Project Summary/Abstract Clostridium difficile is the most common cause of antibiotic associated diarrhea and has become one of the most frequent hospital acquired infections in the US and Europe. In the early 2000’s, there was a world-wide outbreak of Clostridium difficile Infection (CDI) with increased disease severity. RT078 strains emerged as epidemic strains in 2003 and are among the most commonly isolated strains in hospitals. Several studies have characterized RTo78 strains, along with RT027, as among the most prevalent ribotypes of C. difficile during recent outbreaks; however, the reason for increased prevalence and disease severity remains poorly understood. Interestingly RT078 are the most abundant ribotype found in livestock and contain a novel 4 gene metabolic operon that we hypothesize promotes zoonotic transfer. This proposal seeks to investigate diet as an important factor that enables zoonotic transfer of C. difficile from animals to humans. The overall objectives of this proposal are to assess the impact of metabolism of polysaccharides recently added to the human diet on the competitive fitness and disease severity of clinically isolated RT078 strains and to understand why this ribotype is so dominant in farm animals around the world. Understanding how clinically significant C. difficile lineages have utilized changes in dietary nutrient sources and how these adaptations impacts the transmission of these strains may inform hospitals on dietary guidelines for patients during CDI outbreaks.