterling R.K.
      • White M.B.
      • Gavis E.A.
      • et al.
      Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial.
      Currently published trials are not powered for efficacy but nonetheless showed results that support the development and further refinement of FMT.
      Hepatic encephalopathy: 1 case report, 1 case series and 2 small randomised controlled trials using enema, colonoscopy, and capsules have shown the safety of FMT. In studies that assessed cognition, FMT was shown to be associated with more frequent improvements than placebo/standard of care. Also, there were trends towards lower adverse events in the FMT compared to no-FMT group.
      Alcohol use disorder: in a double-blind, placebo-controlled randomised clinical trial of men with AUD who had failed several attempts at pharmacological or behavioural therapy for abstinence, one-time enema FMT was safe over 6 months. There was a short-term reduction in alcohol craving and consumption accompanied by better microbial diversity and SCFA production in patients who underwent FMT. Over the long-term, AUD-related serious adverse events were significantly reduced in patients randomised to FMT (compared to placebo).
      Alcohol-related hepatitis: the safety and potential benefit of FMT (compared to historical controls) was observed in steroid-ineligible patients over 1 year, while another open-label trial confirmed the safety of FMT.
      The next steps are (a) defining efficacy (b) dose-response, (c) route of administration and (d) which microbe(s) are essential for potential beneficial impact. The risks and benefits of FMT must be balanced against the potential risks or absence of a viable therapeutic alternative. There should be an equipoise when employing FMT for cirrhosis. Given that the underlying liver aetiology also needs to be treated, it is important to continue efforts towards correcting the aetiology while pursuing FMT.

      Antibiotics in cirrhosis: A double-edged sword

      Perturbations in the gut microbiome underpin the increased susceptibility of patients with cirrhosis to the development of infections, which may be asymptomatic in up to 50% of cases.
      • Borzio M.
      • Salerno F.
      • Piantoni L.
      • Cazzaniga M.
      • Angeli P.
      • Bissoli F.
      • et al.
      Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study.
      Bacterial translocation is a significant driver of cirrhosis-associated immune dysfunction, although the mechanisms by which intestinal dysbiosis drives immune cell dysfunction remain poorly characterised.
      • Cirera I.
      • Bauer T.M.
      • Navasa M.
      • Vila J.
      • Grande L.
      • Taura P.
      • et al.
      Bacterial translocation of enteric organisms in patients with cirrhosis.
      ,
      • Albillos A.
      • Lario M.
      • Alvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      As infection is a potent precipitant of decompensating events, ACLF, and contributes to high mortality, patients are frequently prescribed broad-spectrum antibiotics.
      • Fernandez J.
      • Acevedo J.
      • Wiest R.
      • Gustot T.
      • Amoros A.
      • Deulofeu C.
      • et al.
      Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
      ,
      • Fernandez J.
      • Prado V.
      • Trebicka J.
      • Amoros A.
      • Gustot T.
      • Wiest R.
      • et al.
      Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe.
      Furthermore, approximately 25% of all patients with cirrhosis are on long-term antibiotics for the primary and secondary prophylaxis of spontaneous bacterial peritonitis (SBP)
      European Association for the Study of the Liver
      Electronic address eee, clinical practice guideline panel C, panel m, representative EGB. EASL clinical practice guidelines: drug-induced liver injury.
      and to prevent the recurrence of overt HE.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • Cordoba J.
      • Ferenci P.
      • Mullen K.D.
      • et al.
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American association for the study of liver diseases and the European association for the study of the liver.
      Whilst life-saving on the one hand, antibiotics are very much a double-edged sword, exacerbating pre-existing gut dysbiosis, augmenting disruption of the normally symbiotic population of intestinal bacteria and potentially predisposing to further opportunistic infections and SIBO.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      • Francino M.P.
      Antibiotics and the human gut microbiome: dysbiosesand accumulation of resistances.
      • Bajaj J.S.
      • Liu E.J.
      • Kheradman R.
      • Fagan A.
      • Heuman D.M.
      • White M.
      • et al.
      Fungal dysbiosis in cirrhosis.
      This in turn adversely impacts on microbial diversity, composition, activity and gut wall integrity. Moreover, between 2011 and 2017/18, the prevalence of multidrug antimicrobial resistance (AMR) increased from 29% to 38% in culture-positive infections in patients with decompensated cirrhosis and ACLF.
      • Fernandez J.
      • Prado V.
      • Trebicka J.
      • Amoros A.
      • Gustot T.
      • Wiest R.
      • et al.
      Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe.
      Targeting the microbiota may influence the rate of decompensation and thereby outcome in these patients.

      Manipulation of the gut microbiome in cirrhosis to reduce hepatic decompensation and improve outcomes

      Rifaximin is an antibacterial drug of the rifamycin class that irreversibly binds the beta sub-unit of the bacterial enzyme DNA-dependent RNA polymerase and consequently inhibits bacterial RNA synthesis. It has a broad antimicrobial spectrum against most gram-positive and negative, aerobic and anaerobic bacteria, including ammonia-producing species. It may inhibit the division of urea-deaminating bacteria, thereby reducing the production of ammonia and other compounds that play an important role in the pathogenesis of HE. Rifaximin can downregulate microbe-induced gut epithelial inflammatory responses by inhibiting activation of NF-κB via the pregnane X receptor and by reducing the expression of the pro-inflammatory cytokines interleukin-1β and tumour necrosis factor-alpha (TNF-α).
      • Hirota S.A.
      Understanding the molecular mechanisms of rifaximin in the treatment of gastrointestinal disorders--A focus on the modulation of host tissue function.
      ,
      • Mencarelli A.
      • Migliorati M.
      • Barbanti M.
      • Cipriani S.
      • Palladino G.
      • Distrutti E.
      • et al.
      Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells.
      Rifaximin also has eubiotic effects by selecting beneficial bacterial taxa.
      • Brigidi P.
      • Swennen E.
      • Rizzello F.
      • Bozzolasco M.
      • Matteuzzi D.
      Effects of rifaximin administration on the intestinal microbiota in patients with ulcerative colitis.
      ,
      • Ponziani F.R.
      • Zocco M.A.
      • D'Aversa F.
      • Pompili M.
      • Gasbarrini A.
      Eubiotic properties of rifaximin: disruption of the traditional concepts in gut microbiota modulation.
      Lactobacilli can grow in response to rifaximin administration, an effect restricted only to this antibiotic and not seen with another poorly absorbed antibiotic, neomycin.
      • Xu D.
      • Gao J.
      • Gillilland 3rd, M.
      • Wu X.
      • Song I.
      • Kao J.Y.
      • et al.
      Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats.
      Rifaximin reduces the risk of recurrence of overt HE and the need for hospitalisation; in conjunction with lactulose, it has become a mainstay second-line therapy for HE.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • Poordad F.
      • Neff G.
      • Leevy C.B.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      Rifaximin has been associated with significant reductions in hospitalisation, bed days, emergency department attendances and 30-day readmission.
      • Orr J.G.
      • Currie C.J.
      • Berni E.
      • Goel A.
      • Moriarty K.J.
      • Sinha A.
      • et al.
      The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-alpha.
      ,
      • Hudson M.
      • Radwan A.
      • Di Maggio P.
      • Cipelli R.
      • Ryder S.D.
      • Dillon J.F.
      • et al.
      The impact of rifaximin-alpha on the hospital resource use associated with the management of patients with hepatic encephalopathy: a retrospective observational study (IMPRESS).
      The specific mechanism of action of rifaximin in HE remains to be elucidated and it has not been shown to appreciably lower blood ammonia levels in any study. As mentioned earlier, its action has been linked to bacteriophages that target urease-producing Streptococcus. Rifaximin reduces all-cause admissions, episodes of SBP and variceal bleeding, and length of hospitalisation in patients with advanced cirrhosis.
      • Kang D.J.
      • Kakiyama G.
      • Betrapally N.S.
      • Herzog J.
      • Nittono H.
      • Hylemon P.B.
      • et al.
      Rifaximin exerts beneficial effects independent of its ability to alter microbiota composition.
      • Goel A.
      • Rahim U.
      • Nguyen L.H.
      • Stave C.
      • Nguyen M.H.
      Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis.
      • Ibrahim E.S.
      • Alsebaey A.
      • Zaghla H.
      • Moawad Abdelmageed S.
      • Gameel K.
      • Abdelsameea E.
      Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome.
      • Salehi S.
      • Tranah T.H.
      • Lim S.
      • Heaton N.
      • Heneghan M.
      • Aluvihare V.
      • et al.
      Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list.
      Furthermore, the use of rifaximin by patients on the liver transplant waiting list has been linked to reduced early allograft dysfunction following transplantation.
      • Ito T.
      • Nakamura K.
      • Kageyama S.
      • Korayem I.M.
      • Hirao H.
      • Kadono K.
      • et al.
      Impact of rifaximin therapy on ischemia/reperfusion injury in liver transplantation: a propensity score-matched analysis.
      However, considerable concern remains regarding whether long-term rifaximin use may contribute to AMR in cirrhosis. Indeed, in a recent study, 50% of patients prescribed rifaximin for HE developed rifaximin-resistant staphylococcal isolates after as little as 1-7 weeks of rifaximin treatment.
      • Chang J.Y.
      • Kim S.E.
      • Kim T.H.
      • Woo S.Y.
      • Ryu M.S.
      • Joo Y.H.
      • et al.
      Emergence of rifampin-resistant staphylococci after rifaximin administration in cirrhotic patients.

      Antibiotics as modulators of inflammation in cirrhosis

      Rifaximin reduces circulating levels of gut-derived endotoxins such as lipopolysaccharide.
      • Kalambokis G.N.
      • Tsianos E.V.
      Rifaximin reduces endotoxemia and improves liver function and disease severity in patients with decompensated cirrhosis.
      ,
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • Hylemon P.B.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      Studies examining changes in the composition of the faecal microbiome in response to rifaximin have categorically failed to demonstrate any clear changes in microbial abundance by 16S rRNA faecal microbiota profiling.
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • Hylemon P.B.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      ,
      • Kimer N.
      • Pedersen J.S.
      • Tavenier J.
      • Christensen J.E.
      • Busk T.M.
      • Hobolth L.
      • et al.
      Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: a randomized trial.
      However, a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin has been observed. Rifaximin led to a shift from pathogenic to beneficial metabolite linkages using network connectivity analysis centred on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae.
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • Hylemon P.B.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      There are emerging data to suggest that rifaximin has potent anti-inflammatory actions including reducing anti-TNF-α and neutrophil toll-like receptor 4 expression.
      • Zeng X.
      • Tang X.J.
      • Sheng X.
      • Ni W.
      • Xin H.G.
      • Chen W.Z.
      • et al.
      Does low-dose rifaximin ameliorate endotoxemia in patients with cirrhosis: a prospective study.
      Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that display altered functions during chronic inflammatory diseases. MAIT cells are reduced in patients with alcoholic or NAFLD-related cirrhosis while they accumulate in liver fibrotic septa. In 2 models of chronic liver injury, MAIT cell-enriched mice show increased liver fibrosis and accumulation of hepatic fibrogenic cells, whereas MAIT cell-deficient mice were resistant to fibrosis. Long-term prophylactic antibiotic therapy with norfloxacin or rifaximin was significantly associated with a lower reduction in MAIT cell frequency.
      • Hegde P.
      • Weiss E.
      • Paradis V.
      • Wan J.
      • Mabire M.
      • Sukriti S.
      • et al.
      Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver.
      Antibiotic-exposed patients with cirrhosis displayed significant reductions in CD25 expression, suggesting that long-term antibiotic therapy partially prevents MAIT cell reduction and activation .
      • Hegde P.
      • Weiss E.
      • Paradis V.
      • Wan J.
      • Mabire M.
      • Sukriti S.
      • et al.
      Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver.

      Adsorbents

      Manipulation of the gut microbiome may also be achieved via adsorption of intraluminal host or microbial metabolites or ligands. Studies to date have focused on targeting enterosorption of pathogenic factors such as ammonia or endotoxin or modulation of bile acid pathways. The advantage of such an approach is that it does not confer a risk of AMR or introduce potential pathobionts. Conceptually the enterosorbants act as a ‘sink’ for pathological factors that would otherwise drive pathogenesis in liver disease.

      Enterosorption of pathological bacterial ligands and metabolites

      The first carbon-based enterosorbant to be evaluated in cirrhosis was AST-120 (Ocera Therapeutics Inc), a microporous carbon which had been demonstrated to efficiently adsorb ammonia in vitro. Bosoi et al. evaluated the capacity of AST-120 to lower blood ammonia, oxidative stress and brain oedema in bile duct ligated (BDL) rats, as both a prophylactic and therapeutic strategy.
      • Bosoi C.R.
      • Parent-Robitaille C.
      • Anderson K.
      • Tremblay M.
      • Rose C.F.
      AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats.
      Plasma ammonia concentrations in BDL rats were significantly decreased by AST-120 in a dose-dependent manner with normalisation of brain water content and locomotor activity. A multicentre, double-blind, randomised, placebo-controlled, dose-ranging study of AST-120 was conducted in patients with compensated cirrhosis, an MELD score ≤25 and covert hepatic encephalopathy (Astute study). AST-120 was found to be well tolerated but failed to achieve its primary endpoint of improvement in covert hepatic encephalopathy (Bajaj et al., personal communication). A Cochrane review concluded that whilst AST-120 lowers blood ammonia concentrations compared to placebo, there was little evidence this translated into clinical benefit.
      • Zacharias H.D.
      • Zacharias A.P.
      • Gluud L.L.
      • Morgan M.Y.
      Pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis.
      Yaq-001 (Yaqrit Limited, UK) is a more recent carbon-based enterosorbant that has been studied in cirrhosis. In contrast to AST-120, Yaq-001 is a non-absorbable synthetic carbon with a tailored bimodal distribution of porous domains within the macroporous range (>50 nm) and microporous range (<2 nm) and a very large surface area. The biological significance of this is that, in addition to binding smaller mediators such as indoles, acetaldehyde and fMLP, Yaq-001 exhibits rapid adsorption kinetics for larger molecular weight factors such as endotoxin, exotoxins and cytokines.
      • Tripisciano C.
      • Kozynchenko O.P.
      • Linsberger I.
      • Phillips G.J.
      • Howell C.A.
      • Sandeman S.R.
      • et al.
      Activation-dependent adsorption of cytokines and toxins related to liver failure to carbon beads.
      Yaq-001 was found to reduce liver injury, portal pressure and lipopolysaccharide-induced reactive oxygen species production in an in vivo model of cirrhosis and ACLF.
      • De Chiara F.
      • Li J.
      • Lu W.
      • Davies N.
      • Mookerjee R.P.
      • Jalan R.
      • et al.
      Characterization of the protective effects of Yaq-001 on organ injury in cirrhosis.
      Whilst not exerting a direct effect on bacterial growth kinetics, shifts in microbiome composition were observed in stool.
      • Macnaughtan J.
      • Ranchal I.
      • Soeda J.
      • Sawhney R.
      • Oben J.
      • Davies N.
      • et al.
      Oral therapy with non-absorbable carbons of controlled porosity (Yaq-001) selectively modulates stool microbiome and its function and this is associated with restoration of immune function and inflammasome activation.
      Phase II clinical studies to evaluate safety, tolerability, and secondary efficacy endpoints have now been completed, with results due later this year.
      Diet, lactulose, antibiotics (e.g. rifaximin), faecal microbial transplantation and enterosorbents (e.g. Yaq-001) are tools to prevent acute decompensation.

      Modulation of bile acid pathways

      Intraluminal bile acid availability exerts a selection pressure on microbiome composition. The gut microbiota has a reciprocal influence on the biotransformation of bile acids and downstream FXR and G protein-coupled membrane receptor 5 signalling pathways. Thus, manipulation of these pathways, using FXR agonists or by intraluminal sequestration of bile acids, represents a strategy to target the microbiome and impact on clinical outcomes.
      The most well studied compound is the synthetic FXR agonist obeticholic acid (OCA), although many other therapeutic options have been developed, principally for pre-cirrhotic non-alcoholic steatohepatitis. An exhaustive discussion of these studies is beyond the scope of this review. In a rodent model of cirrhosis, OCA was found to significantly reduce bacterial translocation from 78.3% to 33.3% and significantly modulate mucosal microbiota composition.
      • Ubeda M.
      • Lario M.
      • Munoz L.
      • Borrero M.J.
      • Rodriguez-Serrano M.
      • Sanchez-Diaz A.M.
      • et al.
      Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats.
      Treatment was associated with favourable effects on ileal antimicrobial peptide, tight junction expression, intestinal inflammation and liver fibrosis. Clinical translation however has been hampered by safety concerns over OCA in patients with advanced disease.

      Bile acid sequestration

      The bile acid sequestrant colesevelam has been shown to attenuate cholestatic liver and bile duct injury in Mdr2-/- mice by modulating composition, signalling and excretion of faecal bile acids. Fuch et al. demonstrated that colesevelam increased faecal bile acid excretion and enhanced conversion to secondary bile acids, thereby attenuating liver and bile duct injury in Mdr2-/- mice.
      • Fuchs C.D.
      • Paumgartner G.
      • Mlitz V.
      • Kunczer V.
      • Halilbasic E.
      • Leditznig N.
      • et al.
      Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2(-/-) mice by modulating composition, signalling and excretion of faecal bile acids.
      The phosphate sequestrant sevelamer has been studied in murine models of NASH because of its favourable effects on LDL cholesterol, attributed to sequestration of hydrophilic bile acids. Indeed, sevelamer was shown to prevent hepatic steatosis, inflammation and fibrosis.
      • Tsuji Y.
      • Kaji K.
      • Kitade M.
      • Kaya D.
      • Kitagawa K.
      • Ozutsumi T.
      • et al.
      Bile acid sequestrant, sevelamer ameliorates hepatic fibrosis with reduced overload of endogenous lipopolysaccharide in experimental nonalcoholic steatohepatitis.
      Sevelamer improved a lower α-diversity and bound intraluminal endotoxin. Takahashi et al. demonstrated that in addition to demonstrating efficacy as a prophylactic strategy, sevelamer could reverse liver injury.
      • Takahashi S.
      • Luo Y.
      • Ranjit S.
      • Xie C.
      • Libby A.E.
      • Orlicky D.J.
      • et al.
      Bile acid sequestration reverses liver injury and prevents progression of nonalcoholic steatohepatitis in Western diet-fed mice.
      Metabolomic and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and bile acid composition, which are linked to improvements in insulin resistance.

      Areas of controversy

      There remain several areas of controversy in this burgeoning field, which can inform future trials.
      The depth of coverage, functional assessment, metabolic activity and host response to microbiota vary between studies.
      • Tilg H.
      • Cani P.D.
      • Mayer E.A.
      Gut microbiome and liver diseases.
      These factors, along with differing geographic areas, dietary practices, sex, ethnic variations, and aetiological differences can potentially alter the microbiome.
      • Johnson A.J.
      • Zheng J.J.
      • Kang J.W.
      • Saboe A.
      • Knights D.
      • Zivkovic A.M.
      A guide to diet-microbiome study design.
      ,
      • Saboo K.
      • Shamsaddini A.
      • Iyer M.V.
      • Hu C.
      • Fagan A.
      • Gavis E.A.
      • et al.
      Sex is associated with differences in gut microbial composition and function in hepatic encephalopathy.
      Therefore, these variables need to be controlled for in microbial analyses.
      We do not know whether the microbiota is the “chicken or the egg” in human studies. In mice that have been humanised with stools from carefully phenotyped human donors, there is liver injury but not to the extent that is achieved by exposing the mice to the aetiological agent or to that found in the donor humans.
      • Kang D.J.
      • Hylemon P.B.
      • Gillevet P.M.
      • Sartor R.B.
      • Betrapally N.S.
      • Kakiyama G.
      • et al.
      Gut microbial composition can differentially regulate bile acid synthesis in humanized mice.
      ,
      • Llopis M.
      • Cassard A.M.
      • Wrzosek L.
      • Boschat L.
      • Bruneau A.
      • Ferrere G.
      • et al.
      Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease.
      ,
      • Mazagova M.
      • Wang L.
      • Anfora A.T.
      • Wissmueller M.
      • Lesley S.A.
      • Miyamoto Y.
      • et al.
      Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice.
      Therefore, the focus needs to be on determining the complicity of microbes at this stage.
      An important source of controversy, is whether microbiota or their products mediate clinical outcomes.
      • Bajaj J.S.
      • Reddy K.R.
      • O'Leary J.G.
      • Vargas H.E.
      • Lai J.C.
      • Kamath P.S.
      • 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.
      ,
      • Kakiyama G.
      • Pandak W.M.
      • Gillevet P.M.
      • Hylemon P.B.
      • Heuman D.M.
      • Daita K.
      • et al.
      Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.
      ,
      • Duan Y.
      • Llorente C.
      • Lang S.
      • Brandl K.
      • Chu H.
      • Jiang L.
      • et al.
      Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.
      ,
      • Chu H.
      • Duan Y.
      • Lang S.
      • Jiang L.
      • Wang Y.
      • Llorente C.
      • et al.
      The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease.
      ,
      • Levy M.
      • Thaiss C.A.
      • Elinav E.
      Metabolites: messengers between the microbiota and the immune system.
      ,
      • Hartmann P.
      • Hochrath K.
      • Horvath A.
      • Chen P.
      • Seebauer C.T.
      • Llorente C.
      • et al.
      Modulation of the intestinal bile acid-FXR-FGF15 axis improves alcoholic liver disease in mice.
      There are redundancies in microbial function that can cross bacterial taxa and may be more relevant than composition. Studies isolating microbial products and/or dead bacteria offer a controversial insight into these differences.
      Modern medical care has had a huge impact on the changes induced in the microbiome. The rampant overuse of antibiotics and PPIs can make the gut milieu in patients with cirrhosis hostile.
      • Horvath A.
      • Rainer F.
      • Bashir M.
      • Leber B.
      • Schmerboeck B.
      • Klymiuk I.
      • et al.
      Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis.
      ,
      • Bajaj J.S.
      • Acharya C.
      • Fagan A.
      • White M.B.
      • Gavis E.
      • Heuman D.M.
      • et al.
      Proton pump inhibitor initiation and withdrawal affects gut microbiota and readmission risk in cirrhosis.
      The controversy over routine use of antibiotic prophylaxis in patients with cirrhosis, especially in those who have not experienced SBP, is important from a clinical and microbiological perspective.
      • Fernandez J.
      • Tandon P.
      • Mensa J.
      • Garcia-Tsao G.
      Antibiotic prophylaxis in cirrhosis: good and bad.
      Antibiotics such as rifaximin may beneficially select taxa such as Lactobacilli which may protect against inflammation and hepatic decompensation
      • Xu D.
      • Gao J.
      • Gillilland 3rd, M.
      • Wu X.
      • Song I.
      • Kao J.Y.
      • et al.
      Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats.
      ,
      • Salehi S.
      • Tranah T.H.
      • Lim S.
      • Heaton N.
      • Heneghan M.
      • Aluvihare V.
      • et al.
      Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list.
      but others may promote hepatic toxicity. Further mechanistic studies are therefore warranted.
      Furthermore, non-antibiotic drugs have a huge effect on the microbiome and may contribute to the development of antibiotic resistance, a growing problem in this patient population.
      • Maier L.
      • Pruteanu M.
      • Kuhn M.
      • Zeller G.
      • Telzerow A.
      • Anderson E.E.
      • et al.
      Extensive impact of non-antibiotic drugs on human gut bacteria.
      Finally, we need to account for the impact of planned and also necessary endoscopic procedures, fasting periods and other interventions (e.g. professional periodontal cleaning) that may also induce at least temporary changes in the microbiome.
      • Liu Z.
      • Dai X.
      • Zhang H.
      • Shi R.
      • Hui Y.
      • Jin X.
      • et al.
      Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment.
      ,
      • Bajaj J.S.
      • Matin P.
      • White M.B.
      • Fagan A.
      • Deeb J.G.
      • Acharya C.
      • et al.
      Periodontal therapy favorably modulates the oral-gut-hepatic axis in cirrhosis.
      These factors may be crucial in the interpretation of cross-sectional microbiome research and require longitudinal large-scale and in-depth analysis with cautious interpretation that controls for these factors.
      In addition, the role of non-bacterial microbiota such as fungi and viruses are important to elucidate since they interact with bacteria, with each other, and with their host in a complex ecosystem.
      • Lang S.
      • Duan Y.
      • Liu J.
      • Torralba M.G.
      • Kuelbs C.
      • Ventura-Cots M.
      • et al.
      Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis.
      • Chu H.
      • Duan Y.
      • Lang S.
      • Jiang L.
      • Wang Y.
      • Llorente C.
      • et al.
      The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease.
      • Jiang L.
      • Lang S.
      • Duan Y.
      • Zhang X.
      • Gao B.
      • Chopyk J.
      • et al.
      Intestinal virome in patients with alcoholic hepatitis.
      ,
      • Bajaj J.S.
      • Liu E.J.
      • Kheradman R.
      • Fagan A.
      • Heuman D.M.
      • White M.
      • et al.
      Fungal dysbiosis in cirrhosis.
      In selected circumstances they can become pathogenic. Virome constituents could potentially be used to treat specific infections or modulate the activity of target bacteria and their potential products.
      • Duan Y.
      • Llorente C.
      • Lang S.
      • Brandl K.
      • Chu H.
      • Jiang L.
      • et al.
      Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.
      ,
      • Abedon S.T.
      • Thomas-Abedon C.
      Phage therapy pharmacology.
      Microbial changes in easily accessible biofluids such as stool and saliva have been studied, but there are relatively few reports on microbiota from ascites, mucosal surfaces, liver tissue, bile and other tissues.
      • Bajaj J.S.
      • Betrapally N.S.
      • Hylemon P.B.
      • Heuman D.M.
      • Daita K.
      • White M.B.
      • et al.
      Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy.
      • Tuomisto S.
      • Pessi T.
      • Collin P.
      • Vuento R.
      • Aittoniemi J.
      • Karhunen P.J.
      Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics.
      • Santiago A.
      • Pozuelo M.
      • Poca M.
      • Gely C.
      • Nieto J.C.
      • Torras X.
      • et al.
      Alteration of the serum microbiome composition in cirrhotic patients with ascites.
      • Schierwagen R.
      • Alvarez-Silva C.
      • Madsen M.S.A.
      • Kolbe C.C.
      • Meyer C.
      • Thomas D.
      • et al.
      Circulating microbiome in blood of different circulatory compartments.
      • Ye F.
      • Shen H.
      • Li Z.
      • Meng F.
      • Li L.
      • Yang J.
      • et al.
      Influence of the biliary system on biliary bacteria revealed by bacterial communities of the human biliary and upper digestive tracts.
      Microbial alterations in these tissues may be more closely linked to organ dysfunction. Therefore, the microbial milieu of these organs may be different and should not be conflated with stool or saliva unless there is further evidence.

      Future perspectives

      More detailed longitudinal, large-scale and in-depth analyses of the microbiota’s role in liver disease are warranted. There remain several factors that can influence the microbiota, such as demographics (geographic area, sex and diet), aetiology, drugs, interventions, and finally the sampling compartment. These factors need to be controlled for and considered in the interpretation of future studies. Moreover, more mechanistic investigations on the role of the microbiota and its components are required to develop treatment strategies that can benefit patients without negatively influencing the gut ecosystem.
      Current understanding on the composition and function of the gut microbiome and how this relates to progression and outcomes in patients with cirrhosis remains in its infancy and is based on descriptive snapshots afflicted with confounders and lacking robust clinical validation. As perturbations in the gut microbiome are a hallmark of advanced CLD that influence the rate of progression to liver failure and drive the susceptibility to infection, unlocking the potential of the microbiome and developing antibiotic-free therapies such as FMT to tackle these unmet needs is a research priority. Further multicentre randomised controlled trials are now needed to prove the efficacy of FMT in larger populations of patients with cirrhosis and to elucidate its mechanisms of action, which remain unclear.

      Abbreviations

      ACLF, acute-on-chronic liver failure; AD, acute decompensation; AUD, alcohol use disorder; BDL, bile duct ligated; CLD, chronic liver disease; FMT, faecal microbiota transplantation; FXR, farnesoid X receptor; HE, hepatic encephalopathy; MELD, model for end-stage liver disease; PPI, proton pump inhibitor; SBP, spontaneous bacterial peritonitis; SCFAs, short-chain fatty acids; SIBO, small intestine bacterial overgrowth.

      Financial support

      This review is supported by MICROB-PREDICT project. The MICROB-PREDICT project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 825694. This reflects only the author’s view, and the European Commission is not responsible for any use that may be made of the information it contains.

      Authors’ contributions

      J.T. was responsible for drafting the chapters “Summary, Introduction, Alteration of the microbiome and its associated changes in cirrhosis, future perspectives”, coordinating the writing and compiling the final version. J.M was responsible for drafting the chapter “Adsorbents”. B.S. was responsible for drafting the chapters “Microbiome changes and development of decompensation, future perspectives” D.L.S. was responsible for drafting the chapters “Antibiotics in cirrhosis: A double-edged sword, future perspectives” J.S.B. was responsible for drafting the chapters “Faecal transplantation as a promising tool, Area of controversy, future perspectives”. All authors revised and approved the manuscript.

      Conflict of interest

      J.T. has received speaking and/or consulting fees from Gore, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, and Martin Pharmaceutical. J.M. is a co-founder of Yaqrit Limited and has received speaker fees from Norgine and Yakult Europe. B.S. has been consulting for Ferring Research Institute, Intercept Pharmaceuticals, HOST Therabiomics, Mabwell Therapeutics and Patara Pharmaceuticals. B.S.’s institution UC San Diego has received grant support from BiomX, NGM Biopharmaceuticals, CymaBay Therapeutics, Synlogic Operating Company and Axial Biotherapeutics. D.L.S. has been consulting for Norgine, Kaleido Biosciences, Shionogi and Mallinckrodt Pharmaceuticals and has undertaken paid lectures for Norgine, Alfa Sigma and Falk Pharma. D.L.S’s institution King’s College London has received grant support from Norgine. J.S.B. has been an advisor to Valeant, Norgine, Kaleido and Takeda and his institution has received support from Bausch Health, Kaleido, Grifols and Mallinckrodt pharmaceuticals.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      J.T. is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57, P18 and CRC 1382, A09), European Union’s Horizon 2020 Research and Innovation Programme (Galaxy, No. 668031 and MICROB-PREDICT, No. 825694) and Societal Challenges - Health, Demographic Change and Wellbeing (LIVERHOPE No. 731875), and Cellex Foundation (PREDICT). J.M. is supported by grants from the European Union’s 2020 Research and Innovation Programme (CARBALIVE, No. 634579 and MICROB-PREDICT, No. 825694). B.S. was supported in part by services provided by NIH centers P30 DK120515 and P50 AA011999. D.L.S. is supported by grants from the European Union’s Horizon 2020 Research and Innovation Programme (MICROB-PREDICT, No. 825694) and the National Institute for Health Research (PROFIT Trial No. PB-PG-0215-36070). J.S.B. was supported in part by VA Merit Review 2I0CX001076 and NCATS R21 TR002024 and R21TR003095.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

      Transparency declaration

      This article is published as part of a supplement entitled New Concepts and Perspectives in Decompensated Cirrhosis. Publication of the supplement was supported financially by CSL Behring. The sponsor had no involvement in content development, the decision to submit the manuscript or in the acceptance of the manuscript for publication.

      References

        • Tsochatzis E.A.
        • Bosch J.
        • Burroughs A.K.
        Cirrhosis Lancet. 2014; 383: 1749-1761
        • Friedman S.L.
        Mechanisms of hepatic fibrogenesis.
        Gastroenterology. 2008; 134: 1655-1669
        • Arroyo V.
        • Moreau R.
        • Jalan R.
        Acute-on-Chronic liver failure.
        N Engl J Med. 2020; 382: 2137-2145
        • Tilg H.
        • Cani P.D.
        • Mayer E.A.
        Gut microbiome and liver diseases.
        Gut. 2016; 65: 2035-2044
        • Tripathi A.
        • Debelius J.
        • Brenner D.A.
        • Karin M.
        • Loomba R.
        • Schnabl B.
        • et al.
        The gut-liver axis and the intersection with the microbiome.
        Nat Rev Gastroenterol Hepatol. 2018; 15: 397-411
        • Albillos A.
        • de Gottardi A.
        • Rescigno M.
        The gut-liver axis in liver disease: pathophysiological basis for therapy.
        J Hepatol. 2020; 72: 558-577
        • Trebicka J.
        • Reiberger T.
        • Laleman W.
        Gut-liver Axis links portal hypertension to acute-on-chronic liver failure.
        Visc Med. 2018; 34: 270-275
        • Trebicka J.
        • Fernandez J.
        • Papp M.
        • Caraceni P.
        • Laleman W.
        • Gambino C.
        • et al.
        PREDICT identifies precipitating events associated with clinical course of acutely decompensated cirrhosis.
        J Hepatol. 2020; (accepted)
        • Moreau R.
        • Jalan R.
        • Gines P.
        • Pavesi M.
        • Angeli P.
        • Cordoba J.
        • et al.
        Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
        Gastroenterology. 2013; 144 (1437 e1421-1429): 1426-1437
        • Trebicka J.
        • Fernandez J.
        • Papp M.
        • Caraceni P.
        • Laleman W.
        • Gambino C.
        • et al.
        The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
        J Hepatol. 2020;
        • Arroyo V.
        • Moreau R.
        • Kamath P.S.
        • Jalan R.
        • Gines P.
        • Nevens F.
        • et al.
        Acute-on-chronic liver failure in cirrhosis.
        Nat Rev Dis Primers. 2016; 2: 16041
        • Sarin S.K.
        • Choudhury A.
        Acute-on-chronic liver failure: terminology, mechanisms and management.
        Nat Rev Gastroenterol Hepatol. 2016; 13: 131-149
        • O'Leary J.G.
        • Reddy K.R.
        • Garcia-Tsao G.
        • Biggins S.W.
        • Wong F.
        • Fallon M.B.
        • et al.
        NACSELD acute-on-chronic liver failure (NACSELD-ACLF) score predicts 30-day survival in hospitalized patients with cirrhosis.
        Hepatology. 2018; 67: 2367-2374
        • Bajaj J.S.
        • Reddy K.R.
        • O'Leary J.G.
        • Vargas H.E.
        • Lai J.C.
        • Kamath P.S.
        • 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;
        • Schnabl B.
        • Brenner D.A.
        Interactions between the intestinal microbiome and liver diseases.
        Gastroenterology. 2014; 146: 1513-1524
        • Bajaj J.S.
        Alcohol, liver disease and the gut microbiota.
        Nat Rev Gastroenterol Hepatol. 2019; 16: 235-246
        • Bajaj J.S.
        • Heuman D.M.
        • Hylemon P.B.
        • Sanyal A.J.
        • White M.B.
        • Monteith P.
        • et al.
        Altered profile of human gut microbiome is associated with cirrhosis and its complications.
        J Hepatol. 2014; 60: 940-947
        • Qin N.
        • Yang F.
        • Li A.
        • Prifti E.
        • Chen Y.
        • Shao L.
        • et al.
        Alterations of the human gut microbiome in cirrhosis.
        Nature. 2014; 513: 59-64
        • Bajaj J.S.
        • Betrapally N.S.
        • Gillevet P.M.
        Decompensated cirrhosis and microbiome interpretation.
        Nature. 2015; 525: E1-2
        • Bauer T.M.
        • Steinbruckner B.
        • Brinkmann F.E.
        • Ditzen A.K.
        • Schwacha H.
        • Aponte J.J.
        • et al.
        Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis.
        Am J Gastroenterol. 2001; 96: 2962-2967
        • Chang C.S.
        • Chen G.H.
        • Lien H.C.
        • Yeh H.Z.
        Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis.
        Hepatology. 1998; 28: 1187-1190
        • Fukui H.
        • Wiest R.
        Changes of intestinal functions in liver cirrhosis.
        Inflamm Intest Dis. 2016; 1: 24-40
        • Peng L.
        • Li Z.R.
        • Green R.S.
        • Holzman I.R.
        • Lin J.
        Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers.
        J Nutr. 2009; 139: 1619-1625
        • Park J.
        • Kim M.
        • Kang S.G.
        • Jannasch A.H.
        • Cooper B.
        • Patterson J.
        • et al.
        Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway.
        Mucosal Immunol. 2015; 8: 80-93
        • Chu H.
        • Duan Y.
        • Yang L.
        • Schnabl B.
        Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease.
        Gut. 2019; 68: 359-370
        • Chen Y.
        • Yang F.
        • Lu H.
        • Wang B.
        • Chen Y.
        • Lei D.
        • et al.
        Characterization of fecal microbial communities in patients with cirrhosis.
        Hepatology. 2011; 54: 562-572
        • Oh T.G.
        • Kim S.M.
        • Caussy C.
        • Fu T.
        • Guo J.
        • Bassirian S.
        • et al.
        A universal gut-microbiome-derived signature predicts cirrhosis.
        Cell Metab. 2020;
        • Addolorato G.
        • Ponziani F.R.
        • Dionisi T.
        • Mosoni C.
        • Vassallo G.A.
        • Sestito L.
        • et al.
        Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol-associated liver disease.
        Liver Int. 2020; 40: 878-888
        • Ponziani F.R.
        • Putignani L.
        • Paroni Sterbini F.
        • Petito V.
        • Picca A.
        • Del Chierico F.
        • et al.
        Influence of hepatitis C virus eradication with direct-acting antivirals on the gut microbiota in patients with cirrhosis.
        Aliment Pharmacol Ther. 2018; 48: 1301-1311
        • Ponziani F.R.
        • Bhoori S.
        • Castelli C.
        • Putignani L.
        • Rivoltini L.
        • Del Chierico F.
        • et al.
        Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease.
        Hepatology. 2019; 69: 107-120
        • Bajaj J.S.
        • Fagan A.
        • Sikaroodi M.
        • White M.B.
        • Sterling R.K.
        • Gilles H.
        • et al.
        Liver transplant modulates gut microbial dysbiosis and cognitive function in cirrhosis.
        Liver Transpl. 2017; 23: 907-914
        • Kakiyama G.
        • Pandak W.M.
        • Gillevet P.M.
        • Hylemon P.B.
        • Heuman D.M.
        • Daita K.
        • et al.
        Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.
        J Hepatol. 2013; 58: 949-955
        • Ridlon J.M.
        • Alves J.M.
        • Hylemon P.B.
        • Bajaj J.S.
        Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship.
        Gut Microbes. 2013; 4: 382-387
        • Kakiyama G.
        • Hylemon P.B.
        • Zhou H.
        • Pandak W.M.
        • Heuman D.M.
        • Kang D.J.
        • et al.
        Colonic inflammation and secondary bile acids in alcoholic cirrhosis.
        Am J Physiol Gastrointest Liver Physiol. 2014; 306: G929-937
        • Wang Y.D.
        • Chen W.D.
        • Moore D.D.
        • Huang W.
        FXR: a metabolic regulator and cell protector.
        Cell Res. 2008; 18: 1087-1095
        • Sorribas M.
        • Jakob M.O.
        • Yilmaz B.
        • Li H.
        • Stutz D.
        • Noser Y.
        • et al.
        FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.
        J Hepatol. 2019; 71: 1126-1140
        • Verbeke L.
        • Farre R.
        • Verbinnen B.
        • Covens K.
        • Vanuytsel T.
        • Verhaegen J.
        • et al.
        The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.
        Am J Pathol. 2015; 185: 409-419
        • Ubeda M.
        • Lario M.
        • Munoz L.
        • Borrero M.J.
        • Rodriguez-Serrano M.
        • Sanchez-Diaz A.M.
        • et al.
        Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats.
        J Hepatol. 2016; 64: 1049-1057
        • Munoz L.
        • Borrero M.J.
        • Ubeda M.
        • Conde E.
        • Del Campo R.
        • Rodriguez-Serrano M.
        • et al.
        Intestinal immune dysregulation driven by dysbiosis promotes barrier disruption and bacterial translocation in rats with cirrhosis.
        Hepatology. 2019; 70: 925-938
        • Shindo K.
        • Machida M.
        • Miyakawa K.
        • Fukumura M.
        A syndrome of cirrhosis, achlorhydria, small intestinal bacterial overgrowth, and fat malabsorption.
        Am J Gastroenterol. 1993; 88: 2084-2091
        • Pelletier G.
        • Briantais M.J.
        • Buffet C.
        • Pillot J.
        • Etienne J.P.
        Serum and intestinal secretory IgA in alcoholic cirrhosis of the liver.
        Gut. 1982; 23: 475-480
        • Teltschik Z.
        • Wiest R.
        • Beisner J.
        • Nuding S.
        • Hofmann C.
        • Schoelmerich J.
        • et al.
        Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense.
        Hepatology. 2012; 55: 1154-1163
        • 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: 1272-1284
        • Claria J.
        • Stauber R.E.
        • Coenraad M.J.
        • Moreau R.
        • Jalan R.
        • Pavesi M.
        • et al.
        Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
        Hepatology. 2016; 64: 1249-1264
        • Sole C.
        • Sola E.
        • Morales-Ruiz M.
        • Fernandez G.
        • Huelin P.
        • Graupera I.
        • et al.
        Characterization of inflammatory response in acute-on-chronic liver failure and relationship with prognosis.
        Sci Rep. 2016; 6: 32341
        • Gronbaek H.
        • Rodgaard-Hansen S.
        • Aagaard N.K.
        • Arroyo V.
        • Moestrup S.K.
        • Garcia E.
        • et al.
        Macrophage activation markers predict mortality in patients with cirrhosis without or with acute-on-chronic liver failure (ACLF).
        J Hepatol. 2016; 64: 813-822
        • Trebicka J.
        • Amoros A.
        • Pitarch C.
        • Titos E.
        • Alcaraz-Quiles J.
        • Schierwagen R.
        • et al.
        Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis.
        Front Immunol. 2019; 10: 476
        • Monteiro S.
        • Grandt J.
        • Uschner F.E.
        • Kimer N.
        • Madsen J.L.
        • Schierwagen R.
        • et al.
        Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.
        Gut. 2020;
        • Praktiknjo M.
        • Monteiro S.
        • Grandt J.
        • Kimer N.
        • Madsen J.L.
        • Werge M.P.
        • et al.
        Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure.
        Liver Int. 2020; 40: 1457-1466
        • Michelena J.
        • Altamirano J.
        • Abraldes J.G.
        • Affo S.
        • Morales-Ibanez O.
        • Sancho-Bru P.
        • et al.
        Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.
        Hepatology. 2015; 62: 762-772
        • Navasa M.
        • Follo A.
        • Filella X.
        • Jimenez W.
        • Francitorra A.
        • Planas R.
        • et al.
        Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
        Hepatology. 1998; 27: 1227-1232
        • Bajaj J.S.
        • Ridlon J.M.
        • Hylemon P.B.
        • Thacker L.R.
        • Heuman D.M.
        • Smith S.
        • et al.
        Linkage of gut microbiome with cognition in hepatic encephalopathy.
        Am J Physiol Gastrointest Liver Physiol. 2012; 302: G168-175
        • Cirera I.
        • Bauer T.M.
        • Navasa M.
        • Vila J.
        • Grande L.
        • Taura P.
        • et al.
        Bacterial translocation of enteric organisms in patients with cirrhosis.
        J Hepatol. 2001; 34: 32-37
        • Wiest R.
        • Lawson M.
        • Geuking M.
        Pathological bacterial translocation in cirrhosis.
        J Hepatol. 2014; 60: 197-209
        • Frances R.
        • Zapater P.
        • Gonzalez-Navajas J.M.
        • Munoz C.
        • Cano R.
        • Moreu R.
        • et al.
        Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis.
        Hepatology. 2008; 47: 978-985
        • Bajaj J.S.
        • Reddy R.K.
        • Tandon P.
        • Wong F.
        • Kamath P.S.
        • Biggins S.W.
        • et al.
        Prediction of fungal infection development and their impact on survival using the NACSELD cohort.
        Am J Gastroenterol. 2018; 113: 556-563
        • Shao L.
        • Ling Z.
        • Chen D.
        • Liu Y.
        • Yang F.
        • Li L.
        Disorganized gut microbiome contributed to liver cirrhosis progression: a meta-omics-based study.
        Front Microbiol. 2018; 9: 3166
        • Duan Y.
        • Llorente C.
        • Lang S.
        • Brandl K.
        • Chu H.
        • Jiang L.
        • et al.
        Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.
        Nature. 2019; 575: 505-511
        • Lang S.
        • Duan Y.
        • Liu J.
        • Torralba M.G.
        • Kuelbs C.
        • Ventura-Cots M.
        • et al.
        Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis.
        Hepatology. 2020; 71: 522-538
        • Chu H.
        • Duan Y.
        • Lang S.
        • Jiang L.
        • Wang Y.
        • Llorente C.
        • et al.
        The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease.
        J Hepatol. 2020; 72: 391-400
        • Jiang L.
        • Lang S.
        • Duan Y.
        • Zhang X.
        • Gao B.
        • Chopyk J.
        • et al.
        Intestinal virome in patients with alcoholic hepatitis.
        Hepatology. 2020;
        • Bajaj J.
        • Sikaroodi M.
        • Shamsaddini A.
        • Henseler Z.
        • Santiago-Rodriguez T.
        • Acharya C.
        • et al.
        Interaction of bacterial metagenome and virome in patients with cirrhosis and hepatic encephalopathy.
        Gut. 2020; (in press)
        • Chen P.
        • Starkel P.
        • Turner J.R.
        • Ho S.B.
        • Schnabl B.
        Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice.
        Hepatology. 2015; 61: 883-894
        • Munoz L.
        • Jose Borrero M.
        • Ubeda M.
        • Lario M.
        • Diaz D.
        • Frances R.
        • et al.
        Interaction between intestinal dendritic cells and bacteria translocated from the gut in rats with cirrhosis.
        Hepatology. 2012; 56: 1861-1869
        • Hartmann P.
        • Hochrath K.
        • Horvath A.
        • Chen P.
        • Seebauer C.T.
        • Llorente C.
        • et al.
        Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice.
        Hepatology. 2018; 67: 2150-2166
        • Brandl K.
        • Hartmann P.
        • Jih L.J.
        • Pizzo D.P.
        • Argemi J.
        • Ventura-Cots M.
        • et al.
        Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.
        J Hepatol. 2018; 69: 396-405
        • Shi Y.
        • Yang Y.
        • Hu Y.
        • Wu W.
        • Yang Q.
        • Zheng M.
        • et al.
        Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.
        Hepatology. 2015; 62: 232-242
        • Li H.
        • Chen L.Y.
        • Zhang N.N.
        • Li S.T.
        • Zeng B.
        • Pavesi M.
        • et al.
        Characteristics, diagnosis and prognosis of acute-on-chronic liver failure in cirrhosis associated to hepatitis B.
        Sci Rep. 2016; 6: 25487
        • Zhang Y.
        • Zhao R.
        • Shi D.
        • Sun S.
        • Ren H.
        • Zhao H.
        • et al.
        Characterization of the circulating microbiome in acute-on-chronic liver failure associated with hepatitis B.
        Liver Int. 2019; 39: 1207-1216
        • Zhai S.
        • Zhu L.
        • Qin S.
        • Li L.
        Effect of lactulose intervention on gut microbiota and short chain fatty acid composition of C57BL/6J mice.
        Microbiologyopen. 2018; 7e00612
        • Chae J.P.
        • Pajarillo E.A.
        • Oh J.K.
        • Kim H.
        • Kang D.K.
        Revealing the combined effects of lactulose and probiotic enterococci on the swine faecal microbiota using 454 pyrosequencing.
        Microb Biotechnol. 2016; 9: 486-495
        • Ferreira M.D.F.
        • Salavati Schmitz S.
        • Schoenebeck J.J.
        • Clements D.N.
        • Campbell S.M.
        • Gaylor D.E.
        • et al.
        Lactulose drives a reversible reduction and qualitative modulation of the faecal microbiota diversity in healthy dogs.
        Sci Rep. 2019; 9: 13350
        • Ziada D.H.
        • Soliman H.H.
        • El Yamany S.A.
        • Hamisa M.F.
        • Hasan A.M.
        Can Lactobacillus acidophilus improve minimal hepatic encephalopathy? A neurometabolite study using magnetic resonance spectroscopy.
        Arab J Gastroenterol. 2013; 14: 116-122
        • Riggio O.
        • Varriale M.
        • Testore G.P.
        • Di Rosa R.
        • Di Rosa E.
        • Merli M.
        • et al.
        Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients.
        J Clin Gastroenterol. 1990; 12: 433-436
        • Sarangi A.N.
        • Goel A.
        • Singh A.
        • Sasi A.
        • Aggarwal R.
        Faecal bacterial microbiota in patients with cirrhosis and the effect of lactulose administration.
        BMC Gastroenterol. 2017; 17: 125
        • Bajaj J.S.
        • Gillevet P.M.
        • Patel N.R.
        • Ahluwalia V.
        • Ridlon J.M.
        • Kettenmann B.
        • et al.
        A longitudinal systems biology analysis of lactulose withdrawal in hepatic encephalopathy.
        Metab Brain Dis. 2012; 27: 205-215
        • Bajaj J.S.
        • Idilman R.
        • Mabudian L.
        • Hood M.
        • Fagan A.
        • Turan D.
        • et al.
        Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort.
        Hepatology. 2018; 68: 234-247
        • Bajaj J.S.
        • Vargas H.E.
        • Reddy K.R.
        • Lai J.C.
        • O'Leary J.G.
        • Tandon P.
        • et al.
        Association between intestinal microbiota collected at hospital admission and outcomes of patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2019; 17: 756-765 e753
        • Kang D.J.
        • Hylemon P.B.
        • Gillevet P.M.
        • Sartor R.B.
        • Betrapally N.S.
        • Kakiyama G.
        • et al.
        Gut microbial composition can differentially regulate bile acid synthesis in humanized mice.
        Hepatol Commun. 2017; 1: 61-70
        • Liu R.
        • Kang J.D.
        • Sartor R.B.
        • Sikaroodi M.
        • Fagan A.
        • Gavis E.A.
        • et al.
        Neuroinflammation in murine cirrhosis is dependent on the gut microbiome and is attenuated by fecal transplant.
        Hepatology. 2020; 71: 611-626
        • Llopis M.
        • Cassard A.M.
        • Wrzosek L.
        • Boschat L.
        • Bruneau A.
        • Ferrere G.
        • et al.
        Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease.
        Gut. 2016; 65: 830-839
        • Weingarden A.
        • Gonzalez A.
        • Vazquez-Baeza Y.
        • Weiss S.
        • Humphry G.
        • Berg-Lyons D.
        • et al.
        Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection.
        Microbiome. 2015; 3: 10
        • Bajaj J.S.
        • Khoruts A.
        Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis.
        J Hepatol. 2020; 72: 1003-1027
        • Pringle P.L.
        • Soto M.T.
        • Chung R.T.
        • Hohmann E.
        Patients with cirrhosis require more fecal microbiota capsules to cure refractory and recurrent Clostridium difficile infections.
        Clin Gastroenterol Hepatol. 2019; 17: 791-793
        • Meighani A.
        • Alimirah M.
        • Ramesh M.
        • Salgia R.
        Fecal microbiota transplantation for clostridioides difficile infection in patients with chronic liver disease.
        Int J Hepatol. 2020; 2020: 1874570
        • Cheng Y.W.
        • Alhaffar D.
        • Saha S.
        • Khanna S.
        • Bohm M.
        • Phelps E.
        • et al.
        Fecal microbiota transplantation is safe and effective in patients with clostridioides difficile infection and cirrhosis.
        Clin Gastroenterol Hepatol. 2020;
        • Hatton G.B.
        • Ran S.
        • Tranah T.H.
        • Shawcross D.L.
        Lessons learned from faecal microbiota transplantation in cirrhosis.
        Curr Hepatol Rep. 2020;
        • DeFilipp Z.
        • Bloom P.P.
        • Torres Soto M.
        • Mansour M.K.
        • Sater M.R.A.
        • Huntley M.H.
        • et al.
        Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant.
        N Engl J Med. 2019; 381: 2043-2050
        • Ianiro G.
        • Mullish B.H.
        • Kelly C.R.
        • Kassam Z.
        • Kuijper E.J.
        • Ng S.C.
        • et al.
        Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic.
        Gut. 2020; 69: 1555-1563
        • Kassam Z.
        • Dubois N.
        • Ramakrishna B.
        • Ling K.
        • Qazi T.
        • Smith M.
        • et al.
        Donor screening for fecal microbiota transplantation.
        N Engl J Med. 2019; 381: 2070-2072
        • Weingarden A.R.
        • Chen C.
        • Bobr A.
        • Yao D.
        • Lu Y.
        • Nelson V.M.
        • et al.
        Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.
        Am J Physiol Gastrointest Liver Physiol. 2014; 306: G310-319
        • Bajaj J.S.
        • Kakiyama G.
        • Savidge T.
        • Takei H.
        • Kassam Z.A.
        • Fagan A.
        • et al.
        Antibiotic-associated disruption of microbiota composition and function in cirrhosis is restored by fecal transplant.
        Hepatology. 2018; 68: 1549-1558
        • Bajaj J.S.
        • Salzman N.H.
        • Acharya C.
        • Sterling R.K.
        • White M.B.
        • Gavis E.A.
        • et al.
        Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial.
        Hepatology. 2019; 70: 1690-1703
        • Borzio M.
        • Salerno F.
        • Piantoni L.
        • Cazzaniga M.
        • Angeli P.
        • Bissoli F.
        • et al.
        Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study.
        Dig Liver Dis. 2001; 33: 41-48
        • Albillos A.
        • Lario M.
        • Alvarez-Mon M.
        Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
        J Hepatol. 2014; 61: 1385-1396
        • Fernandez J.
        • Acevedo J.
        • Wiest R.
        • Gustot T.
        • Amoros A.
        • Deulofeu C.
        • et al.
        Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
        Gut. 2018; 67: 1870-1880
        • Fernandez J.
        • Prado V.
        • Trebicka J.
        • Amoros A.
        • Gustot T.
        • Wiest R.
        • et al.
        Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe.
        J Hepatol. 2019; 70: 398-411
        • European Association for the Study of the Liver
        Electronic address eee, clinical practice guideline panel C, panel m, representative EGB. EASL clinical practice guidelines: drug-induced liver injury.
        J Hepatol. 2019; 70: 1222-1261
        • Vilstrup H.
        • Amodio P.
        • Bajaj J.
        • Cordoba J.
        • Ferenci P.
        • Mullen K.D.
        • et al.
        Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American association for the study of liver diseases and the European association for the study of the liver.
        Hepatology. 2014; 60: 715-735
        • Bajaj J.S.
        • Heuman D.M.
        • Hylemon P.B.
        • Sanyal A.J.
        • White M.B.
        • Monteith P.
        • et al.
        Altered profile of human gut microbiome is associated with cirrhosis and its complications.
        J Hepatol. 2014; 60: 940-947
        • Francino M.P.
        Antibiotics and the human gut microbiome: dysbiosesand accumulation of resistances.
        Front Microbiol. 2016; 6
        • Bajaj J.S.
        • Liu E.J.
        • Kheradman R.
        • Fagan A.
        • Heuman D.M.
        • White M.
        • et al.
        Fungal dysbiosis in cirrhosis.
        Gut. 2018; 67: 1146-1154
        • Hirota S.A.
        Understanding the molecular mechanisms of rifaximin in the treatment of gastrointestinal disorders--A focus on the modulation of host tissue function.
        Mini Rev Med Chem. 2015; 16: 206-217
        • Mencarelli A.
        • Migliorati M.
        • Barbanti M.
        • Cipriani S.
        • Palladino G.
        • Distrutti E.
        • et al.
        Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells.
        Biochem Pharmacol. 2010; 80: 1700-1707
        • Brigidi P.
        • Swennen E.
        • Rizzello F.
        • Bozzolasco M.
        • Matteuzzi D.
        Effects of rifaximin administration on the intestinal microbiota in patients with ulcerative colitis.
        J Chemother. 2002; 14: 290-295
        • Ponziani F.R.
        • Zocco M.A.
        • D'Aversa F.
        • Pompili M.
        • Gasbarrini A.
        Eubiotic properties of rifaximin: disruption of the traditional concepts in gut microbiota modulation.
        World J Gastroenterol. 2017; 23: 4491-4499
        • Xu D.
        • Gao J.
        • Gillilland 3rd, M.
        • Wu X.
        • Song I.
        • Kao J.Y.
        • et al.
        Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats.
        Gastroenterology. 2014; 146: 484-496 e484
        • Bass N.M.
        • Mullen K.D.
        • Sanyal A.
        • Poordad F.
        • Neff G.
        • Leevy C.B.
        • et al.
        Rifaximin treatment in hepatic encephalopathy.
        N Engl J Med. 2010; 362: 1071-1081
        • Orr J.G.
        • Currie C.J.
        • Berni E.
        • Goel A.
        • Moriarty K.J.
        • Sinha A.
        • et al.
        The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-alpha.
        Liver Int. 2016; 36: 1295-1303
        • Hudson M.
        • Radwan A.
        • Di Maggio P.
        • Cipelli R.
        • Ryder S.D.
        • Dillon J.F.
        • et al.
        The impact of rifaximin-alpha on the hospital resource use associated with the management of patients with hepatic encephalopathy: a retrospective observational study (IMPRESS).
        Frontline Gastroenterol. 2017; 8: 243-251
        • Kang D.J.
        • Kakiyama G.
        • Betrapally N.S.
        • Herzog J.
        • Nittono H.
        • Hylemon P.B.
        • et al.
        Rifaximin exerts beneficial effects independent of its ability to alter microbiota composition.
        Clin Transl Gastroenterol. 2016; 7: e187
        • Goel A.
        • Rahim U.
        • Nguyen L.H.
        • Stave C.
        • Nguyen M.H.
        Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis.
        Aliment Pharmacol Ther. 2017; 46: 1029-1036
        • Ibrahim E.S.
        • Alsebaey A.
        • Zaghla H.
        • Moawad Abdelmageed S.
        • Gameel K.
        • Abdelsameea E.
        Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome.
        Eur J Gastroenterol Hepatol. 2017; 29: 1247-1250
        • Salehi S.
        • Tranah T.H.
        • Lim S.
        • Heaton N.
        • Heneghan M.
        • Aluvihare V.
        • et al.
        Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list.
        Aliment Pharmacol Ther. 2019; 50: 435-441
        • Ito T.
        • Nakamura K.
        • Kageyama S.
        • Korayem I.M.
        • Hirao H.
        • Kadono K.
        • et al.
        Impact of rifaximin therapy on ischemia/reperfusion injury in liver transplantation: a propensity score-matched analysis.
        Liver Transpl. 2019; 25: 1778-1789
        • Chang J.Y.
        • Kim S.E.
        • Kim T.H.
        • Woo S.Y.
        • Ryu M.S.
        • Joo Y.H.
        • et al.
        Emergence of rifampin-resistant staphylococci after rifaximin administration in cirrhotic patients.
        PLoS One. 2017; 12e0186120
        • Kalambokis G.N.
        • Tsianos E.V.
        Rifaximin reduces endotoxemia and improves liver function and disease severity in patients with decompensated cirrhosis.
        Hepatology. 2012; 55: 655-656
        • Bajaj J.S.
        • Heuman D.M.
        • Sanyal A.J.
        • Hylemon P.B.
        • Sterling R.K.
        • Stravitz R.T.
        • et al.
        Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
        PLoS One. 2013; 8e60042
        • Kimer N.
        • Pedersen J.S.
        • Tavenier J.
        • Christensen J.E.
        • Busk T.M.
        • Hobolth L.
        • et al.
        Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: a randomized trial.
        J Gastroenterol Hepatol. 2018; 33: 307-314
        • Zeng X.
        • Tang X.J.
        • Sheng X.
        • Ni W.
        • Xin H.G.
        • Chen W.Z.
        • et al.
        Does low-dose rifaximin ameliorate endotoxemia in patients with cirrhosis: a prospective study.
        J Dig Dis. 2015; 16: 665-674