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

Area of Science:

• Immunology
• Microbiology
• Critical Care Medicine

Background:

• Sepsis is a leading cause of ICU mortality.
• Opioids are common analgesics in sepsis but their role in disease progression is unclear.

Purpose of the Study:

• To investigate the impact of morphine on sepsis progression.
• To elucidate the mechanisms by which opioids may exacerbate sepsis.
• To explore potential therapeutic targets for opioid-exacerbated sepsis.

Main Methods:

• Murine model of polymicrobial sepsis.
• Assessment of gut microbiome alterations and bacterial translocation.
• Analysis of immune responses including Toll-like receptor 2 (TLR2), Interleukin-17A (IL-17A), and Interleukin-6 (IL-6) levels.
• Evaluation of intestinal epithelial barrier function.
• IL-17A neutralization studies in vivo.
• Analysis of human intestinal tissue samples from sepsis patients on opioids.

Main Results:

• Morphine alone altered the gut microbiome and induced Gram-positive bacterial translocation.
• Morphine-treated septic mice showed increased Gram-positive bacterial dissemination.
• Activation of TLR2 by Gram-positive bacteria led to sustained IL-17A and IL-6 upregulation.
• Overexpression of IL-17A compromised intestinal barrier function, promoted bacterial spread, and increased systemic inflammation.
• IL-17A neutralization improved barrier integrity and survival in morphine-treated septic mice.
• TLR2 on dendritic cells and T cells are crucial for IL-17A production.
• Human sepsis patients on opioids showed similar gut epithelial disruption.

Conclusions:

• Morphine exacerbates Gram-positive sepsis by disrupting the gut barrier and promoting bacterial translocation.
• The TLR2-IL-17A axis plays a critical role in opioid-induced sepsis exacerbation.
• Neutralization of IL-17A represents a potential therapeutic strategy for Gram-positive sepsis in patients receiving opioid therapy.