Activation of intestinal GR–FXR and PPARα–UGT signaling exacerbates ibuprofen-induced enteropathy in mice

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury (enteropathy) occurs in about two-thirds of regular NSAID users. To date, there is no proven-effective treatment for NSAID enteropathy, and its underlying mechanism remains obscure. The present study showed that glucocorticoids are an important determinant of NSAID enteropathy. High dose dexamethasone (DEX, 75 mg/kg) markedly exacerbated the acute toxicity of ibuprofen (IBU, 200 mg/kg) in the small intestine of mice, which was not due to the pregnane-X-receptor pathway. Instead, glucocorticoid receptor (GR) mediated the effect of DEX (5 mg/kg) on both the acute (200 mg/kg) and 7-day repeated-dose (50 mg/kg) toxicity of IBU in the small intestine. Combined treatment of DEX (5 mg/kg) and IBU (50 mg/kg) synergistically repressed the intestinal farnesoid X receptor (FXR)-cystathionine-γ-lyase signaling, which was accompanied with an elevation in the biliary excretion of bile acids, especially the FXR antagonist tauro-β-muricholic acid. DEX (5 mg/kg) also activated intestinal peroxisome proliferator-activated receptor α (PPARα)-UDP-glucuronosyltransferase (UGT) pathway, which increased the formation and enterohepatic circulation of IBU-acyl glucuronide. Furthermore, DEX (5 mg/kg) and IBU (50 mg/kg) altered the intestinal microbial composition, characterized with a marked decrease in Actinobacteria. To conclude, the present study for the first time suggests that glucocorticoids play vital roles in control of IBU enteropathy via intestinal GR-FXR and PPARα-UGT signaling.

The Nonsteroidal Anti-Inflammatory Drug Ketorolac Alters the Small Intestinal Microbiota and Bile Acids Without Inducing Intestinal Damage or Delaying Peristalsis in the Rat

“…Despite no signs of injury we found overt changes in the small intestinal microbiota following ketorolac treatment, which was primarily characterized by a loss of Firmicutes and increased representation of Enterobacteriaceae. This result corroborates some previous findings that NSAID-induced dysbiosis can appear without the development of enteropathy as well (Uejima et al, 1996;Liang et al, 2015;Montrose et al, 2016;Lu et al, 2018). These studies, however, focused mainly on the NSAID-induced compositional changes of microbiota, and not on the relationship between inflammation and dysbiosis, therefore only morphological alterations of the intestinal mucosa were assessed.…”

“…Because nondamaging COX-inhibitors (e.g. celecoxib or low-dose ibuprofen) caused intestinal dysbiosis mainly after chronic treatment (1-10 weeks) (Montrose et al, 2016;Lu et al, 2018), we administered ketorolac once daily for 4 weeks. Body weight was measured daily during the course of the treatment.…”

“…In addition, the composition of microbiota changed with time and disease progression (Maseda et al, 2019). However, there is some evidence that certain NSAIDs can induce dysbiosis without any detectable intestinal damage as well (Uejima et al, 1996;Lu et al, 2018), suggesting that other factors than mucosal inflammation may also contribute to NSAID-induced microbial alterations.…”

“…Several NSAIDs, such as ibuprofen, naproxen, diclofenac or celecoxib have been reported to possess direct antimicrobial properties in vitro (Jiménez-Serna and Hernández-Sánchez, 2011;Thangamani et al, 2015;Chan et al, 2017). It remains unclear whether these effects have any significant relevance in terms of dysbiosis, but it is noteworthy that ibuprofen and celecoxib are active mainly against Gram-positive bacteria in vitro (Jiménez-Serna and Hernández-Sánchez, 2011;Obad et al, 2015;Thangamani et al, 2015;Chan et al, 2017), and after chronic treatment both decreased the abundance of Firmicutes (Gram-positives) without any significant or reported intestinal injury in vivo (Montrose et al, 2016;Lu et al, 2018). By contrast, chronic treatment with rofecoxib, which lacks direct antibacterial effects, did not cause dysbiosis in the uninflamed gut (Lázár et al, 2019).…”

Intestinal Epithelial Cells-Derived Hypoxia-Inducible Factor-1α Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes

“…Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of disorders in digestive tract mucosa (35). Because NSAIDs mainly causes damage to the small intestine, we investigated the effects of epithelial Hif-1α knockout in NSAIDs-induced small intestinal injury (enteropathy).…”