Abstract
Colonization resistance is a fundamental mechanism by which microbiomes suppress pathogen invasion; however, the ecological and mechanistic determinants of its efficacy remain incompletely understood. Here, we constructed a defined microbial consortium and employed in vivo shrimp infection models to investigate the synergistic interaction between commensal microbes and a pathogen-specific phage in suppressing the pathogen Vibrio parahaemolyticus. Our in vitro experiment revealed that combining key taxa, particularly with phage integration, markedly enhanced pathogen exclusion. Furthermore, we demonstrated that establishing the consortium prior to pathogen exposure resulted in the irreversible suppression of pathogen proliferation, highlighting the critical importance of timing. Mechanistic analyses revealed that nutrient competition from commensals triggered prophage activation in the pathogen, thereby inhibiting its proliferation. Leveraging these insights, we rationally designed a minimalist, yet effective consortium that, when coupled with phage predation, consistently conferred robust colonization resistance in shrimp. This study delineates the core ecological principle underlying microbiota-mediated colonization resistance and establishes a tractable phage-commensal framework for pathogen control, with translational relevance in the context of rising antibiotic resistance in aquatic and potentially mammalian systems.