| Title: | Concomitant COX-1 and COX-2 suppression is not sufficient to induce enteropathy associated with chronic NSAID use |
| Journal: | Journal of Clinical Investigation |
| Published: | 27 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41591833/ |
| DOI: | https://doi.org/10.1172/jci190575 |
| URL: | http://www.jci.org/articles/view/190575/files/pdf |
Publication 18462
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Abstract
NSAIDs are the most widely used medications for the management of chronic pain; however, they are associated with numerous gastrointestinal (GI) adverse events. Although many mechanisms have been suggested, NSAID-induced enteropathy is thought to be primarily due to inhibition of both COX-1 and -2, which results in suppression of prostaglandin synthesis. Yet surprisingly, we found that concomitant postnatal deletion of Cox-1 and -2 over 10 months failed to cause intestinal injury in mice unless they were treated with naproxen or its structural analog, phenylpropionic acid, which is not a COX inhibitor. Cox double-knockout mice exhibited a distinct gut microbiome composition, and cohousing them with controls rescued their dysbiosis and delayed the onset of NSAID-induced GI bleeding. In both the UK Biobank and All of Us human cohorts, coadministration of antibiotics with NSAIDs was associated with an increased frequency of GI bleeding. These results showed that prostaglandin suppression played a trivial role in NSAID-induced enteropathy. However, Cox deletion caused dysbiosis of the gut microbiome, which amplified the enteropathic response to NSAIDs.</p>
15 Keywords
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
- Cyclooxygenase 1
- Cyclooxygenase 2
- Dysbiosis
- Female
- Gastrointestinal Hemorrhage
- Gastrointestinal Microbiome
- Humans
- Intestinal Diseases
- Male
- Membrane Proteins
- Mice
- Mice, Knockout
- Naproxen
22 Authors
- Kayla Barekat
- Soumita Ghosh
- Christin Herrmann
- Karl Keat
- Charles-Antoine Assenmacher
- Ceylan Tanes
- Naomi Wilson
- Ronan Lordan
- Antonijo Mrčela
- Lubica Rauova
- Arjun Sengupta
- Ujjalkumar Subhash Das
- Robin Joshi
- Elliot Friedman
- Marylyn D. Ritchie
- Kyle Bittinger
- Aalim Weljie
- Ken Cadwell
- Frederic D. Bushman
- Gary D. Wu
- Garret A. FitzGerald
- Emanuela Ricciotti
1 Application
| Application ID | Title |
|---|---|
| 32133 | Integration of multi-organ imaging phenotypes, clinical phenotypes, and genomic data |
Enabling scientific discoveries that improve human health