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.