Proton Pump Inhibitors Exacerbate NSAID-Induced Small Intestinal Injury by Inducing Dysbiosis
Abstract
Background & aims Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used classes of drugs, with the former frequently coprescribed to reduce gastroduodenal injury caused by the latter. However, suppression of gastric acid secretion by PPIs is unlikely to provide any protection against the damage caused by NSAIDs in the more distal small intestine.Methods Rats were treated with antisecretory doses of omeprazole or lanzoprazole for 9 days, with concomitant treatment with anti-inflammatory doses of naproxen or celecoxib on the final 4 days. Small intestinal damage was blindly scored, and changes in hematocrit were measured. Changes in small intestinal microflora were evaluated by denaturing gradient gel electrophoresis and reverse-transcription polymerase chain reaction.Results Both PPIs significantly exacerbated naproxen- and celecoxib-induced intestinal ulceration and bleeding in the rat. Omeprazole treatment did not result in mucosal injury or inflammation; however, there were marked shifts in numbers and types of enteric bacteria, including a significant reduction (∼80%) of jejunal Actinobacteria and Bifidobacteria spp. Restoration of small intestinal Actinobacteria numbers through administration of selected (Bifidobacteria enriched) commensal bacteria during treatment with omeprazole and naproxen prevented intestinal ulceration/bleeding. Colonization of germ-free mice with jejunal bacteria from PPI-treated rats increased the severity of NSAID-induced intestinal injury, as compared with mice colonized with bacteria from vehicle-treated rats.Conclusions PPIs exacerbate NSAID-induced intestinal damage at least in part because of significant shifts in enteric microbial populations. Prevention or reversal of this dysbiosis may be a viable option for reducing the incidence and severity of NSAID enteropathy.
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In rats, a PPI-driven significant reduction of Actinobacteria and Bifidobacteria spp. in the jejunum was shown to exacerbate NSAID-induced enteropathy.
“In rats, a PPI-driven significant reduction of Actinobacteria and Bifidobacteria spp. in the jejunum was shown to exacerbate NSAID-induced enteropathy[98].”
From Proton pump inhibitors and dysbiosis: current knowledge and aspects to be clarified (2019) · cites this paper as [98]
Germ-free mice are less susceptible to intestinal lesions induced by NSAIDs and NSAID-induced enteropathy is transferable via microbiota.
“Moreover, germ-free mice are less susceptible to intestinal lesions induced by NSAIDs and it has been documented that NSAID-induced enteropathy is transferable via microbiota[98,101,102].”
From Proton pump inhibitors and dysbiosis: current knowledge and aspects to be clarified (2019) · cites this paper as [98]
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- Authors
- Wallace, J. L., Syer, S., Denou, E., de Palma, G., Vong, L., McKnight, W., Jury, J., Bolla, M., Bercik, P., Collins, S. M., Verdu, E., & Ongini, E.
- Affiliations
- McMaster University (CA)
- Corresponding author
- Wallace, John L.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 141
- Issue
- 4
- Pages
- 1314-1322.e5
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2002924275
- Cited by
- 460
- References
- 52
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 16 · 2023: 29 · 2022: 17 · 2021: 31 · 2020: 36 · 2019: 33 · 2018: 37 · 2017: 46 · 2016: 40 · 2015: 39 · 2014: 40 · 2013: 30 · 2012: 28
- FWCI
- 23.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- proton pump inhibitors, NSAID-induced intestinal injury, dysbiosis, small intestinal mucosal damage, omeprazole, naproxen, celecoxib, Bifidobacterium, actinobacteria, enteric microbiota, NSAID-induced enteropathy, germ-free mice, intestinal ulceration
- MeSH terms
- Celecoxib, Animals, Anti-Inflammatory Agents, Non-Steroidal, Bifidobacterium, Colon, Disease Models, Animal, Drug Interactions, Hematocrit, Gastrointestinal Hemorrhage, Jejunum, Male, Naproxen, Omeprazole, Peptic Ulcer, Pyrazoles, Sulfonamides, Time Factors, Rats, Wistar, Probiotics, Reverse Transcriptase Polymerase Chain Reaction, Actinobacteria, Rats, 2-Pyridinylmethylsulfinylbenzimidazoles, Proton Pump Inhibitors, Denaturing Gradient Gel Electrophoresis, Lansoprazole
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