Abstract The mammalian GI tract is colonized by trillions of microbes, which live in a predominantly symbiotic relationship with their host and exert a profound affect on host physiology. Enterococcus faecalis is a common colonizer of the mammalian gut and normally behaves as a symbiont. However, under certain circumstances, E. faecalis acts as an opportunistic pathogen, invading from the gut and causing systemic infection. To gain a better understanding of E. faecalis’s transition from symbiont to pathogen, we have developed a novel mouse model of E. faecalis colonization that does not require disruption of the intestinal microbiota. This allows the study of E. faecalis colonization during homeostasis. Our recent work, using this model, demonstrated the role of enterococcal bacteriocins, plasmid-encoded antimicrobial peptides produced by E. faecalis, in intestinal niche competition, and demonstrated a proof-of-concept that bacteriocin-producing E. faecalis can be used therapeutically to eliminate colonization by multidrug resistant enterococcal strains. Cephalosporin treatment of the mice induces E. faecalis expansion, invasion, and systemic spread, recapitulating the process seen in human disease. Thereby, our model allows the study of several challenging questions regarding commensal colonization and host interaction and the mechanisms that determine the balance between homeostasis and disease. The focus of our work addresses the following key questions regarding host-commensal interaction: 1. What are the mechanisms that commensals, such as E. faecalis, use to adapt and colonize the intestines? 2. What are the host mechanisms that contribute to commensal colonization and containment? 3. How does inflammatory or antibiotic disruption of the intestinal environment alter E. faecalis adaptation and drive transition from symbiotic to pathogenic behavior? 4. What are the roles of bacteriocins in mediated bacterial- bacterial and bacterial-host interaction? 5. Can we use our understanding of intestinal niche competition and bacteriocin function to alter intestinal colonization to specifically eliminate multi-drug resistant bacterial populations? A more complete understanding of the mechanistic contributions of both host and microbe to commensal colonization will ultimately allow rational targeted manipulation of the microbiota for the prevention and treatment of disease. !