Recurring principles of metabolic interactions in Enterococcus faecalis polymicrobial communities

Enterococcus faecalis is a human gut commensal and major opportunistic pathogen that is frequently found within polymicrobial communities at biofilm-associated infection sites, including the catheterized urinary tract, surgical and chronic wounds, the gut, and oral and mucosal niches. Its interactions with co-isolated bacteria and fungi can alter biofilm formation, antimicrobial susceptibility, immune signaling, and disease severity, yet the molecular basis of these interactions, and whether the same mechanisms recur across anatomically distinct sites, remains incompletely understood. In this review, we explore mechanistic studies of E. faecalis polymicrobial biology, organized around recurring interaction types. We first describe microbial mechanisms such as metabolic cross-feeding and iron-restricted physiology, notably ornithine/arginine exchange, lactate, and heme, as well as quorum sensing and interspecies signaling through the Fsr system, and cross-kingdom interactions with Candida albicans, emphasizing motifs that recur across different infections. We then examine host-coupled dynamics, in which the host participates mechanistically through nutritional immunity, tissue injury, immune modulation, and feedback loops that reshape the community. Throughout this review, we highlight how defined, host-relevant synthetic communities can facilitate mechanistic determinants for clinical co-occurrence, and we outline some of the limitations of current models while proposing priorities for further research.