Celecoxib has been demonstrated effective in the prevention and treatment of chronic inflammatory disorders through inhibition of altered cyclooxygenase-2 (COX-2) pathways. Despite the benefits for preventing colorectal cancer (CRC), 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 faecal microbiota to evaluate 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 both 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 cell models simulating inflammatory milieu in the gut. Our results suggest that celecoxib-microbiome-host interactions may not only elicit adaptations in community composition but also in microbiota functionality and may need to be considered for guaranteeing efficient COX-2 inhibition.IMPORTANCEAs 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 energy. 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.

Soluble corn fiber (SCF) has demonstrated prebiotic effects in clinical studies. Using an in vitro mucosal simulator of the human intestinal microbial ecosystem (M-SHIME®) model, the effects of SCF treatment on colonic microbiota composition and metabolic activity and on host-microbiome interactions were evaluated using fecal samples from healthy donors of different ages (baby [≤ 2 years], n = 4; adult [18–45 years], n = 2; elderly [70 years], n = 1). During the 3-week treatment period, M-SHIME® systems were supplemented with SCF daily (baby, 1.5, 3, or 4.5 g/d; adult, 3 or 8.5 g/d; and elderly, 8.5 g/d). M-SHIME® supernatants were evaluated for their effect on the intestinal epithelial cell barrier and inflammatory responses in lipopolysaccharide. (LPS)-stimulated cells. Additionally, short-chain fatty acid (SCFA) production and microbial community composition were assessed. In the baby and adult models, M-SHIME® supernatants from SCF treated vessels protected Caco-2 membrane integrity from LPS-induced damage. SCF treatment resulted in the expansion of Bacteroidetes, Firmicutes, and Bifidobacterial, as well as increased SCFA production in all age groups. SCF tended to have the greatest effect on propionate production. These findings demonstrate the prebiotic potential of SCF in babies, adults, and the elderly and provide insight into the mechanisms behind the observed prebiotic effects.

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