O157:H7 Senses Microbiota-produced Riboflavin to Increase Its Virulence in the Gut

Riboflavin is produced by most commensal bacteria in the human colon, where enterohemorrhagic (EHEC) colonizes and causes diseases. Sensing environmental signals to site-specifically express the type-III secretion system (T3SS), which injects effectors into host cells leading to intestinal colonization and disease, is key to the pathogenesis of EHEC. Here, we reveal that EHEC O157:H7, a dominant EHEC serotype frequently associated with severe diseases, acquired a previously uncharacterized two-component regulatory system , which senses microbiota-produced riboflavin to directly activate the expression of LEE genes encoding the T3SS in the colon. is present in O157:H7 and O145:H28 but absent from other EHEC serotypes. The binding site of RbfR through which it regulates LEE gene expression was identified and is conserved in all EHEC serotypes and , a surrogate for EHEC in mice. Introducing into enabled bacteria to sense microbiota-produced riboflavin in the mouse colon to increase the expression of LEE genes, causing increased disease severity in mice. Phylogenic analysis showed that the O55:H7 ancestor of O157:H7 obtained which has been kept in O157:H7 since then. Thus, acquiring represents an essential step in the evolution of the highly pathogenic O157:H7. The expression of LEE genes and cell attachment ability of other EHEC serotypes in the presence of riboflavin significantly increased when was introduced into them, indicating that those serotypes are ready to use RbfSR to increase their pathogenicity. This may present a potential public health issue as horizontal gene transfer is frequent in enteric bacteria.