Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
J Crohns Colitis. 2020 Jul 9;14(6):801-817. doi: 10.1093/ecco-jcc/jjz188.
Opioids are the most prescribed analgesics for pain in inflammatory bowel diseases [IBD]; however, the consequences of opioid use on IBD severity are not well defined. This is the first study investigating consequences of hydromorphone in both dextran sodium sulphate [DSS]-induced colitis and spontaneous colitis (IL-10 knockout [IL-10-/-]) mouse models of IBD.
To determine the consequences of opioids on IBD pathogenesis, wild-type [WT] mice were treated with clinically relevant doses of hydromorphone and colitis was induced via 3% DSS in drinking water for 5 days. In parallel we also determined the consequences of opioids in a spontaneous colitis model.
Hydromorphone and DSS independently induced barrier dysfunction, bacterial translocation, disruption of tight junction organisation and increased intestinal and systemic inflammation, which were exacerbated in mice receiving hydromorphone in combination with DSS. Hydromorphone + DSS-treated mice exhibited significant microbial dysbiosis. Predictive metagenomic analysis of the gut microbiota revealed high abundance in the bacterial communities associated with virulence, antibiotic resistance, toxin production, and inflammatory properties. Hydromorphone modulates tight junction organisation in a myosin light chain kinase [MLCK]-dependent manner. Treatment with MLCK inhibitor ML-7 ameliorates the detrimental effects of hydromorphone on DSS-induced colitis and thus decreases severity of IBD. Similarly, we demonstrated that hydromorphone treatment in IL-10-/- mice resulted in accelerated clinical manifestations of colitis compared with control mice.
Opioids used for pain management in IBD accelerate IBD progression by dysregulation of the gut microbiota, leading to expansion of pathogenic bacteria, translocation of bacteria, immune deregulation and sustained inflammation.
阿片类药物是治疗炎症性肠病（IBD）疼痛的最常用镇痛药；然而，阿片类药物使用对 IBD 严重程度的影响尚未明确。这是第一项研究，旨在调查氢吗啡酮在葡聚糖硫酸钠（DSS）诱导的结肠炎和自发性结肠炎（IL-10 基因敲除[IL-10-/-]）IBD 小鼠模型中对 IBD 发病机制的影响。
为了确定阿片类药物对 IBD 发病机制的影响，用临床相关剂量的氢吗啡酮处理野生型[WT]小鼠，并通过饮用水中的 3% DSS 诱导 5 天结肠炎。同时，我们还在自发性结肠炎模型中确定了阿片类药物的影响。
氢吗啡酮和 DSS 独立诱导屏障功能障碍、细菌易位、紧密连接组织的破坏以及肠道和全身炎症的增加，而在接受氢吗啡酮联合 DSS 治疗的小鼠中则加剧了这些情况。接受氢吗啡酮+DSS 治疗的小鼠表现出明显的微生物失调。对肠道微生物群的预测性宏基因组分析显示，与毒力、抗生素耐药性、毒素产生和炎症特性相关的细菌群落丰度较高。氢吗啡酮通过肌球蛋白轻链激酶[MLCK]依赖性方式调节紧密连接组织。用 MLCK 抑制剂 ML-7 治疗可改善氢吗啡酮对 DSS 诱导的结肠炎的不良影响，从而降低 IBD 的严重程度。同样，我们证明，与对照小鼠相比，氢吗啡酮治疗在 IL-10-/-小鼠中导致结肠炎的临床症状加速。
阿片类药物用于治疗 IBD 中的疼痛会通过调节肠道微生物群而加速 IBD 进展，导致致病菌扩张、细菌易位、免疫失调和持续炎症。
