Here, we conducted faecal incubations to assess short-term effect of celecoxib on activity and composition of colon microbial communities. Moreover, we assessed whether colon microbiota modulates anti-inflammatory efficacy of celecoxib in an in vitro enterohepatic cell model. Our results suggest a possible interplay of gut microbiota on the efficacy of colon-targeted coxibs. Exploring the diagnostic utility of only screening variations in bacterial relative abundances may be misleading. For this reason, focus on functionality rather than taxonomic diversity may be the next frontier for developing predictive markers of CRC-induced dysbiosis, and ultimately for the use of microbiome-based therapies.