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A2775 - The Gut Microbiota Promotes Intravascular Immunity Against Bacterial Dissemination During Sepsis
Author Block: B. McDonald, C. Jenne; Critical Care Medicine, University of Calgary, Cumming School of Medicine, Calgary, AB, Canada.
Rationale: Within the intensive care unit, significant alterations in the gut microbiota have been identified in critically ill septic patients, but the impact of this “dysbiosis” on host immune defenses during sepsis are poorly understood. Understanding the nature and mechanisms by which the microbiota impacts host immune function (or dysfunction) during sepsis represents a important unanswered question in the field of critical care research, and may uncover new therapeutic avenues to combat the scourge of sepsis-related morbidity and mortality. We hypothesized that the normal gut microbiota protects against the spread of infection during sepsis through the regulation of intravascular innate immune defenses.
Methods: We tested our hypothesis in a well-characterized mouse model of bacterial sepsis induced by Staphylococcus aureus (MRSA, USA300) bacteremia in mice with normal gut microbiota compared to animals with disrupted microbiota using antibiotic-mediated microbiota ablation. Intravascular immune function was characterized using in vivo multi-color confocal microscopy of neutrophil and macrophage function within the liver microvasculature of septic mice.
Results: In septic controls, neutrophils and macrophages within the microvasculature efficiently captured and cleared S. aureus from the bloodstream through the release of intravascular neutrophil extracellular traps (NETs) as well as macrophage-mediated phagocytosis of bacteria. In contrast, animals with depleted gut microbiota displayed severe abnormalities of intravascular anti-bacterial defenses, leading to increased levels of bacteremia as well as dissemination of infection. In vivo characterization of neutrophil and macrophage effector functions revealed profound impairment of neutrophil extracellular trap (NET) production in microbiota-depleted mice, resulting in an inability to capture and clear bacteria from the bloodstream. In addition to defects in host defense, microbiota-depleted animals displayed further immunopathology including augmented systemic inflammation with increased serum levels of pro-inflammatory cytokines as well as increased inflammatory lung injury.
Conclusions: Disruption of the normal gut microbiota results in impaired host defense during sepsis as a result of defective intravascular neutrophil extracellular trap production, resulting in the spread of bacterial infections, as well as augmented systemic inflammation and end-organ damage. These findings identify the gut microbiota as a critical regulator of intravascular immunity during sepsis.