Activation of the farnesoid-X receptor protects against gastrointestinal injury caused by non-steroidal anti-inflammatory drugs in mice.

BACKGROUND AND PURPOSE

Low doses of acetyl salicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage. The farnesoid X receptor (FXR) is a bile acid sensor essential for maintenance of intestinal homeostasis. Here, we have investigated whether FXR is required for mucosal protection in models of gastrointestinal injury caused by ASA and NSAIDs and if FXR activation has potential in the treatment or prevention of gastrointestinal injury caused by these agents.

EXPERIMENTAL APPROACH

FXR(+/+) and FXR(-/-) mice were given ASA (10 to 100 mg·kg(-1) ) or NSAIDs. Gastric and intestinal mucosal damage assessed by measuring lesion scores. FXR were activated by giving mice natural (chenodeoxycholic acid; CDCA) or synthetic (GW4064) FXR agonists.

KEY RESULTS

FXR, mRNA and protein, was detected in human and mouse stomach. FXR(-/-) mice were more prone to develop severe gastric and intestinal injury in response to ASA and NSAIDs and showed a severe reduction in the gastrointestinal expression of cystathionine-γ-lyase (CSE), an enzyme required for generation of hydrogen sulphide. CSE expression was reduced by ≈50% in wild-type mice challenged with ASA. Treating wild-type mice but not FXR(-/-) mice with CDCA or GW4064 protected against gastric injury caused by ASA and NSAIDs, by a CSE-dependent and cycloxygenase- and NO-independent, mechanism. FXR activation by GW4064 rescued mice from intestinal injury caused by naproxen.

CONCLUSIONS AND IMPLICATIONS

FXR was essential to maintain gastric and intestinal mucosal barriers. FXR agonists protected against gastric injury caused by ASA and NSAIDs by a CSE-mediated mechanism.