The gastrointestinal tract of humans and other mammals contain a multitude of microorganisms representing a complex, predominantly symbiotic relationship with the host. With nearly 100 trillion intestinal bacteria with which humans have coevolved over millions of years, it is clear that the intestine has had success in navigating host– microbe interactions. As the rise of microbial resistance to antibiotics continues, there is a pressing need for new therapeutic strategies, awakening an interest in targeting antimicrobial peptides (AMPs) as host defense molecules. Epithelial AMPs represent an ancient arm of the innate immune system and play a critical role in maintaining host-microbial interactions. In work recently published by our lab we identified that Ruminococcus gnavus induces expression of a broad suite of intestinal AMPs, including Reg3γ, Reg3β, lysozyme, and α- defensin 5. Interestingly, probiotic administration of R. gnavus protects mice against infection with Clostridioides difficile, a clinically relevant gram-positive pathogen. The overarching objective of this proposal is to investigate these host–microbiota relationships as an opportunity to bolster endogenous defenses. Therefore, the central hypothesis for this proposal is that R. gnavus-mediated induction of AMP expression will prevent infection with intestinal antibiotic-resistant bacteria. I am interested in understanding the underlying mechanism(s) that govern R. gnavus induction of AMP expression, and whether R. gnavus-induced AMP expression protects against a variety of antimicrobial resistant pathogens. In Aim 1, I will explore the specific role of Myd88 and IL-22 in R. gnavus-mediated induction of Reg3γ, Reg3β, lysozyme, and α-defensin 5. In Aim 2, I will determine whether R. gnavus can protect against vancomycin-resistant enterococci (VRE), C. difficile, and Salmonella typhimurium in a Reg3γ- or Reg3β-dependent manner. This proposal will aim to bridge discordant findings relating to mechanisms thought to govern commensal-induced AMP expression and highlight the potential use of probiotic mediated induction of endogenous AMPs as a therapeutic.