Role of biliary phosphatidylcholine in bile acid protection and NSAID injury of the ileal mucosa in rats

Background & Aims: We explored the role of biliary phosphatidylcholine (PC) in protection of the intestinal mucosa against bile salt (BS)-induced intestinal injury and how this property may be blocked by indomethacin (Indo), a nonsteroidal anti-inflammatory drug (MSAID) that is secreted into the bile. Methods: We performed in vivo studies in which bile was collected over a 2-hour period after rats were intragastrically administered Indo (25 mg/kg) or an equivalent volume of saline (controls). The bile samples (some of which were supplemented with PC) were then instilled into a loop of distal ileum of anesthetized rats. After a 30-minute exposure period, we measured the hemoglobin concentration of the ileal loop fluid, as an index of bleeding, and mucosal contact angles, as an index of surface hydrophobicity. A similar in vivo experiment was performed in which model bile containing 5 mmol/L each of the BS, sodium deoxycholate, PC, or Indo, alone and in combination, was instilled into ileal loops. In our in vitro test system, human erythrocytes were exposed to the above biliary constituents, and hemolysis was measured spectrophotometrically. Results: Bile from Indo-pretreated rats decreased the surface hydrophobicity and induced bleeding of ileal loops in comparison with control bile, and both NSAID-induced changes were reversed if PC was added to the bile. Similarly, synthetic BS caused gastrointestinal bleeding, decreased ileal contact angles, and induced erythrocyte hemolysis, all of which were reversed by addition of equimolar PC. This protective role of PC in both the in vivo and in vitro systems was partially blocked by Indo, although the NSAID had no effect on these properties on its own. Conclusions: These findings support the hypothesis that PC protects the intestinal mucosa against injurious actions of BS, possibly by forming less toxic mixed micelles. Indo and perhaps other NSAIDs that enter the bile may damage the mucosa, not by a direct action, but by competing for the available protective PC molecules.