Bile Acid-Induced Virulence Gene Expression of Vibrio parahaemolyticus Reveals a Novel Therapeutic Potential for Bile Acid Sequestrants

Abstract

Vibrio parahaemolyticus, a bacterial pathogen, causes human gastroenteritis. A type III secretion system (T3SS2) encoded in pathogenicity island (Vp-PAI) is the main contributor to enterotoxicity and expression of Vp-PAI encoded genes is regulated by two transcriptional regulators, VtrA and VtrB. However, a host-derived inducer for the Vp-PAI genes has not been identified. Here, we demonstrate that bile induces production of T3SS2-related proteins under osmotic conditions equivalent to those in the intestinal lumen. We also show that bile induces vtrA-mediated vtrB transcription. Transcriptome analysis of bile-responsive genes revealed that bile strongly induces expression of Vp-PAI genes in a vtrA-dependent manner. The inducing activity of bile was diminished by treatment with bile acid sequestrant cholestyramine. Finally, we demonstrate an in vivo protective effect of cholestyramine on enterotoxicity and show that similar protection is observed in infection with a different type of V. parahaemolyticus or with non-O1/non-O139 V. cholerae strains of vibrios carrying the same kind of T3SS. In summary, these results provide an insight into how bacteria, through the ingenious action of Vp-PAI genes, can take advantage of an otherwise hostile host environment. The results also reveal a new therapeutic potential for widely used bile acid sequestrants in enteric bacterial infections.

Bile salt–induced intermolecular disulfide bond formation activates Vibrio cholerae virulence

“…Bile salts have previously been implicated in virulence in Vibrio parahaemolyticus (19), but the mechanism of induction is unclear. Interestingly, it has been shown that in a classical strain of V. cholerae (20), bile salts also may affect ToxR activity to enhance ctx production independent of ToxT.…”

The Vibrio cholerae trh Gene Is Coordinately Regulated In Vitro with Type III Secretion System Genes by VttR A /VttR B but Does Not Contribute to Caco2-BBE Cell Cytotoxicity

“…Alternatively, bile may provide a signal for positively modulating the activity of these three regulators. Interestingly, homologs of VttR A and VttR B in V. parahaemolyticus, VtrA and VtrB, were shown to regulate TDH production in the presence and absence of bile, suggesting that different regulatory circuits may control expression in that species (29,38). In V. parahaemolyticus, only a few studies have examined the role of ToxR as a regulator of TDH (29,41).…”

Repression of Salmonella entericaphoPExpression by Small Molecules from Physiological Bile

“…Vibrio cholerae, for example, has been shown to repress the expression of its cholera toxin and toxin-coregulated pilus while upregulating motility in response to bile (15), and some of the molecules involved have been defined (5). Vibrio parahaemolyticus, on the other hand, can sense bile acids to induce the production of its thermostable direct hemolysin, capsule polysaccharide, and other virulence traits (11,24,25). In many cases, hypotheses for the evolutionary advantage of sensing bile and responding in specific manners can be made, although empirical evidence is lacking in most of these cases.…”