Probiotic nutrition is frequently claimed to improve human health. In particular, live probiotic bacteria obtained with food are believed to reduce pathogen colonization and thus, susceptibility to infection. However, the underlying mechanisms remain poorly understood. Here, we report that the consumption of probiotic Bacillus bacteria comprehensively abolishes colonization with the dangerous pathogen, Staphylococcus aureus . We discovered that the widespread fengycin class of Bacillus lipopeptides achieves colonization resistance by inhibiting the S. aureus Agr quorum-sensing signaling system. Our study presents a detailed molecular mechanism underlining the importance of probiotic nutrition in reducing infectious disease. Notably, we provide human evidence supporting the biological significance of probiotic bacterial interference and show for the first time that such interference can be achieved by blocking a pathogen’s signaling system. Furthermore, our findings suggest a probiotic-based method for S. aureus decolonization and new ways to fight S. aureus infections.

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Social interactions play an increasingly recognized key role in bacterial physiology 1 . One of the best studied is quorum sensing (QS), a mechanism by which bacteria sense and respond to the status of cell density 2 . While QS is generally deemed crucial for bacterial survival, QS-dysfunctional mutants frequently arise in in-vitro culture. This has been explained by the fitness cost an individual mutant, a “quorum cheater”, saves at the expense of the community 3 . QS mutants are also often isolated from biofilm-associated infections, including cystic fibrosis lung infection 4 , as well as medical device infection and associated bacteremia 5 – 7 . However, despite the frequently proposed use of QS blockers to control virulence 8 , the mechanisms underlying QS dysfunctionality during infection have remained poorly understood. Here we show that in the major human pathogen Staphylococcus aureus , QS-dysfunctional mutants arise exclusively in biofilm infection, while in non-biofilm-associated infection there is a high selective pressure to maintain QS control. We demonstrate that this infection-type dependence is due to QS-dysfunctional bacteria having a significant survival advantage in biofilm infection, because they form dense and enlarged biofilms that provide resistance to phagocyte attacks. Our results link the benefit of QS-dysfunctional mutants in vivo to biofilm-mediated immune evasion, thus to mechanisms that are specific to the in-vivo setting. Notably, our findings explain why QS mutants are frequently isolated from biofilm-associated infections and provide guidance for the therapeutic application of QS blockers.