Meng Jingjing, Banerjee Santanu, Li Dan, Sindberg Gregory M, Wang Fuyuan, Ma Jing, Roy Sabita
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota.
Department of Surgery, Division of Infection, Inflammation, and Vascular Biology, University of Minnesota Medical School, Minneapolis, Minnesota.
Sci Rep. 2015 Jun 3;5:10918. doi: 10.1038/srep10918.
Sepsis is the predominant cause of mortality in ICUs, and opioids are the preferred analgesic in this setting. However, the role of opioids in sepsis progression has not been well characterized. The present study demonstrated that morphine alone altered the gut microbiome and selectively induced the translocation of Gram-positive gut bacteria in mice. Using a murine model of poly-microbial sepsis, we further demonstrated that morphine treatment led to predominantly Gram-positive bacterial dissemination. Activation of TLR2 by disseminated Gram-positive bacteria induced sustained up-regulation of IL-17A and IL-6. We subsequently showed that overexpression of IL-17A compromised intestinal epithelial barrier function, sustained bacterial dissemination and elevated systemic inflammation. IL-17A neutralization protected barrier integrity and improved survival in morphine-treated animals. We further demonstrated that TLR2 expressed on both dendritic cells and T cells play essential roles in IL-17A production. Additionally, intestinal sections from sepsis patients on opioids exhibit similar disruption in gut epithelial integrity, thus establishing the clinical relevance of this study. This is the first study to provide a mechanistic insight into the opioid exacerbation of sepsis and show that neutralization of IL-17A might be an effective therapeutic strategy to manage Gram-positive sepsis in patients on an opioid regimen.
脓毒症是重症监护病房（ICU）患者死亡的主要原因，阿片类药物是该情况下首选的镇痛药。然而，阿片类药物在脓毒症进展中的作用尚未得到充分阐明。本研究表明，单独使用吗啡会改变小鼠肠道微生物群，并选择性诱导革兰氏阳性肠道细菌易位。利用多微生物脓毒症小鼠模型，我们进一步证明吗啡治疗主要导致革兰氏阳性菌播散。播散的革兰氏阳性菌激活Toll样受体2（TLR2）可诱导白细胞介素-17A（IL-17A）和白细胞介素-6（IL-6）持续上调。我们随后表明，IL-17A过表达会损害肠道上皮屏障功能，导致细菌持续播散并加剧全身炎症。中和IL-17A可保护屏障完整性，并提高吗啡治疗动物的存活率。我们进一步证明，树突状细胞和T细胞上表达的TLR2在IL-17A产生中起关键作用。此外，接受阿片类药物治疗的脓毒症患者的肠道切片显示肠道上皮完整性存在类似破坏，从而确立了本研究的临床相关性。这是第一项深入探究阿片类药物加重脓毒症机制的研究，表明中和IL-17A可能是治疗接受阿片类药物治疗的革兰氏阳性脓毒症患者的有效策略。
