Role of the resident microbiota in protecting against enteric infection and inflammation.

We have begun to address the interplay between the resident host microbiota and bacterial pathogens such as Salmonella enterica and Escherichia coli during enteric infection, and the impact of their interactions on host immune response, including inflammation. We are also studying the shifts in microbial populations that occur in inflammatory bowel diseases. Some of our seminal findings in this area indicate that composition of the microbiota plays a significant role in susceptibility and resistance to enteric diseases.

For example, we have found that Citrobacter rodentium, a natural mouse pathogen, which is used as a model for pathogenic E. coli infections of humans, triggers a large shift in the resident microbiota during infection. This shift, including a decrease in overall population and changes in distribution, is caused by pathogen-induced host inflammatory responses. These changes create an environment in which Citrobacter and related species can proliferate. However, once the acquired immune response is triggered, the pathogen is cleared and microbial numbers and composition return to normal.

We’ve been using clinically relevant doses of various antibiotics to cause defined shifts in microbiota and examining how these shifts translate into host susceptibility to infection with enteric pathogens. We have found that animals with some shifts in microbiota result in a marked increase in susceptibility to enteric infections while others do not, and are now working to determine which host, pathogen and resident microbial factors are responsible for the observed effects.

Moreover, we are looking at the role of the microbiota in the development of immune responses. For example, we have shown that Th17 cell development is critically determined by microbial composition. We are probing other immune responses, both innate and acquired, to further examine the role in immune development and disease.

Ultimately, this work will further help us to understand the interplay between the host, the pathogen and the microbiota during infectious diseases, eventually translating into improvements in the management and prevention of enteric infections.