Bile Acid Imbalance in Morphine Induced Gut Barrier Compromise and Systemic Inflammation: Role of CYP7A1 and F-x-R

Despite being predominant drugs of choice for anti-nociception, morphine and its pharmacological derivatives result in severe co-morbidities studied in numerous disease models in mice and humans due to peripheral side effects. Opioids have been shown to promote gram-positive bacterial translocation across the gut mucosa, leading to systemic inflammation and sepsis in a TLR2 dependent manner. We have also shown that bacterial translocation due to the gut mucosal barrier compromise are a part of the commensal flora. In this study, we show for the first time that morphine fosters significant gut microbial dysbiosis and altered cholesterol/bile acid metabolism in WT mice. Recent studies have strongly correlated microbial/bile-acid dysbiosis to gut barrier disruption and host inflammation. In this context, role of hepatic cholesterol-7α-hydroxylase (CYP7A1) and Farnesoid-x-receptor (FxR; hepatic and intestinal) have been strongly implicated in complications arising due to bile acid imbalance. Here, we show the role of bile acid changes due to chronic morphine in gut barrier dysfunction in the context of TLR2/cholesterol hydroxylase/farnesoid-x-receptor modulation.