Short-term supplementation of celecoxib-shifted butyrate production on a simulated model of the gut microbial ecosystem and ameliorated in vitro inflammation
Short-term supplementation of celecoxib-shifted butyrate production on a simulated model of the gut microbial ecosystem and ameliorated in vitro inflammation
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DOI：
10.1038/s41522-020-0119-0
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发表时间：
2020-02-19
影响因子：
9.2
通讯作者：
Van de Wiele, Tom
中科院分区：
文献类型：
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作者：
Hernandez-Sanabria, Emma;Heiremans, Evelien;Van de Wiele, Tom
塞来昔布通过抑制改变的环氧合酶-2(COX-2)通路而有效地预防和治疗慢性炎症性疾病。尽管有好处，但持续给药可能会增加心血管事件的风险。了解微生物-药物-宿主相互作用对于改善结肠靶向制剂的药物处置和安全反应是基本的，但关于单个微生物群与塞来昔布之间的双向相互作用的信息很少。在这里，我们进行了人类粪便微生物区系的体外批量培养，以获得塞来昔布对结肠细菌群落的活性和组成的短期影响的机械性概念证明。塞来昔布暴露的微生物区系改变了代谢活性和群落组成，而转录活性细菌总数没有显著变化。丁酸产量以供体依赖的方式减少了50%，这表明塞来昔布对体外发酵有影响。微生物区系衍生的醋酸盐与癌症标志物的抑制有关，我们的结果表明，当提供塞来昔布时，细菌功能摄取了醋酸盐，这可能有利于细菌对乙酰辅酶A的竞争。我们使用简化的炎症模型和一种新的肠肝代谢的体外模拟，进一步评估了结肠微生物区系是否调节了塞来昔布的抗炎效果。塞来昔布只解释了细菌群落组成变化的5%，但在我们的两个模拟肠道炎症环境的模型中，塞来昔布暴露的微生物区系以供体依赖的方式保留了屏障功能并降低了IL-8和CXCL16的浓度。我们的结果表明，塞来昔布-微生物-宿主的相互作用不仅可能在群落组成上引起适应，而且在微生物区系功能上也可能引起适应，这些可能需要被考虑以确保有效地抑制COX-2。
Celecoxib has been effective in the prevention and treatment of chronic inflammatory disorders through inhibition of altered cyclooxygenase-2 (COX-2) pathways. Despite the benefits, continuous administration may increase risk of cardiovascular events. Understanding microbiome-drug-host interactions is fundamental for improving drug disposition and safety responses of colon-targeted formulations, but little information is available on the bidirectional interaction between individual microbiomes and celecoxib. Here, we conducted in vitro batch incubations of human faecal microbiota to obtain a mechanistic proof-of-concept of the short-term impact of celecoxib on activity and composition of colon bacterial communities. Celecoxib-exposed microbiota shifted metabolic activity and community composition, whereas total transcriptionally active bacterial population was not significantly changed. Butyrate production decreased by 50% in a donor-dependent manner, suggesting that celecoxib impacts in vitro fermentation. Microbiota-derived acetate has been associated with inhibition of cancer markers and our results suggest uptake of acetate for bacterial functions when celecoxib was supplied, which potentially favoured bacterial competition for acetyl-CoA. We further assessed whether colon microbiota modulates anti-inflammatory efficacy of celecoxib using a simplified inflammation model, and a novel in vitro simulation of the enterohepatic metabolism. Celecoxib was responsible for only 5% of the variance in bacterial community composition but celecoxib-exposed microbiota preserved barrier function and decreased concentrations of IL-8 and CXCL16 in a donor-dependent manner in our two models simulating gut inflammatory milieu. Our results suggest that celecoxib-microbiome-host interactions may not only elicit adaptations in community composition but also in microbiota functionality, and these may need to be considered for guaranteeing efficient COX-2 inhibition.