CRITICAL FUNCTIONS OF THE GUT MICROBIOTA THAT MEDIATE RECOVERY FROM RECURRENT CLOSTRIDIUM DIFFICILE INFECTION

ABSTRACTRecurrent Clostridium difficile infection (CDI) affects 20-30% of patients following successful treatment of aninitial disease episode. It is hypothesized that the gut microbiota, the microbial community within thegastrointestinal tract, is involved in the development of and recovery from recurrence. Microbial-basedtreatments that promote the growth of `healthy' bacteria, such as fecal microbiota transplantation (FMT), haveemerged as an effective treatment method for recurrent CDI. Nevertheless, there is a fundamental lack ofknowledge of the microbes responsible for functions that contribute to colonization resistance against C.difficile. We have characterized a murine model of recurrent infection, and observed that murine fecal materialfrom healthy mice is capable of mediating efficient clearance of C. difficile. Previous studies using germ-freemice have successfully established colonization resistance against C. difficile with human microbiota. Contraryto this, we observed that FMT from healthy humans did not resolve CDI in our model. While both FMTtreatments changed the microbiota composition, we observed deficient levels of several metabolites. Ourmouse model of recurrent CDI provides us with a method to understand how community structures assembleto provide colonization resistance against CDI, enabling us to differentiate the critical microbial features incolonization resistance against C. difficile. We hypothesize that the metabolic environment that limits C. difficilecolonization and growth is dependent on the assembly of succinct microbiota communities. The scientificobjective of this proposal is to elucidate the link between the structure and function of a microbial communitycapable of mediating resistance to or recovery from CDI. We aim to do this using the following specific aims: 1)define structural features in microbial communities that mediate colonization resistance to C. difficile and 2)identify metabolic pathways in microbial communities that resolve CDI. The training objective of this proposal isto complement the trainee's background in microbial ecology with bioinformatic and experimental skills thatfocus on functions of microbial communities to support transition of the candidate into an independent,translational investigator. Completion of these aims will result in more comprehensive knowledge of howmicrobes function to provide colonization resistance, aiding the critical need to prevent or treat CDI, animportant healthcare-associated infection. In conjunction with the exceptional mentoring team and institutionalenvironment, this proposal will provide the candidate with scientific skills and career mentorship to become anindependent investigator in an inter-disciplinary field encompassing both microbial ecology and infectiousdisease.