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Introduction
Non-Steroidal Anti-Inflammatory Drugs ( NSAIDs) are used worldwide both as prescription and
over-the-counter products for their analgesic, anti-inflammatory and cardiovascular disease (CVD)
risk-reduction properties, and are among the most used pharmaceuticals in the world today 1 .
Chronic, low-dose use (commonly defined as 75-325 mg daily) of the NSAID Acetylsalicylic Acid
(ASA) is widely recommended for both primary and secondary prevention of CVD. More than 30%
of the US population aged above 40 are estimated to be on chronic, daily, low-dose ASA for that
reason alone 2 . However, chronic use of ASA is also associated with adverse side effects including
small-intestinal mucosal lesions and ulcers, perforations, major hemorrhage and in rare instances
death 3,4,5 . A recent review and meta-analysis addressing both the efficacy of ASA in prevention of
CVD and also bleeding-related side-effects concluded that a balanced, cautious approach should be
taken in the case of primary CVD prevention due to these side-effects 6 , highlighting the unmet need
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to reduce the risk of side-effects of chronic ASA use.
For decades endoscopists have acknowledged the vulnerability of the gastroduodenal mucosa to
NSAID-induced enteropathy. Complications include ulceration, blood loss, protein loss, perforation
and occasional strictures. The pathogenesis of tissue injury at the gastric and small-intestinal sites
appears to differ 7,8 , and therefore distinct and separate preventative strategies are probably required
to combat enteropathy and gastropathy. For example, the risk of gastropathy can be offset by acid
suppression, usually with proton pump inhibitors (PPIs). However, the pathogenesis of NSAID-
induced damage in the small bowel seems to be much more complex and has been shown to involve
microbiota composition, bile and enterohepatic circulation of the certain NSAIDs 8 . Moreover, there
is evidence to suggest that PPIs may actually increase the risk of NSAID-associated small bowel
injury 9 , possibly by disturbing the composition of the small bowel microbiota 10 . The importance of
the microbiota is emphasised by the fact that administration of NSAIDs to germ-free animals is
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