Celecoxib supplementation impacts compositional and functional features of in vitro gut microbial ecosystem

Abstract: Cyclooxygenase-2 (COX-2) inflammatory pathways are altered in colon carcinogenesis (CRC). COX-2 inhibitors (coxibs), such as celecoxib, have successfully reduced COX-2 and prevented CRC recurrence. Alas, their continuous administration may increase cardiovascular events risk [1]. Currently, little information is available on how inter-individual variations in colon microbiota impact overall celecoxib disposition. Thus, characterisation of the players involved is necessary to understand microbiome-drug-host interactions, and relevance towards ADME and safety responses for intestinal targets [2]. In vitro batch culture experiments were conducted to assess short-term effect of celecoxib on activity and composition of the colon microbial community. Faecal slurries from eight volunteers were supplied with 100 mg/ml of celecoxib and anaerobically incubated for 16h, to simulate conditions and transit time of the proximal colon. Short-chain fatty acid (SCFAs), and particularly butyrate production showed overall shift compared to control incubations, suggesting that celecoxib impacts in vitro fermentation, in a donor-dependent manner. Total active bacterial population was not significantly different between treatments, but composition and structure were influenced. Celecoxib determination post-bacterial exposure implied bacterial transformation of celecoxib, but quantification of the metabolised amount varied due to a donor-dependent extraction efficiency. However, bacterially-exposed celecoxib decreased inflammatory response and preserved barrier function in a multicompartment cell model. Our results provide preliminary information about the microbiota interplay on the efficacy of colon-targeted coxibs. As the colonocyte-protective properties of gut microbiome products such as butyrate may be impacted, the colon environment may result altered [3]. Hence, potentially stratifying patients based on their microbiome may be a future strategy for guaranteeing efficient COX-2 inhibition in CRC therapy.

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