Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID

Abstract

The small intestine is a significant site of ulceration and bleeding induced by nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis is poorly understood. The present study explored the roles of bile, bacteria, and enterohepatic circulation to NSAID enteropathy, using both a conventional NSAID (naproxen) and a gastrointestinal-safe naproxen derivative (ATB-346), as well as proton pump inhibitors (PPIs). Rats were treated orally with naproxen or equimolar doses of ATB-346 over a 5-day period, with or without PPI administration, and intestinal damage was quantified. The cytotoxicity of bile from the rats was evaluated in vitro. Biliary excretion of naproxen and ATB-346 was determined. The impact of the NSAIDs and of PPIs on the composition of the intestinal microbiota was examined by deep sequencing of 16s rRNA. Naproxen caused significant intestinal damage and inflammation, whereas ATB-346 did not. Naproxen, but not ATB-346, dose dependently increased the cytotoxicity of bile, and it was further increased by PPI coadministration. Whereas biliary excretion of naproxen was significant in naproxen-treated rats, it was greatly reduced in rats treated with ATB-346. The enteric microbiota of naproxen-treated rats was distinct from that in vehicle- or ATB-346-treated rats, and PPI administration caused significant intestinal dysbiosis. The increase in cytotoxicity of bile induced by naproxen and PPIs may contribute significantly to intestinal ulceration and bleeding. Some of these effects may occur secondary to significant changes in the jejunal microbiota induced by both naproxen and PPIs.

The microbiota-derived metabolite indole decreases mucosal inflammation and injury in a murine model of NSAID enteropathy

“…38 Mice treated with indole and indomethacin did not have a change in the abundance of Bacteroidia but did have an increase in several members of the gram-positive family Clostridiales in concert with diminution of the severity of intestinal mucosal damage. Evidence exists that the microbiota plays an important role in the development of NSAID enteropathy.…”

Prescription drugs associated with false-positive results when using faecal immunochemical tests for colorectal cancer screening

“…By contrast, acid inhibition does not confer protection to NSAID-induced damage distal to the ligament of Treitz [16,[22][23][24], and, in fact, studies report that PPIs could contribute to small intestinal injury. Wallace et al [13] and Blacker et al [25] have reported that PPIs exacerbate NSAID-induced small intestinal injury in rodents. Their study showed that PPIs induced a low acid gastric environment that resulted in dysbiosis, which exacerbated NSAID-induced small intestinal injury.…”

Chronic Gastritis Clinical Features and Stomach Functional State During Nonsteroidal Anti-Inflammatory Drugs Administration in Patients With Osteoarthritis

“…Most of NSAID from the chemical point of view have acid properties with dissociation constant (pKa) 3-5. In the stomach acidic environment, these molecules are easily ionized and penetrate the epithelial cells of gastroduodenal SM, accumulating there and providing a direct damaging effect [14,15]. It was determined, that some time after the administration of these drugs, penetration of hydrogen and sodium ions into SM increasing is observed.…”

“…But these drugs safety was proved in patients with intact SM [7,14]. At the same time at CG a number of inflammatory and degenerative processes in the gastric epithelium develops [19], which, possibly may cause the increased risk of erosive gastropathy at NSAID-therapy.…”