title: Pseudomonas aeruginosa virulence expression is directly activated by morphine and is capable of causing lethal gut-derived sepsis in mice during chronic morphine administration.
abstract: OBJECTIVE
  This study was designed to examine the effect of morphine administration on the intestinal mucus barrier and determine its direct effect on the virulence and lethality of Pseudomonas aeruginosa, one of the most frequent pathogens to colonize the gut of critically ill patients.
  
  
  BACKGROUND
  Surgical injury is associated with significant exposure of host tissues to morphine from both endogenous release and its use as a potent analgesic agent. Morphine use in surgical patients exposed to extreme physiologic stress is well established to result in increased infection risk. Although morphine is a known immunosuppressant, whether it directly induces virulence expression and lethality in microbes that colonize the human gut remains unknown.
  
  
  METHODS
  Mice were implanted with a slow release morphine or placebo pellet with and without intestinal inoculation of P. aeruginosa created by direct cecal injection. Mucus production and epithelial integrity was assessed in cecal tissue via Alcian blue staining and histologic analysis. In vivo and in vitro P. aeruginosa virulence expression was examined using reporter strains tagged to the epithelial barrier disrupting protein PA-I lectin. P. aeruginosa chemotaxis toward morphine was also assayed in vitro. Finally, the direct effect of morphine to induce PA-I lectin expression was determined in the absence and presence of methylnaltrexone, a μ opioid receptor antagonist.
  
  
  RESULTS
  Mice intestinally inoculated with P. aeruginosa and implanted with a morphine pellet demonstrated significant suppression of intestinal mucus, disrupted intestinal epithelium, and enhanced mortality; whereas exposure of mice to either systemic morphine or intestinal P. aeruginosa alone enhanced intestinal mucus without mortality, suggesting a shift in P. aeruginosa during morphine exposure to a mucus suppressing, barrier disrupting, and lethal phenotype. Direct exposure of P. aeruginosa to morphine in vitro confirmed that morphine can transform P. aeruginosa to a more virulent phenotype that is attenuated in part by methylnaltrexone.
  
  
  CONCLUSIONS
  Morphine administration shifts intestinal P. aeruginosa to express a virulent phenotype and may play a role in its ability to causes lethal gut-derived sepsis in a susceptible host.
authors: Center of Surgical Infection Research and Therapeutics, Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors: Trissa
authors: T
authors: Babrowski
authors: Christopher
authors: C
authors: Holbrook
authors: Jonathan
authors: J
authors: Moss
authors: Lawrence
authors: L
authors: Gottlieb
authors: Vesta
authors: V
authors: Valuckaite
authors: Alexander
authors: A
authors: Zaborin
authors: Valeriy
authors: V
authors: Poroyko
authors: Donald C
authors: DC
authors: Liu
authors: Olga
authors: O
authors: Zaborina
authors: John C
authors: JC
authors: Alverdy
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002633:Chemotaxis; D007413:Intestinal Mucosa / Q000382:microbiology* / Q000503:physiopathology; D037102:Lectins / Q000378:metabolism*; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D011552:Pseudomonas Infections / Q000382:microbiology* / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000382:microbiology* / Q000401:mortality; D014774:Virulence / Q000187:drug effects; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D000701:Analgesics, Opioid; D037102:Lectins; D037521:Virulence Factors; C038692:adhesin, Pseudomonas; D009020:Morphine