Abstract
Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious comorbidities, such as dependence, tolerance, immunosuppression and gastrointestinal disorders limit their long-term use. In the current study, a morphine-murine model was used to investigate the role of the gut microbiome and metabolome as a potential mechanism contributing to the negative consequences associated with opioid use. Results reveal a significant shift in the gut microbiome and metabolome within one day following morphine treatment compared to that observed after placebo. Morphine-induced gut microbial dysbiosis exhibited distinct characteristic signatures, including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance and significant impairment in bile acids and morphine-3-glucuronide/morphine biotransformation in the gut. Moreover, expansion of Enterococcus faecalis was strongly correlated with gut dysbiosis following morphine treatment, and alterations in deoxycholic acid (DCA) and phosphatidylethanolamines (PEs) were associated with opioid-induced metabolomic changes. Collectively, these results indicate that morphine induced distinct alterations in the gut microbiome and metabolome, contributing to negative consequences associated with opioid use. Therapeutics directed at maintaining microbiome homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management.
Highlights
Morphine is the gold standard for pain management
Low microbial diversity correlates with obesity[10,11], inflammatory bowel disease (IBD)[12], and recurrent Clostridium difficile-associated diarrhea (CDAD)[13]
To determine the effect of morphine treatment on the gut microbial profile, we analyzed the gut microbiome based on Illumina sequencing of intestinal microbial 16S-rRNA genes
Summary
Morphine is the gold standard for pain management. Opioid analgesics are frequently prescribed in the United States and worldwide[1]. Our recent study demonstrated that opioid-induced gut microbial disruption and bile acid dysregulation leads to gut barrier compromise and sustained systemic inflammation[18]. It is not yet clear whether morphine treatment perturbs gut microbial homeostasis, resulting in increased growth of potential www.nature.com/scientificreports/. Our results demonstrate that morphine treatment induces a decrease in the diversity of the microbial community and leads to distinct clustering and profiling of the gut microbiome and metabolome when compared to the observations in placebo-treated mice. We demonstrate a cross-correlation and an association between reduced intestinal bacterial communities and bile acid metabolism These results demonstrate that morphine induces a distinct alteration in the gut microbiome and metabolome contributing to opioid-induced pathogenesis and disrupted morphine pharmacokinetics
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