Dynamic interaction between Escherichia coli enterotoxins and bacteriocins.

The intestinal microbiota constitutes a crucial defense barrier against pathogenic invasion; however, the molecular mechanisms enabling pathogens to evade or modulate this defense remain poorly understood. Here, we established a coculture model combining the commensal Escherichia coli Y18J, isolated from the piglet gut, and the enterotoxigenic E. coli (ETEC) strain W25K to investigate microbe-pathogen interactions. Our findings reveal a bidirectional regulatory mechanism between Y18J and W25K mediated by bacteriocin and toxin signaling. Colicin B/M produced by Y18J upregulates the expression of heat-stable enterotoxin (ST) in W25K during the early phase of coculture, while ST suppresses colicin B/M synthesis in Y18J. At later stages, colicin B/M stimulates heat-labile enterotoxin (LT) expression, which in turn enhances colicin B/M production. Notably, LT markedly reduces intestinal colonization of W25K(ST⁻LT⁺) in murine hosts. Leveraging metagenomic and bioinformatic analyses, we further identified a Ligilactobacillus strain within the murine gut microbiota capable of producing multiple bacteriocins that effectively inhibit W25K colonization. Transcriptomic profiling of Y18J revealed glutamine synthetase as a pivotal regulator of colicin B/M-mediated antagonism. Mechanistic investigations demonstrated that ST suppresses colicin B/M expression through the cGMP signaling pathway, whereas LT enhances it via the cAMP signaling pathway. Collectively, these findings uncover a dual regulatory mechanism through which bacterial enterotoxins modulate probiotic antimicrobial activity, providing new insights into the molecular dialog between commensal and pathogenic bacteria. This study establishes a conceptual framework for developing microbiota-based strategies to prevent and control enteric infections.