Morphine Induces Bacterial Translocation in Mice by Compromising Intestinal Barrier Function in a TLR-Dependent Manner

• Published in: PloS one Vol. 8; no. 1; p. e54040
• Main Authors: Meng, Jingjing, Yu, Haidong, Ma, Jing, Wang, Jinghua, Banerjee, Santanu, Charboneau, Rick, Barke, Roderick A., Roy, Sabita
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.01.2013; Public Library of Science (PLoS)
• Subjects: Abuse; Analgesics, Opioid - pharmacology; Animals; Azepines - pharmacology; Bacteria; Bacterial infections; Bacterial Translocation - drug effects; Biology; Blotting, Western; Cell Line; Colon; Colon - drug effects; Colon - metabolism; Colon - microbiology; Defects; Digestive system; Digestive tract; Disease susceptibility; Drug abuse; Drug development; Drugs; Epithelium - drug effects; Epithelium - metabolism; Epithelium - microbiology; Gastrointestinal tract; Health aspects; Ileum; Ileum - drug effects; Ileum - metabolism; Ileum - microbiology; Immune response; Immune system; Immunosuppressive agents; Infection; Infections; Inflammation; Intestinal Mucosa - metabolism; Intestine; Intestines - drug effects; Intestines - microbiology; Kinases; Laboratories; Liver; Liver - drug effects; Liver - metabolism; Liver - microbiology; Lymph nodes; Lymph Nodes - drug effects; Lymph Nodes - metabolism; Lymph Nodes - microbiology; Medical schools; Medicine; Mesentery; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Morphine; Morphine - pharmacology; Muscle proteins; Myosin; Myosin-light-chain kinase; Myosin-Light-Chain Kinase - antagonists & inhibitors; Myosin-Light-Chain Kinase - metabolism; Naphthalenes - pharmacology; Narcotics; Opiates; Opioids; Pain; Permeability; Phosphorylation; Physiology; Prescriptions (Drugs); Proteins; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Sepsis; Signaling; Small intestine; Studies; Surgery; Tight Junctions - drug effects; Tight Junctions - metabolism; TLR2 protein; TNF inhibitors; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Translocation; Tumor necrosis factor-TNF; Zonula Occludens-1 Protein - metabolism; United States > US; Minnesota
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054040

Opiates are among the most prescribed drugs for pain management. However, morphine use or abuse results in significant gut bacterial translocation and predisposes patients to serious infections with gut origin. The mechanism underlying this defect is still unknown. In this report, we investigated the mechanisms underlying compromised gut immune function and bacterial translocation following morphine treatment. We demonstrate significant bacterial translocation to mesenteric lymph node (MLN) and liver following morphine treatment in wild-type (WT) animals that was dramatically and significantly attenuated in Toll-like receptor (TLR2 and 4) knockout mice. We further observed significant disruption of tight junction protein organization only in the ileum but not in the colon of morphine treated WT animals. Inhibition of myosin light chain kinase (MLCK) blocked the effects of both morphine and TLR ligands, suggesting the role of MLCK in tight junction modulation by TLR. This study conclusively demonstrates that morphine induced gut epithelial barrier dysfunction and subsequent bacteria translocation are mediated by TLR signaling and thus TLRs can be exploited as potential therapeutic targets for alleviating infections and even sepsis in morphine-using or abusing populations.