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Archives of Toxicology

, Volume 92, Issue 3, pp 1249–1265 | Cite as

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

  • Zhiqiang Lu
  • Yuanfu Lu
  • Xue Wang
  • Fangyu Wang
  • Youcai Zhang
Organ Toxicity and Mechanisms

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.

Keywords

NSAID enteropathy Glucocorticoids FXR Ibuprofen 

Notes

Acknowledgements

We are very thankful to Dr. Curtis D. Klaassen (retired, University of Kansas, Kansas City, KS) for his assistance in preparing the manuscript. This work was supported by grants from the National Natural Science Foundation of China (no. 81673523) and by the Project of National Basic Research (973) Program of China (2015CB856500).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical standards

The manuscript does not contain clinical studies or participant data.

Supplementary material

204_2017_2139_MOESM1_ESM.docx (2.9 mb)
Supplementary material 1 (DOCX 2994 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.School of Pharmaceutical Science and TechnologyTianjin UniversityTianjinPeople’s Republic of China
  2. 2.Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of EducationZunyi Medical UniversityZunyiPeople’s Republic of China

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