Respiratory Tract Dysbiosis is Associated With Worse Outcomes in Mechanically-Ventilated Patients

RATIONALE Host inflammatory responses have been strongly associated with adverse outcomes in critically-ill patients, but the biological underpinnings of such heterogeneous responses have not been defined. OBJECTIVES We examined whether respiratory tract microbiota profiles are associated with host inflammation and clinical outcomes of acute respiratory failure. METHODS We collected oral swabs, endotracheal aspirates (ETA) and plasma samples from mechanically-ventilated patients. We performed 16S rRNA gene sequencing to characterize upper and lower respiratory tract microbiota and classified patients into host-response subphenotypes based on clinical variables and plasma biomarkers of innate immunity and inflammation. We derived diversity metrics and composition clusters with Dirichlet Multinomial Models (DMM) and examined for associations with subphenotypes and clinical outcomes. MEASUREMENTS AND MAIN RESULTS Oral and ETA microbial communities from 301 mechanically-ventilated subjects had substantial heterogeneity in alpha- and beta-diversity. DMM revealed a cluster with low alpha-diversity and enrichment for pathogens (e.g. high Staphylococcus or Pseudomonadaceae relative abundance) in 35% of ETA samples, associated with a hyperinflammatory subphenotype, worse 30-day survival and longer time-to-liberation from mechanical ventilation (adjusted p<0.05), compared to patients with higher alpha-diversity and relative abundance of typical oral microbiota. Patients with evidence of dysbiosis (low alpha diversity and low relative abundance of "protective" oral-origin commensal bacteria) in both oral and ETA samples (17%, combined dysbiosis) had significantly worse 30-day survival and time-to-liberation compared to patients without dysbiosis (55%, adjusted p<0.05). CONCLUSIONS Respiratory tract dysbiosis may represent an important, modifiable contributor to patient-level heterogeneity in systemic inflammatory responses and clinical outcomes.