Grant: Project Grant

Canada has the highest reported prevalence and incidence of inflammatory bowel disease (IBD) in the world. Today, there are 270,000 Canadian adults and children living with IBD, equating to 1 in every 140 people. It is now accepted that Crohn's disease, a major form of IBD, is an inflammatory disease driven by microbes in our gut. However, the mechanisms by which pathogenic or commensal bacteria participate in the disease are not well understood. What is known is that gut inflammation enriches for a population of Escherichia coli, called adherent-invasive E. coli (or AIEC) that have pathogen-like characteristics and are commonly found in Crohn's disease. Using an animal model that my group established, we discovered that AIEC can overcome our body's natural host defenses and gain access to sites in the gastrointestinal tract that normally exclude bacteria. Open questions remain around the origins and evolutionary history of AIEC, preventing a deeper understanding of the evolutionary trajectories and host environments that select for this bacterium in the gut. To address this, we developed a natural host-to-host transmission model to track how AIEC adapts and evolves in the gut over time. AIEC traits that emerged from this model were linked to human disease using clinical E. coli isolates from CD patients, thereby establishing strong clinical relevance. Using this novel transmission model, population metagenomics, and transposon mutant sequencing approaches, our immediate goals are to understand the genetic requirements for AIEC colonization of the inflamed gut and to track the biogeography of AIEC in the gastrointestinal tract at the anatomic and cellular levels. This research is poised to uncover relevant host-microbe interactions in CD that until now have remained enigmatic and hampered progress into the translational domain.