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Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high risk human users, leading to an underestimate of the true toxicity of the drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, and hypertensive rats and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence.

The clinical significance of small intestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains under-appreciated. It occurs with greater frequency than the damage caused by these drugs in the upper gastrointestinal tract, but is much more difficult to diagnose and treat. Although the pathogenesis of NSAID enteropathy remains incompletely understood, it is clear that bacteria, bile, and the enterohepatic circulation of NSAIDs are all important factors. However, they are also interrelated with one another. Bacterial enzymes can affect the cytotoxicity of bile and are essential for enterohepatic circulation of NSAIDs. Gram-negative bacteria appear to be particularly important in the pathogenesis of NSAID enteropathy, possibly through release of endotoxin. Inhibitors of gastric acid secretion significantly aggravate NSAID enteropathy, and this effect is due to significant changes in the intestinal microbiome. Treatment with antibiotics can, in some circumstances, reduce the severity of NSAID enteropathy, but published results are inconsistent. Specific antibiotic-induced changes in the microbiota have not been causally linked to prevention of intestinal damage. Treatment with probiotics, particularly Bifidobacterium, Lactobacillus, and Faecalibacteriaum prausnitzii, has shown promising effects in animal models. Our studies suggest that these beneficial effects are due to colonization by the bacteria, rather than to products released by the bacteria.

At first sight, environmental enteropathy and NSAID enteropathy may appear to have little in common. One occurs almost exclusively in poor countries and the other primarily in rich countries. One is the consequence of unhygienic living conditions, while the other is a consequence of use of a drug for relief of pain and inflammation. However, there may be a common pathogenic link between these two conditions, namely a significant alteration in the microbiome (dysbiosis), and this raises the possibility of common approaches to treatment. Correction of the dysbiosis that is central to the intestinal tissue injury and dysfunction observed in environmental and nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathies is a logical approach to bringing about restoration of intestinal function. For both conditions, removal of the trigger for dysbiosis is the simplest approach, but is not always feasible. Correcting the underlying dysbiosis through the use of probiotics or prebiotics may be a viable option.

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Rats were orally treated with vehicle or Bifidobacterium longum subsp. Adolescentis (BA), a low acetate producer, or B. longum subsp. longum (BL), a high acetate producer (both at 109 CFU), for 9 days. In addition, two isogenic strains were also tested: a second BL strain (BN) and its derivative (BNKO) in which a gene deletion results in low acetate production. Naproxen (20 mg/kg) was co‐administered on the final 4 days, then small intestinal damage was blindly scored.Treatment with BA decreased naproxen‐induced intestinal damage by 82%; p<0.05, while BL exerted no effect. BN reduced damage by 75% (p<0.05), and a similar beneficial effect was observed with the low acetate‐producing knockout bacterium, BNKO (62% reduction; p<0.05).Small intestinal injury by NSAIDs is a serious clinical problem, with no available treatments. Acetate production by these Bifidobacterium strains does not appear to be important for prevention of NSAID‐enteropathy, given that a high acetate producing Bifidobacteria (BL) exhibited no protective effect, while a low acetate‐producing mutant (BNKO) was as effective in reducing damage as another high acetate‐producing bacterium (BN).