Progression of chronic liver diseases is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections, impact gut microbiome composition and metabolite production. Using a multi-omics approach on 850 fecal samples from 263 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal Bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen, which, in combination, can reduce the growth of antibiotic-resistant pathobionts such as Vancomycin-resistant Enterococcus faecium. Our studies suggest that lactulose and Bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.

The authors have declared no competing interest.

This work was funded privately by the Duchossois Family Institute at the University of Chicago Authors were funded by the National Institutes of Health as follows: T32DK007074 (M.A.O.) U01AA026975 (T.G.C.)

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The Institutional Review Board of the University of Chicago gave ethical approval for this work.

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In addition to the repositories specified below, all raw data included in the manuscript is publicly available at: https://github.com/yingeddi2008/DFILiverDiseaseMicrobiome. 1. Metagenomic information is publicly available on NCBI under BioProject ID PRJNA912122. 2. Quantitative fecal metabolomic information paired to fecal metagenomic information is publicly available on NCBI under BioProject ID PRJNA912122. 3. Raw data files are publicly available on MetaboLights project ID MTBLS7046.