Pathological expansion of gut microbiome-associatedEnterococcusin advanced cirrhosis corresponds with multilevel perturbations of the gut-liver-immune axis
Authors: Dalby Matthew J , Kiu Raymond , Stamouli Marilena , Arefaine Betsy , Leong Lex E X , Hales Jack , Bernsmeier Christine , Singanayagam Arjuna , Støy Sidsel , Maxan Maria-Emanuela , Mohamad Merianne , Zamalloa Ane , Lewis Matt , Vincent Royce P. , Cox I. Jane , Le Guennec Adrien , Williams Roger , Edwards Lindsey A , Chokshi Shilpa , Thursz Mark , Beraza Naiara , Antoniades Charalambos G , Rogers Geraint B , Wendon Julia A , Bruce Kenneth D , Shawcross Debbie L , McPhail Mark JW , Hall Lindsay J , Patel Vishal C 
Published: February 2025

AbstractBackgroundChronic liver disease (CLD) is a progressive condition that, in its advanced stages, leads to cirrhosis with related clinical complications, and can lead to acute-on-chronic liver failure (ACLF) - a syndrome marked by critical illness, multi-organ dysfunction and high mortality. Systemic inflammation in ACLF can occur without overt infection, indicating alternative pathways of immune activation and microbial translocation. Intestinal perturbations, bacterial translocation, and the resulting systemic inflammation and immune dysfunction are defining features of ACLF, yet the identification of specific microbial contributors remains poorly elucidated.ObjectiveTo investigate the relationship between gut microbiome alterations, systemic inflammation, and clinical markers of disease severity across the cirrhosis spectrum.DesignThis cross-sectional, prospective study analysed faecal microbiota, plasma bile acids, urinary and plasma metabolites, markers of gut and systemic inflammation and translocation, and monocyte dysfunction, in a well-phenotyped cohort of patients with ACLF, decompensated cirrhosis and stable cirrhosis, in comparison with healthy individuals.ResultsAdvanced stages of cirrhosis were marked by a higher abundance ofEnterococcus, which correlated with markers of systemic inflammation, particularly in ACLF patients. Concurrently, the abundance of anaerobic commensal genera such asRoseburia,Ruminococcus, andFaecalibacteriumwere significantly lower. Lower urinary hippurate and trimethylamine N-oxide TMAO levels, linked to reduced microbial metabolism and dietary fibre intake, paralleled these microbiome changes. While elevated plasma primary bile acids reflected hepatic dysfunction, systemic inflammatory markers suggested parallel gut barrier dysfunction and microbial translocation in advanced cirrhosis.ConclusionThis study underscores a potential role of greater intestinalEnterococcusabundance, as cirrhosis severity increases and where clinically there is more antibiotic exposure, as a driver of gut barrier inflammation and dysfunction, and systemic immune dysfunction in advanced cirrhosis. Further research into tailored microbiome-targeted therapies, including prebiotics and probiotics, and more focused antibiotic use may preventEnterococcusdominance and restore gut-liver axis homeostasis and mitigate disease progression in CLD.Key messagesWhat is already known on this topicCLD can progress to ACLF, a life-threatening syndrome with high mortality rates characterised by systemic inflammation, impaired phagocytosis and immune dysfunction with associated multiple organ failure.The gut microbiome’s role in underpinning the gut-liver axis is recognised, with microbial perturbations and gut barrier dysfunction associated with CLD, yet the exact microbiome changes and their link to inflammatory pathways remain unclear.What this study addsThis study reveals thatEnterococcussignificantly increases with CLD severity and antibiotic use and correlates with markers of systemic inflammation and gut barrier dysfunction.Reductions in obligate anaerobe commensal bacteria, such asRoseburiaandFaecalibacterium, are observed, alongside depressed levels of key microbial metabolites, including hippurate and TMAO, across CLD stages.These changes suggest thatEnterococcuspredominance and gut microbiome perturbations driven by factors including disease severity and antibiotic use may actively drive inflammation and impaired monocyte function in CLD.How this study might affect research, practice, or policyFindings indicate thatEnterococcusand wider gut microbiome perturbations provide a rationale for targeting as therapeutic strategies to modulate the gut-liver axis in CLD.This highlights the potential of microbiome-focused interventions, such as faecal microbial transplantation, probiotics, prebiotics or phages, to improve gut health, reduce gut and systemic inflammation, and ultimately mitigate cirrhosis-related complications.Future research and development of targeted microbiome therapeutics may positively influence CLD management including a focus on antimicrobial stewardship, and inform clinical guidelines whilst improving patient outcomes.