Role of bile in pathogenesis of indomethacin-induced enteropathy

Abstract

Ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) causes an enteropathy. The pathogenesis involves biochemical initiation of intestinal mucosal damage due to NSAID-induced inhibition of cyclooxygenase and the topical effects of these drugs. These effects lead to increased intestinal permeability and inflammation. Luminal bile acids play a controversial role in the damage produced by these drugs. The aim of this study was to determine the role of bile in producing the enteropathy caused by indomethacin, an NSAID commonly used in toxicity studies. Sprague-Dawley rats were subjected to bile duct ligation. Twenty-four hours later, they were dosed with indomethacin. Intestinal permeability ((51)Cr-EDTA) and inflammation (faecal calprotectin) were measured in the animals at various time periods after the dose. Intestinal permeability was significantly higher in rats 1-6 h after dosing with indomethacin, but not at 24-29 h or day 4, when compared with corresponding values for control animals. Excretion of faecal calprotectin was elevated in the indomethacin-treated rats. The drug-treated animals showed no evidence of ulceration when they were sacrificed 29 h or a week after the dose of indomethacin. Bile acids per se did not affect intestinal permeability or faecal excretion of calprotectin, when given along with indomethacin or its vehicle. We conclude that macroscopic small bowel damage does not occur with indomethacin if bile is excluded, despite the induction of permeability and inflammation. This study highlights the importance of luminal factors, such as bile, in producing indomethacin-induced ulceration in the rat small intestine.

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

“…Fecal calprotectin is a well-established, noninvasive indicator of intestinal mucosal injury induced by NSAIDs in human patients and animal models, and correlates well with 4-day fecal excretion of 111 Indium-labeled leukocytes. 34,35 The findings of decreased fecal calprotectin and decreased microscopic pathology have important clinical implications. A variety of NSAIDs are used widely for an array of clinical conditions ranging from pain-relief for minor injuries to management of rheumatoid arthritis or cancer.…”

Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy

“…Ligation of the bile duct in rats prevents NSAID-induced intestinal damage [75][76][77][78] . There have also been reports that NSAIDs that do not re-circulate enterohepatically do not cause small intestinal damage [52,75] , although aspirin is a notable exception, at least when administered intraduodenally or in an enteric-coated formulation [11,78] .…”

“…These effects may be in part attributable to activation of neutrophils in the mucosal microcirculation, which has been shown to contribute significantly to ulceration [100][101][102][103][104] , and local generation of tumor necrosis factor-alpha may be one of the main triggers leading to neutrophil recruitment and/or activation [93,[105][106][107] . As mentioned above, one of the key observations supporting an important role of bacteria in the pathogenesis of NSAID-enteropathy was that germ-free animals do not develop significant small intestinal damage following NSAID administration [75][76][77][78] . However, one must bear in mind that ligation of the bile duct blocks the secretion of bile and the enterohepatic circulation of NSAIDs, both of which have been implicated in intestinal injury by these drugs (Figure 3).…”

Non-steroidal Anti-inflammatory Drug Induced Injury to the Small Intestine

“…Intraluminal content (such as bile acids, luminal bacteria and their degradation products, food macromolecules and other toxins) overcomes the weakened intestinal mucosal barrier and leads to inflammation (69). In experimental studies, NSAIDs did not induce enteropathy in germ-free rats or rats after bile duct ligation (46,70). Nitric oxide formed by inducible isoform of nitric oxide synthase is often mentioned as another important factor in pathogenesis of NSAID-induced enteropathy.…”