Critical functions of the gut microbiota that mediate recovery from recurrent Clostridium difficile infection

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ABSTRACT Recurrent Clostridium difficile infection (CDI) affects 20-30% of patients following successful treatment of an initial disease episode. It is hypothesized that the gut microbiota, the microbial community within the gastrointestinal tract, is involved in the development of and recovery from recurrence. Microbial-based treatments that promote the growth of `healthy' bacteria, such as fecal microbiota transplantation (FMT), have emerged as an effective treatment method for recurrent CDI. Nevertheless, there is a fundamental lack of knowledge 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 material from healthy mice is capable of mediating efficient clearance of C. difficile. Previous studies using germ-free mice have successfully established colonization resistance against C. difficile with human microbiota. Contrary to this, we observed that FMT from healthy humans did not resolve CDI in our model. While both FMT treatments changed the microbiota composition, we observed deficient levels of several metabolites. Our mouse model of recurrent CDI provides us with a method to understand how community structures assemble to provide colonization resistance against CDI, enabling us to differentiate the critical microbial features in colonization resistance against C. difficile. We hypothesize that the metabolic environment that limits C. difficile colonization and growth is dependent on the assembly of succinct microbiota communities. The scientific objective of this proposal is to elucidate the link between the structure and function of a microbial community capable 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 is to complement the trainee's background in microbial ecology with bioinformatic and experimental skills that focus 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 how microbes function to provide colonization resistance, aiding the critical need to prevent or treat CDI, an important healthcare-associated infection. In conjunction with the exceptional mentoring team and institutional environment, this proposal will provide the candidate with scientific skills and career mentorship to become an independent investigator in an inter-disciplinary field encompassing both microbial ecology and infectious disease.