Opioids and Sepsis: Elucidating the Role of the Microbiome and microRNA-146

Abstract

Sepsis has recently been defined as life-threatening organ dysfunction caused by the dysregulated host response to an ongoing or suspected infection. To date, sepsis continues to be a leading cause of morbidity and mortality amongst hospitalized patients. Many risk factors contribute to development of sepsis, including pain-relieving drugs like opioids, which are frequently prescribed post-operatively. In light of the opioid crisis, understanding the interactions between opioid use and the development of sepsis has become extremely relevant, as opioid use is associated with increased risk of infection. Given that the intestinal tract is a major site of origin of sepsis-causing microbes, there has been an increasing focus on how alterations in the gut microbiome may predispose towards sepsis and mediate immune dysregulation. MicroRNAs, in particular, have emerged as key modulators of the inflammatory response during sepsis by tempering the immune response, thereby mediating the interaction between host and microbiome. In this review, we elucidate contributing roles of microRNA 146 in modulating sepsis pathogenesis and end with a discussion of therapeutic targeting of the gut microbiome in controlling immune dysregulation in sepsis.

Keywords: endotoxin; inflammation; miR-146; miRNA; microbiome; opioids; sepsis.

Figure 1

Dysregulated immune responses in sepsis. Sepsis has recently been defined as life-threatening organ dysfunction caused by the dysregulated host response to an ongoing or suspected infection. Sepsis is marked by simultaneous inflammation and immune suppression, which may persist well past the immediate recovery period. The excessive response of the innate immune system following bacterial invasion results in an overwhelming inflammatory response known as a cytokine storm. Later immunosuppression during sepsis contributes to increased 6- and 12-month mortality rates in up to 20% of survivors of sepsis and septic shock primarily from secondary infections; this results in organ dysfunction and failure. Supportive care and broad-spectrum antibiotic treatment—the mainstays of treatment—have not significantly improved morbidity and mortality amongst hospitalized patients, or patients in the post-recovery period due to persistent immunosuppression and immune dysfunction. Created with BioRender.com.

Figure 2

Interactions between opioids, the microbiome, and sepsis. Accumulating studies have implicated opioid-induced microbial dysbiosis in the development of sepsis and septic shock. The microbiome plays a critical role in intestinal homeostasis; under physiological conditions, intestinal microbial homeostasis promotes resistance to pathogen colonization through maintenance of the gut epithelial barrier, production of short-chain fatty acids (SCFA), and regulation of immune cells. Chronic opioid treatment results in loss of gut commensals and protective metabolites responsible for maintaining the gut epithelial barrier. Increased intestinal epithelial cell permeability allows for bacterial translocation in extra-intestinal spaces, which results in intestinal and systemic inflammation (mediated by TLR signaling) and dysregulated immune responses. Mir-146a, which plays a key role in immune tolerance by inhibiting IRAK1 and TRAF6, as well as other signaling pathways such as Notch-1 to lessen the inflammatory response, has been shown to be attenuated with morphine treatment. Altogether, this dysregulated immune response can predispose to sepsis. The mainstays of sepsis treatment, in particular antibiotics, further contribute to gut microbial dysbiosis, perpetuating this cycle. Figure created with BioRender.com.