Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization.

Jingjing Meng,Sabita Roy,Gregory M Sindberg,Fuyuan Wang,Dan Li,Jing Ma,Santanu Banerjee

doi:10.1038/srep10918

Abstract

Sepsis is the predominant cause of mortality in ICUs, and opioids are the preferred analgesic in this setting. However, the role of opioids in sepsis progression has not been well characterized. The present study demonstrated that morphine alone altered the gut microbiome and selectively induced the translocation of Gram-positive gut bacteria in mice. Using a murine model of poly-microbial sepsis, we further demonstrated that morphine treatment led to predominantly Gram-positive bacterial dissemination. Activation of TLR2 by disseminated Gram-positive bacteria induced sustained up-regulation of IL-17A and IL-6. We subsequently showed that overexpression of IL-17A compromised intestinal epithelial barrier function, sustained bacterial dissemination and elevated systemic inflammation. IL-17A neutralization protected barrier integrity and improved survival in morphine-treated animals. We further demonstrated that TLR2 expressed on both dendritic cells and T cells play essential roles in IL-17A production. Additionally, intestinal sections from sepsis patients on opioids exhibit similar disruption in gut epithelial integrity, thus establishing the clinical relevance of this study. This is the first study to provide a mechanistic insight into the opioid exacerbation of sepsis and show that neutralization of IL-17A might be an effective therapeutic strategy to manage Gram-positive sepsis in patients on an opioid regimen.

Highlights

Sepsis is the predominant cause of mortality in intensive care units (ICUs), and opioids are the preferred analgesic in this setting
We further showed that morphine treatment induced enrichment of the Gram-positive bacteria Staphylococcus and Enterococcus in the gut lumen, the same species that were isolated from various systemic organs following cecal ligation and puncture (CLP)
We demonstrated that two commonly prescribed opioids, morphine and methadone, significantly increased mortality rates in a murine model of poly-microbial sepsis, suggesting that the therapeutic window of opioids for pain management might be narrower in septic ICU patients

Summary

Introduction

Sepsis is the predominant cause of mortality in ICUs, and opioids are the preferred analgesic in this setting. In the ICUs, where sepsis is a common occurrence following surgery, attention needs to be directed to the hospital-specific attributes, including (but not limited to) altered metabolism and immune-modulation due to opioid administration, to gain mechanistic insights into poly-microbial sepsis and its potential remedy[4,5]. Due to their analgesic and sedative properties, opioids are widely used in ICUs to optimize patient comfort and facilitate mechanical ventilation[6]. The survival rates of mice were analyzed to investigate the effects of opioids on sepsis progression We demonstrated that both morphine and methadone treatment resulted in high mortality following CLP when compared with placebo-treated animals. Neutralization of IL-17A protected morphine-treated animals from sepsis-induced mortality

Methods

Results

Conclusion