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
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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 
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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

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Supplementary material 1 (DOCX 2994 KB)

References

  1. Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI (1992) Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 327(11):749–754.  https://doi.org/10.1056/NEJM199209103271101 CrossRefPubMedGoogle Scholar
  2. Al-Sadi R, Ye D, Boivin M et al (2014) Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLoS One 9(3):e85345.  https://doi.org/10.1371/journal.pone.0085345 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Boelsterli UA, Ramirez-Alcantara V (2011) NSAID acyl glucuronides and enteropathy. Curr Drug Metab 12(3):245–252CrossRefPubMedGoogle Scholar
  4. Bowen B, Yuan Y, James C, Rashid F, Hunt RH (2005) Time course and pattern of blood loss with ibuprofen treatment in healthy subjects. Clin Gastroenterol Hepatol 3(11):1075–1082CrossRefPubMedGoogle Scholar
  5. Daniels WM, Pietersen CY, Carstens ME, Stein DJ (2004) Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metab Brain Dis 19(1–2):3–14CrossRefPubMedGoogle Scholar
  6. De Palma G, Collins SM, Bercik P (2014) The microbiota-gut-brain axis in functional gastrointestinal disorders. Gut Microb 5(3):419–429.  https://doi.org/10.4161/gmic.29417 CrossRefGoogle Scholar
  7. Distrutti E, Santucci L, Cipriani S et al (2015) Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa. J Gastroenterol 50(7):707–719.  https://doi.org/10.1007/s00535-015-1041-8 CrossRefPubMedGoogle Scholar
  8. Dong Y, Poellinger L, Gustafsson JA, Okret S (1988) Regulation of glucocorticoid receptor expression: evidence for transcriptional and posttranslational mechanisms. Mol Endocrinol 2(12):1256–1264.  https://doi.org/10.1210/mend-2-12-1256 CrossRefPubMedGoogle Scholar
  9. Endo H, Hosono K, Inamori M et al (2009) Incidence of small bowel injury induced by low-dose aspirin: a crossover study using capsule endoscopy in healthy volunteers. Digestion 79(1):44–51.  https://doi.org/10.1159/000204465 CrossRefPubMedGoogle Scholar
  10. Fiorucci S, Santucci L (2011) Hydrogen sulfide-based therapies: focus on H2S releasing NSAIDs. Inflamm Allergy Drug Targets 10(2):133–140CrossRefPubMedGoogle Scholar
  11. Fiorucci S, Antonelli E, Distrutti E et al (2005) Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology 129(4):1210–1224.  https://doi.org/10.1053/j.gastro.2005.07.060 CrossRefPubMedGoogle Scholar
  12. Fiorucci S, Mencarelli A, Cipriani S et al (2011) Activation of the farnesoid-X receptor protects against gastrointestinal injury caused by non-steroidal anti-inflammatory drugs in mice. Br J Pharmacol 164(8):1929–1938.  https://doi.org/10.1111/j.1476-5381.2011.01481.x CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gabriel SE, Jaakkimainen L, Bombardier C (1991) Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 115(10):787–796CrossRefPubMedGoogle Scholar
  14. Gao X, Chen H, Schwarzschild MA, Ascherio A (2011) Use of ibuprofen and risk of Parkinson disease. Neurology 76(10):863–869.  https://doi.org/10.1212/WNL.0b013e31820f2d79 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Henry D, Lim LL, Garcia Rodriguez LA et al (1996) Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 312(7046):1563–1566CrossRefPubMedPubMedCentralGoogle Scholar
  16. Heuman DM, Gallagher EJ, Barwick JL, Elshourbagy NA, Guzelian PS (1982) Immunochemical evidence for induction of a common form of hepatic cytochrome P-450 in rats treated with pregnenolone-16 alpha-carbonitrile or other steroidal or non-steroidal agents. Mol Pharmacol 21(3):753–760PubMedGoogle Scholar
  17. Kanaley JA, Weltman JY, Pieper KS, Weltman A, Hartman ML (2001) Cortisol and growth hormone responses to exercise at different times of day. J Clin Endocrinol Metab 86(6):2881–2889.  https://doi.org/10.1210/jcem.86.6.7566 PubMedGoogle Scholar
  18. Kolios G, Valatas V, Ward SG (2004) Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzle. Immunology 113(4):427–437.  https://doi.org/10.1111/j.1365-2567.2004.01984.x CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA (1997) Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 272(6):3406–3410CrossRefPubMedGoogle Scholar
  20. Liddle C, Goodwin B (2002) Regulation of hepatic drug metabolism: role of the nuclear receptors PXR and CAR. Semin Liver Dis 22(2):115–122.  https://doi.org/10.1055/s-2002-30098 CrossRefPubMedGoogle Scholar
  21. Lu Y, Zhang Z, Xiong X et al (2012) Glucocorticoids promote hepatic cholestasis in mice by inhibiting the transcriptional activity of the farnesoid X receptor. Gastroenterology 143(6):1630–1640 e8.  https://doi.org/10.1053/j.gastro.2012.08.029 CrossRefPubMedGoogle Scholar
  22. Maiden L (2009) Capsule endoscopic diagnosis of nonsteroidal antiinflammatory drug-induced enteropathy. J Gastroenterol 44 Suppl 19:64–71.  https://doi.org/10.1007/s00535-008-2248-8 CrossRefPubMedGoogle Scholar
  23. Mawdsley JE, Rampton DS (2005) Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut 54(10):1481–1491.  https://doi.org/10.1136/gut.2005.064261 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Mukhopadhya I, Hansen R, El-Omar EM, Hold GL (2012) IBD-what role do proteobacteria play? Nat Rev Gastroenterol Hepatol 9(4):219–230.  https://doi.org/10.1038/nrgastro.2012.14 CrossRefPubMedGoogle Scholar
  25. Numakawa T, Kumamaru E, Adachi N, Yagasaki Y, Izumi A, Kunugi H (2009) Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-signaling for glutamate release via a glutamate transporter. Proc Natl Acad Sci 106(2):647–652.  https://doi.org/10.1073/pnas.0800888106 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Oakley RH, Cidlowski JA (2013) The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol 132(5):1033–1044.  https://doi.org/10.1016/j.jaci.2013.09.007 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Phan AS, T P, PA D (2016) Formula feeding predisposes gut to NSAID-induced small intestinal injury. Clin Exp Pharmacol 06(06)Google Scholar
  28. Piper JM, Ray WA, Daugherty JR, Griffin MR (1991) Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med 114(9):735–740CrossRefPubMedGoogle Scholar
  29. Renga B, Mencarelli A, Migliorati M, Distrutti E, Fiorucci S (2009) Bile-acid-activated farnesoid X receptor regulates hydrogen sulfide production and hepatic microcirculation. World J Gastroenterol 15(17):2097–2108CrossRefPubMedPubMedCentralGoogle Scholar
  30. Rosales R, Romero MR, Vaquero J et al (2013) FXR-dependent and -independent interaction of glucocorticoids with the regulatory pathways involved in the control of bile acid handling by the liver. Biochem Pharmacol 85(6):829–838.  https://doi.org/10.1016/j.bcp.2013.01.001 CrossRefPubMedGoogle Scholar
  31. Seager JM, Cullen DJ, Pearson G et al. (2000) Ibuprofen versus other non-steroidal anti-inflammatory drugs: use in general practice and patient perception. Aliment Pharmacol Therap 14(2):187–191CrossRefGoogle Scholar
  32. Smith SM, Vale WW (2006) The role of the hypothalamic–pituitary–adrenal axis in neuroendocrine responses to stress. Dialog Clin Neurosci 8(4):383–395Google Scholar
  33. Stranahan AM, Lee K, Mattson MP (2008) Central mechanisms of HPA axis regulation by voluntary exercise. Neuromol Med 10(2):118–127.  https://doi.org/10.1007/s12017-008-8027-0 CrossRefGoogle Scholar
  34. Tsigos C, Chrousos GP (2002) Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53(4):865–871CrossRefPubMedGoogle Scholar
  35. Van Wijck K, Lenaerts K, Van Bijnen AA et al (2012) Aggravation of exercise-induced intestinal injury by Ibuprofen in athletes. Med Sci Sports Exerc 44(12):2257–2262.  https://doi.org/10.1249/MSS.0b013e318265dd3d CrossRefPubMedGoogle Scholar
  36. Vlad SC, Miller DR, Kowall NW, Felson DT (2008) Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70(19):1672–1677.  https://doi.org/10.1212/01.wnl.0000311269.57716.63 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Wallace JL (2012) NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies. Br J Pharmacol 165(1):67–74.  https://doi.org/10.1111/j.1476-5381.2011.01509.x CrossRefPubMedPubMedCentralGoogle Scholar
  38. Wallace JL, Syer S, Denou E, et al. (2011) Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology 141(4):1314–22, 1322 e1–e5  https://doi.org/10.1053/j.gastro.2011.06.075 CrossRefPubMedGoogle Scholar
  39. Wise J (2017) Diclofenac and ibuprofen are associated with increased risk of cardiac arrest. BMJ 356:j1358.  https://doi.org/10.1136/bmj.j1358 CrossRefGoogle Scholar
  40. Woodman TJ, Wood PJ, Thompson AS et al (2011) Chiral inversion of 2-arylpropionyl-CoA esters by human alpha-methylacyl-CoA racemase 1A (P504S)--a potential mechanism for the anti-cancer effects of ibuprofen. Chem Commun 47(26):7332–7334.  https://doi.org/10.1039/c1cc10763a CrossRefGoogle Scholar
  41. Wu GD (2007) Nuclear hormone receptors and intestinal inflammation. Gastroenterology 133(4):1068.  https://doi.org/10.1053/j.gastro.2007.08.052 CrossRefPubMedGoogle Scholar
  42. Xie W, Barwick JL, Downes M et al (2000) Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406(6794):435–439.  https://doi.org/10.1038/35019116 CrossRefPubMedGoogle Scholar
  43. Yoshikawa K, Kurihara C, Furuhashi H et al (2017) Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling. J Gastroenterol 52(1):61–71.  https://doi.org/10.1007/s00535-016-1205-1 CrossRefPubMedGoogle Scholar
  44. Zhang Y, Cheng X, Aleksunes L, Klaassen CD (2012) Transcription factor-mediated regulation of carboxylesterase enzymes in livers of mice. Drug Metab Dispos 40(6):1191–1197.  https://doi.org/10.1124/dmd.111.043877 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Zhou X, Cao L, Jiang C et al (2014) PPARalpha-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis. Nat Commun 5:4573.  https://doi.org/10.1038/ncomms5573 CrossRefPubMedPubMedCentralGoogle Scholar

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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