Exogenous butyrate inhibits butyrogenic metabolism and alters virulence phenotypes in .

The gut microbiome engenders colonization resistance against the diarrheal pathogen but the molecular basis of this colonization resistance is incompletely understood. A prominent class of gut microbiome-produced metabolites important for colonization resistance against is short-chain fatty acids (SCFAs). In particular, one SCFA (butyrate) decreases the fitness of and is correlated with -inhospitable gut environments, both in mice and in humans. Here, we demonstrate that butyrate-dependent growth inhibition in occurs under conditions where also produces butyrate as a metabolic end product. Furthermore, we show that exogenous butyrate is internalized into cells and is incorporated into intracellular CoA pools where it is metabolized in a reverse (energetically unfavorable) direction to crotonyl-CoA and ()-3-hydroxybutyryl-CoA and/or 4-hydroxybutyryl-CoA. This internalization of butyrate and reverse metabolic flow of a butyrogenic pathway(s) in coincides with alterations in toxin release and sporulation. Together, this work highlights butyrate as a marker of a -inhospitable environment to which responds by releasing its diarrheagenic toxins and producing environmentally resistant spores necessary for transmission between hosts. These findings provide foundational data for understanding the molecular and genetic basis of how growth is inhibited by butyrate and how butyrate alters virulence in the face of a highly competitive and dynamic gut environment.IMPORTANCEThe gut microbiome engenders colonization resistance against the diarrheal pathogen but the molecular basis of this colonization resistance is incompletely understood, which hinders the development of novel therapeutic interventions for infection (CDI). We investigated how responds to butyrate, an end-product of gut microbiome community metabolism which inhibits growth. We show that exogenously produced butyrate is internalized into , which inhibits growth by interfering with its own butyrate production. This growth inhibition coincides with increased toxin release from cells and the production of environmentally resistant spores necessary for transmission between hosts. Future work to disentangle the molecular mechanisms underlying these growth and virulence phenotypes will likely lead to new strategies to restrict growth in the gut and minimize its pathogenesis during CDI.