Abstract
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.
Highlights
Prostaglandin E2 (PGE2) is a key mucosal inflammatory mediator produced when membrane phospholipids are metabolized by cyclooxygenase (COX) enzymes
Previous research showed that COX-2 expression correlates to invasiveness, prognosis, and survival in some cancers,[3] such as colorectal cancer (CRC),[4] causing proliferation, enhanced angiogenesis and apoptosis suppression.[5]
Total Short-chain fatty acids (SCFAs) production from separate faecal microbiota incubations of eight different individuals was significantly lower for CX incubations compared to those with PEG (P < 0.05, Table 1b), but pH remained stable throughout the experiment (Supplementary Table 1)
Summary
Prostaglandin E2 (PGE2) is a key mucosal inflammatory mediator produced when membrane phospholipids are metabolized by cyclooxygenase (COX) enzymes. When colon-targeted drugs are orally administered, they encounter the gut microbiota before reaching host tissues. Microbial drug metabolism may impact drug stability and activity, influencing toxicity and inflammation on the host.[15] drugs may alter the gut microbiota, modulating community structure, and potentially resulting in dysbiosis.[16] Understanding microbiome-drug-host interactions is crucial to assess the potential impact on ADME and safety responses of intestinal targets. Besides the microbial modulation of drug bioavailability and pharmacokinetics,[15] low solubility and small aqueous volumes in the colon may hinder drug efficacy.[18] As interest in developing novel colon-targeted NSAID delivery systems has increased, insight into the presystemic biotransformation by the gut microbiota is fundamental. Whether CX presence can modulate the host-microbiome crosstalk remains unresolved
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