The role of the intestinal microbiota in pneumonia and sepsis

Humans carry with them trillions of bacteria, viruses and fungi that are collectively called the human microbiota. The intestinal microbiota fulfills essential functions in human physiology and has recently been suggested as a potential therapeutic target for several diseases. This thesis focuses on the role of the intestinal microbiota in pneumonia and sepsis. Our main hypothesis was that the gut microbiota plays a protective role in innate host defenses against systemic bacterial infections; i.e., that microbiota disruption by antibiotics would negatively affect the innate immune response during pneumonia and sepsis. In a translational fashion we used both murine and human models to test this hypothesis. We observed profound microbial disturbances in septic patients: bacterial genera that are involved in metabolism had disappeared, as well as bacteria that are supposed to have beneficial immunomodulatory effects. In healthy humans, microbiota disruption by broad-spectrum antibiotics slightly affected the innate immune response in vitro, but not in vivo. In mice, microbiota disruption by broad-spectrum antibiotics was associated with increased growth of bacteria during pneumonia-induced sepsis. Furthermore, our data suggest that the intestinal microbiota of different groups of mice may be a confounder in infection- and inflammation-related mouse models. Antibiotics are essential in treating infections, but may have indirect side-effects that we are currently unaware of. The interplay between (intestinal) microbiota, immune system, pathogens and other antibiotics is difficult to dissect. However, modulation of the intestinal microbiota should be further explored as a potential therapeutic tool to boost the immune system of septic patients