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.

中文翻译：

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在肠道微生物生态系统的模拟模型上短期补充塞来昔布移位的丁酸酯生产，并改善了体外炎症。

塞来昔布通过抑制改变的环氧合酶2（COX-2）途径，有效预防和治疗慢性炎症。尽管有好处，但连续给药可能会增加心血管事件的风险。了解微生物与药物-宿主之间的相互作用是改善结肠定位制剂的药物处置和安全性响应的基础，但有关单个微生物组与塞来昔布之间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群的体外分批孵化，以获取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概念验证。塞来昔布暴露的微生物群改变了代谢活性和群落组成，而总的转录活性细菌种群没有显着变化。丁酸酯产量以供体依赖性方式降低了50％，表明塞来昔布影响体外发酵。微生物群来源的乙酸盐与癌症标志物的抑制作用有关，我们的结果表明，在提供塞来昔布后，乙酸盐可吸收细菌功能，这可能促进细菌竞争乙酰-CoA。我们进一步评估了结肠微生物群是否使用简化的炎症模型和肠肝代谢的新型体外模拟来调节塞来昔布的抗炎功效。在我们的两个模拟肠道炎性环境的模型中，塞来昔布仅占细菌群落组成变化的5％，但是塞来昔布暴露的微生物群保留了供体依赖性方式的屏障功能并降低了IL-8和CXCL16的浓度。我们的结果表明，塞来昔布-微生物组-宿主相互作用不仅可能引起群落组成的适应，而且引起微生物群功能的适应，因此可能需要考虑这些因素以保证有效抑制COX-2。