Mitigation of indomethacin-induced gastrointestinal damages in fat-1 transgenic mice via gate-keeper action of ω-3-polyunsaturated fatty acids

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) damage the gastrointestinal (GI) epithelial cell membranes by inducing several signals through lipid raft organization after membrane incorporation, whereas ω-3 polyunsaturated fatty acids (PUFAs) relieve inflammation, reduce oxidative stress, and provide cytoprotection, consequent to lipid raft disorganization. Therefore, we hypothesized that ω-3 PUFAs can protect the GI from NSAID-induced damages by initiating the gatekeeper action of cell membranes, subsequent to anti-inflammatory and anti-oxidative actions. Administration of indomethacin (IND) leads to the formation of lipid rafts and activation of caveolin-1; however, no such observations were made upon co-administration of eicosapentaenoic acid (EPA) and IND. In addition, the EPA-induced lipid raft disorganization, caveolin-1 inactivation, and cellular cytotoxicity were inhibited when target cells were knocked-out using G-protein coupled receptor 120 (GPR 120). EPA significantly attenuated IND-induced oxidative damage and apoptosis. IND administration induced significant ulceration, bleeding, and oedema in the stomach or small intestine of wild-type (WT) mice; however, such severe damages to the GI significantly decreased in fat-1 transgenic (TG) mice (P < 0.001), which exhibited decreased cyclooxygenase-2 expression and apoptosis, decreased interleukin-1β and FAS concentrations, and increased heme oxygenase-1 concentration. Our study indicates that the gatekeeper function of ω-3 PUFAs improves GI safety when administered with NSAID.

Modeling undernutrition with enteropathy in mice

“…Actually, LP diet during pregnancy decreased offspring inflammatory response to acute LPS in the hypothalamus 25 . Indomethacin, a non-steroidal anti-inflammatory drug has been used to induce enteropathy in experimental models 19,20 . Indomethacin challenge at 10 mg/kg in malnourished mice did not worsen body weight loss or growth faltering but increased fecal calprotectin levels compared to mice fed with LP diet.…”

“…Body weight loss is observed in indomethacin-treated mice 29 . It may result from multiple mechanisms such as (i) intestinal damage leading to a reduced food intake, (ii) decreased cyclooxygenase-2 expression leading to decreased mucosal protection 19 , (iii) microbiota changes 29 . Xiao et al have shown that microbiota depletion by antibiotics treatment improved body weight in indomethacin-treated mice 29 .…”

“…As indomethacin injection had an impact on intestinal inflammation, we thus speculated that oral gavage with indomethacin may have a stronger effect on intestinal permeability (Fig. 3a) 19 . Mice fed with lowprotein diet for 5 days gained less weight than mice fed with SD (− 24% for LP, P < 0.0001 vs. SD- Fig.…”

“…Moreover, LPS is also well known to induce gut inflammation via Toll Like Receptor activation in vivo and in vitro 18 . Indomethacin, a non-steroidal anti-inflammatory drug, is commonly used to induce enteropathy in normo-nourished mice 19 , 20 . The aim of our study was to establish a model of undernutrition with EED features, which represents a crucial tool for research applications and further therapeutic approaches.…”

Animal Models of Undernutrition and Enteropathy as Tools for Assessment of Nutritional Intervention

“…Subcutaneous injection of indomethacin (10 mg/kg) in mice resulted in an increased histopathological score in the small intestine at 12 and 24 h [134,135]. Intragastric indomethacin administration at 10 mg/kg increased the histopathological score 48 h later [136]. Indomethacin (10 mg/kg) subcutaneous injection in mice increased intestinal permeability and induced ulcers 24 h post administration [135].…”