Short-term celecoxib supplementation impacts compositional and functional features of in vitro gut microbial ecosystem

ABSTRACT Celecoxib has been demonstrated effective in preventing colorectal cancer (CRC), through inhibition of altered cyclooxygenase-2 (COX-2) inflammatory pathways. Alas, continuous administration may increase cardiovascular events risk. Understanding microbiome-drug-host interactions is fundamental for improving ADME and safety responses of colon-targeted formulations, but little information is available on the two-way interaction between individual microbiome and celecoxib. Here we evaluated short-term impact of celecoxib on in vitro activity and composition of colon bacterial communities using faecal incubations. 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 suggested 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 in an in vitro enterohepatic cell model. Celecoxib-exposed microbiota preserved barrier function and decreased inflammatory response in a donor-dependent manner. IMPORTANCE As inter-individual changes in the microbiome composition and functionality may be a confounder on pharmacotherapy, we obtained mechanistic understanding on how short-term celecoxib exposure impacts the functional activities of colon communities. Celecoxib-exposed microbiota shifted metabolic activity without impacting numbers of total active bacteria, but only community composition. Thus, increased relative abundance of particular genera during celecoxib supplementation may just indicate changes in maintenance activity. Focus on the influence of acetyl-CoA on cancer cells and verifying whether changes in acetate:propionate:butyrate ratios rather than in taxonomic diversity can be used as markers of decreased inflammation may be the next frontiers for predicting successful NSAID therapy, and ultimately for developing microbiome-based therapies.