MlrA, a MerR family regulator in <i>Vibrio cholerae</i>, senses the anaerobic signal in the small intestine of the host to promote bacterial intestinal colonization.

<i>Vibrio cholerae</i> (<i>V. cholerae</i>), one of the most important bacterial pathogens in history, is a gram-negative motile bacterium that causes fatal pandemic disease in humans via oral ingestion of contaminated water or food. This process involves the coordinated actions of numerous regulatory factors. The MerR family regulators, which are widespread in prokaryotes, have been reported to be associated with pathogenicity. However, the role of the MerR family regulators in <i>V. cholerae</i> virulence remains unknown. Our study systematically investigated the influence of MerR family regulators on intestinal colonization of <i>V. cholerae</i> within the host. Among the five MerR family regulators, MlrA was found to significantly promote the colonization capacity of <i>V. cholerae</i> in infant mice. Furthermore, we revealed that MlrA increases bacterial intestinal colonization by directly enhancing the expression of <i>tcpA</i>, which encodes one of the most important virulence factors in <i>V. cholerae</i>, by binding to its promoter region. In addition, we revealed that during infection, <i>mlrA</i> is activated by anaerobic signals in the small intestine of the host through Fnr. In summary, our findings reveal a MlrA-mediated virulence regulation pathway that enables <i>V. cholerae</i> to sense environmental signals at the infection site to precisely activate virulence gene expression, thus providing useful insights into the pathogenic mechanisms of <i>V. cholerae</i>.