Secretory bile salt hydrolases regulate niche displacement and gut colonization of vancomycin-resistant Enterococcus

Vancomycin-resistant enterococci (VRE) residing in the gut are major causes of hospital-acquired infections worldwide. Bacteria belonging to the Bacteroidales order have been linked to protection against VRE, but the mechanism remains unclear. Here, we identify an important role for Bacteroidales species in mediating resistance to VRE through a distinct subtype of bile salt hydrolases (BSHs) that retain an uncleaved N-terminal signal peptide. This subclass of BSHs harbored by Bacteroides species promotes VRE inhibition through deoxycholic acid (DCA) production in the presence of Lachnospiraceae bai⁺ bacteria. Mechanistically, the N-terminal signal peptide is required for extracellular enzyme release, DCA production, and VRE growth inhibition. In the presence of VRE, Bacteroidales species producing this subclass of BSH eliminate and displace VRE from its ecological niche through DCA production. These results reveal a previously unknown regulatory role for BSHs in VRE colonization and suggest therapeutic approaches for individuals at risk of VRE infection.