Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner.
Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner.
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吗啡通过以TLR依赖性方式损害肠道屏障功能来诱导小鼠细菌易位。
DOI：
10.1371/journal.pone.0054040
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Roy S
中科院分区：
文献类型：
--
作者：
Meng J;Yu H;Ma J;Wang J;Banerjee S;Charboneau R;Barke RA;Roy S
阿片类药物是止痛处方最多的药物之一。然而，使用或滥用吗啡会导致严重的肠道细菌移位，并使患者容易受到肠道来源的严重感染。这种缺陷背后的机制尚不清楚。在这份报告中，我们研究了吗啡治疗后肠道免疫功能受损和细菌易位的机制。我们发现，在野生型(WT)动物中，吗啡治疗后细菌显著易位到肠系膜淋巴结(MLN)和肝脏，而在Toll样受体(TLR2和4)基因敲除小鼠中，这种作用显著减弱。我们进一步观察到，在吗啡处理的WT动物中，紧密连接蛋白组织仅在回肠中显着破坏，而在结肠中没有。肌球蛋白轻链激酶(MLCK)的抑制可阻断吗啡和TLR配体的作用，提示MLCK在TLR对紧密连接的调节中起作用。本研究结果表明，吗啡诱导的肠上皮屏障功能障碍和随后的细菌易位是由TLR信号介导的，因此TLRs可以被用作减轻吗啡使用或滥用人群感染甚至脓毒症的潜在治疗靶点。
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.
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