Role of C difficile Colonization in Risk of Disease

Project Summary Clostridioides difficile is a leading cause of healthcare-associated infection with >450,000 cases yearly in the United States. Infection prevention strategies have had limited success at curtailing C. difficile infection rates. Making matters more difficult, individuals can also carry C. difficile asymptomatically. While carriage is both highly prevalent and associated with increased risk of subsequent disease, only a minority of carriers actually progress to disease. The factors responsible for preventing or promoting progression from carriage to disease remain largely unclear. By combining recent improvements in clinical testing algorithms, statistical modeling, and bioinformatics, we aim to undertake a more innovative and comprehensive approach to modeling C. difficile infection. The advent of two-step testing helps to distinguish carriage from disease. Time-to-event models permit accurate and efficient handling of longitudinal outcomes. Finally, advances in bioinformatics facilitate additional insight into the roles of the metagenome and metabolome. Using this multi-modal approach, we seek to improve the current understanding of progression from C. difficile carriage to disease through the following aims: 1) Identify metagenomic/metabolomic risk factors present at time of carriage that are associated with later progression to C. difficile disease; 2) Assess for changes in the metagenome/metabolome temporally associated with progression from carriage to C. difficile disease. 3) Identify C. difficile strain attributes (particularly those related to toxin regulation) associated with risk of progression from carriage to disease; An improved understanding of the factors that prevent or promote progression to disease could inform novel targets for C. difficile prevention and better direct potential therapies to those at highest risk. My short-term goal is to develop a skillset for the analysis of metagenomic and metabolomic data. My long-term goal is to become adept at incorporating metagenomic and metabolomic data into prospective studies of C. difficile acquisition and progression to disease. This proposal is designed to cultivate my development as a future leader in incorporating metagenomic/metabolomic data into studies of infectious disease transmission and prevention.