title: Intestinal GPS: bile and bicarbonate control cyclic di-GMP to provide Vibrio cholerae spatial cues within the small intestine.
abstract: The second messenger cyclic di-GMP (c-di-GMP) regulates numerous phenotypes in response to environmental stimuli to enable bacteria to transition between different lifestyles. Here we discuss our recent findings that the human pathogen Vibrio cholerae recognizes 2 host-specific signals, bile and bicarbonate, to regulate intracellular c-di-GMP. We have demonstrated that bile acids increase intracellular c-di-GMP to promote biofilm formation. We have also shown that this bile-mediated increase of intracellular c-di-GMP is negated by bicarbonate, and that this interaction is dependent on pH, suggesting that V. cholerae uses these 2 environmental cues to sense and adapt to its relative location in the small intestine. Increased intracellular c-di-GMP by bile is attributed to increased c-di-GMP synthesis by 3 diguanylate cyclases (DGCs) and decreased expression of one phosphodiesterase (PDE) in the presence of bile. The molecular mechanisms by which bile controls the activity of the 3 DGCs and the regulators of bile-mediated transcriptional repression of the PDE are not yet known. Moreover, the impact of varying concentrations of bile and bicarbonate at different locations within the small intestine and the response of V. cholerae to these cues remains unclear. The native microbiome and pharmaceuticals, such as omeprazole, can impact bile and pH within the small intestine, suggesting these are potential unappreciated factors that may alter V. cholerae pathogenesis.
authors.affiliation: a Department of Microbiology and Molecular Genetics ; Michigan State University ; East Lansing , MI USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Koestler
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D019761:Phosphorus-Oxygen Lyases / Q000378:metabolism; D014734:Vibrio cholerae / Q000235:genetics / Q000378:metabolism*
chemical_list: D001639:Bicarbonates; D001647:Bile Acids and Salts; D029968:Escherichia coli Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D010727:Phosphoric Diester Hydrolases; D019761:Phosphorus-Oxygen Lyases; C060720:diguanylate cyclase; D006152:Cyclic GMP
keywords: BV, bovine bile; DGC, diguanylate cyclase; GGDEF; HD-GYP; LC-MS/MS, liquid chromatography coupled with tandem mass spectrometry; PDE, phosphodiesterase; SHB, synthetic human bile; Vibrio cholerae; WT, wild type; bicarbonate; bile; c-di-GMP, 3′, 5′-cyclic diguanylic acid; cyclic di-GMP