Exogenous butyrate inhibits butyrogenic metabolism and alters expression of virulence genes 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 in vitro 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, 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 butyrogenic pathway(s) in coincides with alterations in toxin production and sporulation. Together, this work highlights butyrate as a signal of a inhospitable environment to which responds by producing 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 serves as a signal to alter virulence in the face of a highly competitive and dynamic gut environment.