Fecal metabolite profiling identifies critically ill patients with increased 30-day mortality risk

Critically ill patients admitted to the medical intensive care unit (MICU) have reduced intestinal microbiota diversity and altered microbiome-associated metabolite concentrations. Metabolites produced by the gut microbiota have been associated with survival of patients receiving complex medical treatments, including stem cell and organ transplantation or following intensive care treatment for COVID-19, and thus might represent a treatable trait to improve clinical outcomes. Whether microbiota derived metabolites are associated with mortality in non-COVID-19 critically ill patients is, however, unknown. We prospectively collected fecal specimens, defined microbiome compositions by shotgun metagenomic sequencing, and quantified microbiota-derived fecal metabolites by mass spectrometry from 196 critically ill patients admitted to the MICU for non-COVID-19 respiratory failure or shock and correlated microbiota derived metabolites with 30-day mortality. Taxonomic profiling of fecal samples did not correlate with survival outcomes upon correction for confounding variables. Along similar lines, univariate analysis of fecal metabolite concentrations did not identify correlations with mortality in critically ill patients. Multivariable ridge regression analyses using fecal concentrations of 13 microbiota-derived or -modified metabolites, however, enabled development of a metabolic dysbiosis score (MDS) that, independent of potential confounders, predicts survival of critically ill patients with high accuracy, specificity and sensitivity. The MDS complements existing tools to identify patients at high risk of mortality by incorporating potentially modifiable, microbiome-related, independent contributors to host resilience.