Small intestinal bacteria accelerate aspirin-induced small intestinal injuries

Abstract

Background

Small intestinal mucosal injuries are observed during treatment with enteric-coated, low-dose aspirin (LDA) through uncertain mechanism(s). Because aspirin (acetylsalicylic acid, ASA) is an acetylated form of the highly cytotoxic salicylic acid (SA), we hypothesized that SA deacetylated by esterases in the small intestine directly causes mucosal injuries. This study explored the mechanism(s) of ASA deacetylation to SA in the small intestinal environment.

Methods

ASA was added to the x, and deacetylation of added ASA and cell damage were evaluated. To explore the ASA deacetylation mechanism(s) in the intestinal environment, ASA was incubated with different pH phosphate buffers (4.01–9.10), pancreatic enzymes, homogenates of pancreas and IEC-6 cell, and caecum bacterial suspension (CBS). ASA and CBS were co-injected into the murine duodenum, and small intestinal damage was evaluated after an hour by histological observation.

Results

Intestinal cell damage was caused dependently on the deacetylation rate of added ASA to SA in the cell and culture media. In vitro, almost ASA was not deacetylated by incubation with different pH buffer, pancreatic enzymes, or IEC-6 cell homogenate, but deacetylation of ASA was significantly promoted with CBS. ASA deacetylation by bacterial esterases(s) was confirmed by adding an esterase-specific inhibitor, potassium fluoride. Furthermore, severe injuries throughout the entire murine small intestine were found after co-injection of ASA and CBS, but not after ASA alone.

Conclusions

Enteric-coated, LDA-induced mucosal injuries in the small intestine are mainly caused by direct cytotoxicity of SA deacetylated by enterobacterial esterase in the small intestine.