Zoltán S. Zádori1, Bernadette Lázár1, Szilvia B. László1, Mihály Balogh1, Kornél Király1, Mahmoud Al-Khrasani1, Eszter Ostorházi2, Dóra Szabó2, Klára Gyires1
1 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University
2 Institute of Medical Microbiology, Semmelweis University
Introduction: It is increasingly recognized that nonsteroidal anti-inflammatory drugs induce significant small intestinal injury and dysbiosis. Although selective cyclooxygenase-2 (COX-2) inhibitors are considered to be safe for the upper gastrointestinal tract, their long-term safety in the small bowel is less clear. Moreover, the effect of selective COX-2 inhibition on the composition of small intestinal microbiota has never been addressed before. Aims: The present study was designed to evaluate the long-term effects of selective COX-2 inhibitors on the small intestinal mucosal integrity and microbiota in the rat. Method: Male Wistar rats were treated with different doses of celecoxib, rofecoxib, etoricoxib or vehicle for 4 weeks. The non-selective COX inhibitor indomethacin was used as a positive control. NSAID-evoked mucosal changes were evaluated macroscopically and histologically. The composition of jejunal microflora was determined by deep sequencing of 16S rRNA. The direct effects of rofecoxib and celecoxib on the growth of various bacteria were examined by the broth microdilution assay. Results: 1. The non-selective COX inhibitor indomethacin induced dose-dependent intestinal injury. In contrast, none of the selective COX-2 inhibitors caused any appreciable macroscopic or histological intestinal damage. 2. In contrast to celecoxib, rofecoxib had no direct antibacterial effect in vitro, and did not influence the abundance of small intestinal organisms or the diversity of microbiota. Conclusion: Our results so far suggest that chronic selective cyclooxygenase-2 inhibition does not cause mucosal damage in the distal segments of the small intestine. Moreover, we demonstrate for the first time that long-term inhibition of COX-2 does not influence the small intestinal microbiota, and the observed dysbiotic effect of celecoxib may be due to its direct antibacterial property. The research was supported by the National Research, Development and Innovation Office of Hungary (NKFI FK 124878), and by the ÚNKP-17-4 New National Excellence Program of the Ministry of Human Capacities.
Doctoral School: Doctoral School of Pharmaceutical Sciences
Program:Experimental and Clinical Pharmacology (supervisor)
Supervisor: not applicable