Pathological expansion of gut microbiome-associated Enterococcus in advanced cirrhosis corresponds with multilevel perturbations of the gut-liver-immune axis

BackgroundChronic liver disease (CLD) is a progressive condition that can advance to cirrhosis and acute-on-chronic liver failure (ACLF), a syndrome characterised by multi-organ dysfunction, critical illness, and high mortality. ACLF is driven by systemic inflammation, often without overt infection, suggesting alternative immune activation pathways, including microbial translocation. While intestinal perturbations, bacterial translocation, and immune dysfunction are hallmarks of ACLF, the specific microbial contributors remain unclear. ObjectiveTo investigate relationships 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, gut and systemic inflammation and translocation markers, and monocyte dysfunction, in a well-phenotyped cohort of ACLF patients, decompensated and stable cirrhosis, compared to healthy individuals. ResultsAdvanced stages of cirrhosis exhibited higher Enterococcus abundance, correlating with systemic inflammation, particularly in ACLF patients. Anaerobic commensal genera (Roseburia, Ruminococcus, and Faecalibacterium) were significantly lower. Lower urinary hippurate and trimethylamine N-oxide (TMAO) levels, linked to reduced microbial metabolism, paralleled these microbiome changes. Systemic inflammatory markers suggested parallel gut barrier dysfunction and microbial translocation in advanced cirrhosis. ConclusionIntestinal Enterococcus abundance, in advanced cirrhosis with greater antibiotic exposure, is a potential driver of gut barrier inflammation and dysfunction, and systemic immune activation. Further research into tailored microbiome-targeted therapies, including prebiotics, probiotics, phages and focused antibiotic use may prevent Enterococcus dominance, restore gut-liver axis homeostasis, and mitigate disease progression in cirrhosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/25322003v4_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@d0843borg.highwire.dtl.DTLVardef@19966f0org.highwire.dtl.DTLVardef@352be6org.highwire.dtl.DTLVardef@d5146d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LICLD 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. C_LIO_LIThe gut microbiomes 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. C_LI What this study addsO_LIThis study reveals that Enterococcus significantly increases with CLD severity and antibiotic use and correlates with markers of systemic inflammation and gut barrier dysfunction. C_LIO_LIReductions in obligate anaerobe commensal bacteria, such as Roseburia and Faecalibacterium, are observed, alongside depressed levels of key microbial metabolites, including hippurate and TMAO, across CLD stages. C_LIO_LIThese changes suggest that Enterococcus predominance and gut microbiome perturbations driven by factors including disease severity and antibiotic use may actively drive inflammation and impaired monocyte function in CLD. C_LI How this study might affect research, practice, or policyO_LIFindings indicate that Enterococcus and wider gut microbiome perturbations provide a rationale for targeting as therapeutic strategies to modulate the gut-liver axis in CLD. C_LIO_LIThis 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. C_LIO_LIFuture research and development of targeted microbiome therapeutics and rapid infection diagnostics may positively influence CLD management, including a focus on antimicrobial stewardship and informing clinical guidelines whilst improving patient outcomes. C_LI