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. SUMMARY BACKGROUND DATA Surgical injury is associated with significant exposure of host tissues to morphine from both endogenous release as well as 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 histological 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 mu 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.

The Preventative Effect of Dietary <i>Apostichopus japonicus</i> on Intestinal Microflora Dysregulation in Immunosuppressive Mice Induced by Cyclophosphamide

“…The intestinal epithelium is composed of rapidly proliferating cells, and is therefore susceptible to Cy. This results in destruction of mucosal barrier and translocation of intestinal microbiota [25] [26]. In this study, the RT-PCR and PCR-DGGE results showed that Cy caused an imbalance in gut microbiota, including decreased abundance of Bifidobacterium, reduced diversity, and altered microflora composition.…”

The Shift of an Intestinal “Microbiome” to a “Pathobiome” Governs the Course and Outcome of Sepsis Following Surgical Injury

“…We have recently shown by 16SrRNA analysis and culture, that the gut of critically ill septic patients undergoes a nearly complete ecologic collapse with emergence of ultra-low diversity pathogen communities of two to four multi-drug resistant healthcare associated pathogens [35]. These pathogens can express virulence in response to host factors such as inorganic phosphate depletion or the release of opioids which are known to transduce the virulence circuitry of highly problematic bacteria such as Pseudomonas aeruginosa [20]. Our laboratory has shown that limitations of phosphate availability in the intestine results in induction of P. aeruginosa and other pathogens to express a lethal phenotype by triggering phosphosensory and regulatory pathways that connect directly to virulence pathways that in turn become activated [38].…”

The gastrointestinal immune system: Implications for the surgical patient

“…Stressors such as hypotension, opioids hypoxia, ischemia, gut starvation, or reductions in gut motility from opioids upregulate genes responsible for the expression of endotoxin-A and pa-1. 149 , 150 These changes increase the ability of the bacteria to attach to mucosal cells and render them more toxic. When these activated bacteria were induced prior to injury, mortality rates of the injured animals increased.…”