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Pathogen emergence is a poorly understood complex phenomenon. To date, the molecular mechanisms that allow strains within a bacterial population to emerge as human pathogens remain mostly enigmatic. We recently uncovered that toxigenicVibrio choleraeencode preadaptations to host colonization, what we term virulence adaptive polymorphisms (VAPs), however, the molecular mechanisms driving them are not known.ompUis a VAP-encoding gene that is associated with the production of the major outer membrane porin OmpU. Here, we show that theompUORF also encodes a modular small RNA overlapping its 3’ terminus that plays a major role inV. choleraephysiology. We determined that the OmpU-encoded sRNA (OueS) strongly suppresses biofilm formation, a phenotype that is essential for host intestinal colonization, via repression of iron uptake. OueS controls over 84% of the genes regulated by ToxR, a major virulence regulator, and plays an integral role during the infection process. We demonstrate that OueS is critical for intestinal colonization and its bimodular nature dictates the virulence potential ofV. cholerae. Overall, our study reveals specific molecular mechanisms leading to the emergence of pathogenic traits in bacteria unveiling the hidden genetics associated with this process. We propose a scenario where a limited number of modular genes could explain the emergence of novel phenotypic traits in biological systems.