Concomitant COX-1 and COX-2 suppression is not sufficient to induce enteropathy associated with chronic NSAID use
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
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
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Research Article Gastroenterology Inflammation

Concomitant COX-1 and COX-2 suppression is not sufficient to induce enteropathy associated with chronic NSAID use

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.

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

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Figure 2

Chronic naproxen dosing in mice mimics NSAID enteropathy in humans.

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Chronic naproxen dosing in mice mimics NSAID enteropathy in humans. WT C...
WT C57BL/6J mice were treated with either control diet, celecoxib diet (100 mg/kg), or naproxen diet (230 mg/kg) and allowed to feed ad libitum for 3 weeks prior to tissue collection. (A) Ulcer count for total GI tract versus small intestine only as well as pathology score for total GI tract versus small intestine only; males and females are graphed separately. n = 4–6 mice per group. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA. (B) Red blood cell count and hemoglobin measured by complete blood count (CBC); males and females are graphed separately. n = 6–9 mice per group. *P < 0.05 by 1-way ANOVA. (C) Percentage of neutrophils and lymphocytes relative to all white blood cells measured by CBC; males and females are graphed separately. n = 6–9 mice per group. **P < 0.01 by 1-way ANOVA. (D) Spleen weight relative to total BW; males and females are graphed separately. n = 6–9 mice per group. **P < 0.01 by 1-way ANOVA. (E) Serum proteins and liver enzymes measured by clinical automated chemistry analyzer; males and females are graphed separately. n = 3–5 mice per group. *P < 0.05, **P < 0.01 by 1-way ANOVA (top) or unpaired 1-tailed t test (bottom).