title: Prevention of siderophore- mediated gut-derived sepsis due to P. aeruginosa can be achieved without iron provision by maintaining local phosphate abundance: role of pH.
abstract: BACKGROUND
  During extreme physiological stress, the intestinal tract can be transformed into a harsh environment characterized by regio- spatial alterations in oxygen, pH, and phosphate concentration. When the human intestine is exposed to extreme medical interventions, the normal flora becomes replaced by pathogenic species whose virulence can be triggered by various physico-chemical cues leading to lethal sepsis. We previously demonstrated that phosphate depletion develops in the mouse intestine following surgical injury and triggers intestinal P. aeruginosa to express a lethal phenotype that can be prevented by oral phosphate ([Pi]) supplementation.
  
  
  RESULTS
  In this study we examined the role of pH in the protective effect of [Pi] supplementation as it has been shown to be increased in the distal gut following surgical injury. Surgically injured mice drinking 25 mM [Pi] at pH 7.5 and intestinally inoculated with P. aeruginosa had increased mortality compared to mice drinking 25 mM [Pi] at pH 6.0 (p < 0.05). This finding was confirmed in C. elegans. Transcriptional analysis of P. aeruginosa demonstrated enhanced expression of various genes involved in media alkalization at pH 6.0 and a global increase in the expression of all iron-related genes at pH 7.5. Maintaining the pH at 6.0 via phosphate supplementation led to significant attenuation of iron-related genes as demonstrated by microarray and confirmed by QRT-PCR analyses.
  
  
  CONCLUSIONS
  Taken together, these data demonstrate that increase in pH in distal intestine of physiologically stressed host colonized by P. aeruginosa can lead to the expression of siderophore-related virulence in bacteria that can be prevented without providing iron by maintaining local phosphate abundance at pH 6.0. This finding is particularly important as provision of exogenous iron has been shown to have untoward effects when administered to critically ill and septic patients. Given that phosphate, pH, and iron are near universal cues that dictate the virulence status of a broad range of microorganisms relevant to serious gut origin infection and sepsis in critically ill patients, the maintenance of phosphate and pH at appropriate physiologic levels to prevent virulence activation in a site specific manner can be considered as a novel anti-infective therapy in at risk patients.
authors.affiliation: Department of Surgery, the University of Chicago, IL 60637, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Romanowski
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaborin
authors.forename: Hoylan
authors.initials: H
authors.lastname: Fernandez
authors.forename: Valeriy
authors.initials: V
authors.lastname: Poroyko
authors.forename: Vesta
authors.initials: V
authors.lastname: Valuckaite
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gerdes
authors.forename: Donald C
authors.initials: DC
authors.lastname: Liu
authors.forename: Olga Y
authors.initials: OY
authors.lastname: Zaborina
authors.forename: John C
authors.initials: JC
authors.lastname: Alverdy
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000382:microbiology; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000737:chemistry* / Q000382:microbiology; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010710:Phosphates / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D017262:Siderophores / Q000378:metabolism*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D010710:Phosphates; D017262:Siderophores; D007501:Iron