Grant: Project Grant

Our gut is home to trillions of microbes, called the microbiota, that engage in a synergistic relationship with our body's immune system to maintain health. Disruption of the gut microbiota, or "dysbiosis," is linked to the development of immune system dysfunction and disease, including susceptibility to infections. Nowhere is this more relevant than in the intensive care unit (ICU), where many critically ill patients battle life-threatening infections and sepsis as a result of impaired immune defenses. Recent research has revealed that critically ill patients harbour extreme dysbiosis of their gut microbiota, but how this dysbiosis contributes to the breakdown of immune defense during sepsis is unknown. A crucial site of immune defense against the spread of infections in the bloodstream is the liver, as it is home to specialized anti-bacterial immune cells that are responsible for capturing and clearing pathogens from the blood. Positioned between the gut and the systemic circulation, these liver immune cells are constantly exposed to molecules released by the gut microbiota. We hypothesize that communication between the microbiota and liver immune cells is required to maintain this immune firewall against the spread of infections in the bloodstream, whereas dysbiosis causes a breakdown of liver immune cell function resulting in uncontrolled pathogen dissemination and sepsis. Our research will test this hypothesis using cutting-edge mouse models with "designer microbiota", combined with sophisticated imaging that allows us to directly visualize the function of immune cells in the liver as they combat infections. The overall goal of this research is to discover how the microbiota regulates the liver immune firewall, and use this new knowledge to create precision-guided therapies that restore host defense for the prevention and treatment of infections and sepsis in the ICU.