Microbial oral-gut translocation in advanced chronic liver disease is linked to exacerbation of intestinal barrier dysfunction and hepatic fibrosis

While microbiome perturbations are associated with advanced chronic liver disease (ACLD), microbial disease mechanisms are poorly understood. Using multi-omics analyses of paired saliva and faecal samples from an ACLD cohort, we identified next-to-identical oral and gut bacterial strains (including Veillonella and Streptococcus spp.) which increased in absolute abundance in the gut of ACLD patients. These translocators uniquely encoded a collagenase-like proteinase (prtC) with the potential for gut barrier disruption and prtC faecal abundance was a robust ACLD biomarker (auPR=0.91). CCl4-treated mice inoculated with Veillonella and Streptococcus prtC-encoding patient isolates showed exacerbation of gut barrier impairment and hepatic fibrosis. Furthermore, faecal collagenase activity was increased in ACLD patients and experimentally confirmed for the prtC gene from translocating Veillonella parvula. Overall, our study establishes mechanistic links between oral-gut translocation and ACLD pathobiology, and identifies the oral microbiome as an important contributing factor with potential for microbial diagnostics and therapeutics.