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.