Opioid Use Potentiates the Virulence of Hospital Acquired Infection, Increases Systemic Bacterial Dissemination and Exacerbates Gut Dysbiosis in a Murine Model of Citrobacter Rodentium Infection

Abstract

Background: Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit their use. It was recently demonstrated that morphine treatment results in a significant disruption in gut barrier function, leading to an increased translocation of gut commensal bacteria. Further studies have indicated distinct alterations in the gut microbiome and metabolome following morphine treatment, contributing to the negative consequences that are associated with opioid use. However, it is unclear how opioids modulate gut homeostasis in the context of a hospital acquired bacterial infection. Methods: In the current study, a mouse model of C. rodentium infection was used to investigate the role of morphine in the modulation of gut homeostasis in the context of a hospital acquired bacterial infection. Citrobacter rodentium is a natural mouse pathogen that models intestinal infection by enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and causes attaching and effacing lesions and colonic hyperplasia. Findings: Morphine treatment resulted in 1) the promotion of C. rodentium systemic dissemination, 2) an increase in the expression of the virulence factors of C. rodentium colonization in intestinal contents, 3) altered gut microbiome, 4) damaged integrity of gut epithelial barrier function, 5) inhibition of the C. rodentium-induced increase in goblet cells, and 6) dysregulated IL-17A immune response. Interpretation: This is the first study to demonstrate that morphine promotes pathogen dissemination in the context of an intestinal C. rodentium infection, indicating that morphine modulates the virulence factor-mediated adhesion of pathogenic bacteria and induces disruption of mucosal host defense during C. rodentium intestinal infection in mice. This study demonstrates and further validates a positive correlation between opioid drug use/abuse and an increased risk of infections, suggesting that the overprescription of opioids may increase the risk of the emergence of pathogenic strains and should therefore be prescribed cautiously. Therapeutics that are directed at maintaining gut homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management. Funding Statement: This work was supported by the NIH grants R01 DA043252, R01 DA037843, R01 DA044582, and R01 DA047089 to SR. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All animals were maintained in specific-pathogen-free facilities, and all procedures were approved by the University of Minnesota Institutional Animal Care and Use Committee (IACUC). The IACUC protocol number was 1203A11091. All procedures were conducted in line with the guidelines set forth by the National Institutes of Health Guide for the Care and Use of Laboratory Animals.