Inflammatory Bowel Disease and Statins
https://doi.org/10.22416/1382-4376-2020-30-1-7-13
Abstract
Aim. To present up-to-date information on the possibility of using statins in patients with inflammatory bowel disease (IBD).
Highlights. Statins exhibit immunomodulatory effects, which are of particular importance with regard to IBD treatment. Experimental studies, which demonstrate positive effects of statins on various characteristics of the IBD course, were reviewed. The use of statins led to a decrease in the histological activity in models with DSS- and TNBSinduced colitis. Pravastatin was shown to decrease both the epithelial permeability and crypts. Simvastatin changed the composition of the intestinal microflora, which had a potential anti-inflammatory effect. According to the results of clinical studies, atorvastatin administration to IBD patients resulted in a statistically significant decrease in the serum markers of inflammation and the activity index of ulcerative colitis. Retrospective clinical studies demonstrated different effects of statins on the risk of IBD.
Conclusions. A number of potentially protective effects of statins on inflammatory bowel diseases have been identified. However, well-planned randomised clinical trials are needed to evaluate the effects of statins in IBD.
Keywords
statins,
inflammatory bowel disease,
inflammation,
colorectal cancer,
ulcerative colitis,
Crohn's disease
Supporting agencies: South-Ural State Medical University
About the Authors
V. V. Genkel
South-Ural State Medical University
Russian Federation
Russian Federation
Cand. Sci. (Med.), Ass. Prof., Department of Internal Disease Propaedeutics
454092, Chelyabinsk, Vorovskogo str., 64
I. I. Shaposhnik
South-Ural State Medical University
Russian Federation
Russian Federation
Dr. Sci. (Med.), Prof., Departmental Head, Department of Internal Disease Propaedeutics
454092, Chelyabinsk, Vorovskogo str., 64
References
1. Ng S.C., Shi H.Y., Hamidi N., et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390(10114):2769–78. DOI: 10.1016/S0140-6736(17)32448-0
2. Bigeh A., Sanchez A., Maestas C., Gulati M. Inflammatory bowel disease and the risk for cardiovascular disease: Does all inflammation lead to heart disease? Trends Cardiovasc Med. 2019;S1050-1738(19)30139-2. DOI: 10.1016/j.tcm.2019.10.001
3. Zeiser R. Immune modulatory effects of statins. Immunology. 2018;154(1):69–75. DOI: 10.1111/imm.12902
4. Tuñón J., Badimón L., Bochaton-Piallat M.L., et al. Identifying the anti-inflammatory response to lipid lowering therapy: A Position Paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology. Cardiovasc Res. 2019 Jan 1;115(1):10–9. DOI: 10.1093/cvr/cvy293
5. Antonopoulos A.S., Margaritis M., Lee R., et al. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012;18(11):1519–30. DOI: 10.2174/138161212799504803
6. Hechinger A.K., Maas K., Dürr C., et al. Inhibition of protein geranylgeranylation and farnesylation protects against GvHD via effects on CD4 effector T cells. Haematologica. 2013;98:31–40. DOI: 10.3324/haematol.2012.065789
7. Yoshimura K., Nagasawa A., Kudo J., et al. Inhibitory effect of statins on inflammation-related pathways in human abdominal aortic aneurysm tissue. Int J Mol Sci. 2015;16(5):11213–28. DOI: 10.3390/ijms160511213
8. Bekkering S., Arts R.J.W., Novakovic B., et al. Metabolic Induction of Trained Immunity through the Mevalonate Pathway. Cell 2018;172:135–46. DOI: 10.1016/j.cell.2017.11.025
9. Domínguez-Andrés J., Joosten L.A., Netea M.G. Induction of innate immune memory: the role of cellular metabolism. Curr Opin Immunol. 2018;56:10–16. DOI: 10.1016/j.coi.2018.09.001
10. van der Heijden C.D.C.C., Noz M.P., Joosten L.A.B., et al. Epigenetics and Trained Immunity. Antioxid Redox Signal. 2018;29(11):1023–40. DOI: 10.1089/ars.2017.7310
11. Côté-Daigneault J., Mehandru S., Ungaro R., et al. Potential Immunomodulatory Effects of Statins in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016;22(3):724–32. DOI: 10.1097/MIB.0000000000000640
12. Naito Y., Katada K., Takagi T., et al. Rosuvastatin, a new HMG-CoA reductase inhibitor, reduces the colonic inflammatory response in dextran sulfate sodium-induced colitis in mice. Int J Mol Med. 2006;17:997–1004. DOI: 10.3892/ijmm.17.6.997
13. Lee J.Y., Kim J.S., Kim J.M., et al. Simvastatin inhibits NF-KappaB signaling in intestinal epithelial cells and ameliorates acute murine colitis. Int Immunopharmacol. 2007;7:241–8. DOI: 10.1016/j.intimp.2006.10.013
14. Ikeda M., Takeshima F., Isomoto H., et al. Simvastatin attenuates trinitrobenzene sulfonic acid-induced colitis, but not Oxazalone-induced colitis. Dig Dis Sci. 2008;53:1869–75. DOI: 10.1007/s10620-007-0102-0
15. Aktunc E., Kayhan B., Arasli M., et al. The effect of atorvastatin and its role on systemic cytokine network in treatment of acute experimental colitis. Immunopharmacol Immunotoxicol. 2011;33:667–75. DOI: 10.3109/08923973.2011.559475
16. Abe Y., Murano M., Murano N., et al. Simvastatin attenuates intestinal fibrosis independent of the anti-inflammatory effect by promoting fibroblast/myofibroblast apoptosis in the regeneration/healing process from TNBS-induced colitis. Dig Dis Sci. 2012;57:335–44. DOI: 10.1007/s10620-011-1879-4
17. Malekinejad H., Shafie-Irannejad V., Hobbenaghi R., et al. Comparative protective effect of hawthorn berry hydroalcoholic extract, atorvastatin, and mesalamine on experimentally induced colitis in rats. J Med Food. 2013;16:593–601. DOI: 10.1089/jmf.2012.2672
18. Bereswill S., Muñoz M., Fischer A., et al. Anti-inflammatory effects of Resveratrol, Curcumin and simvastatin in acute small intestinal inflammation. PLoS One. 2010;5(12):e15099. DOI: 10.1371/journal.pone.0015099
19. Jahovic N., Gedik N., Ercan F., et al. Effects of statins on experimental colitis in normocholesterolemic rats. Scand J Gastroenterol. 2006;41:954–62. DOI: 10.1080/00365520600554444
20. Sasaki M., Bharwani S., Jordan P., et al. The 3-hydroxy-3-methylglutarylCoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis. J Pharmacol Exp Ther. 2003; 305:78–85. DOI: 10.1124/jpet.102.044099
21. Mirza H., Wu Z., Teo J.D.W., et al. Statin pleiotropy prevents rho kinase-mediated intestinal epithelial barrier compromise induced by Blastocystis сysteine proteases. Cell Microbiol. 2012;14:1474–84. DOI: 10.1111/j.1462-5822.2012.01814.x
22. Toumi R., Soufli I., Rafa H., et al. Probiotic bacteria Lactobacillus and Bifidobacterium attenuate inflammation in dextran sulfate sodium-induced experimental colitis in mice. Int J Immunopathol Pharmacol. 2014;27(4):615–27. DOI: 10.1177/039463201402700418
23. Reinoso Webb C., Koboziev I., Furr K.L., et al. Protective and pro-inflammatory roles of intestinal bacteria. Pathophysiology. 2016;23(2):67–80. DOI: 10.1016/j.pathophys.2016.02.002
24. Oishi M., Tokuhara K., Miki H., et al. Temporal and spatial dependence of inflammatory biomarkers and suppression by fluvastatin in dextran sodium sulfate-induced rat colitis model. Dig Dis Sci. 2014;59:2126–35. DOI: 10.1007/s10620-014-3163-x
25. Grip O., Janciauskiene S., Bredberg A. Use of atorvastatin as an anti-inflammatory treatment in Crohn’s disease. Br J Pharmacol. 2008;155(7):1085–92. DOI: 10.1038/bjp.2008.369
26. Grip O., Janciauskiene S. Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn’s disease. PLoS One. 2009;4(5):e5263. DOI: 10.1371/journal.pone.0005263
27. Higgins P.D., Khan T., Mapili J., et al. Atorvastatin decreases Seo Index in patients with short duration of disease in ulcerative colitis: a randomized placebo-controlled clinical trial. Gastroenterology. 2006;130:A120.
28. Ungaro R., Chang H.L., Côté-Daigneault J., et al. Statins Associated With Decreased Risk of New Onset Inflammatory Bowel Disease. Am J Gastroenterol. 2016;111(10):1416–23. DOI: 10.1038/ajg.2016.233
29. Khalil D., Boktor M., Mortensen E.M., et al. Comparison of frequency of inflammatory bowel disease and noninfectious gastroenteritis among statin users versus nonusers. Am J Cardiol. 2015;115(10):1396–401. DOI: 10.1016/j.amjcard.2015.02.035
30. Crockett S.D., Hansen R.A., Stürmer T., et al. Statins are associated with reduced use of steroids in inflammatory bowel disease: a retrospective cohort study. Inflamm Bowel Dis. 2012;18(6):1048–56. DOI: 10.1002/ibd.21822
31. Ananthakrishnan A.N., Cagan A., Cai T., et al. Statin Use Is Associated With Reduced Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2016;14(7):973–9. DOI: 10.1016/j.cgh.2016.02.017
32. Poynter J.N., Gruber S.B., Higgins P.D.R., et al. Statins and the risk of colorectal cancer. N Engl J Med. 2005;352:2184–92. DOI: 10.1056/NEJMoa043792
33. Samadder N.J., Mukherjee B., Huang S.C., et al. Risk of colorectal cancer in self-reported inflammatory bowel disease and modification of risk by statin and NSAID use. Cancer. 2011;117:1640–8. DOI: 10.1002/cncr.25731
34. Shah S.C., Glass J., Giustino G., et al. Statin Exposure Is Not Associated with Reduced Prevalence of Colorectal Neoplasia in patients with Inflammatory Bowel Disease. Gut Liver. 2019 Jan 15;13(1):54–61. DOI: 10.5009/gnl18178
35. Rea W.E., Durrant D.C., Boldy D.A. Ulcerative colitis after statin treatment. Postgrad Med J. 2002;78:286–7. DOI: 10.1136/pmj.78.919.286
36. Dai C., Jiang M., Sun M.J. Statins and the Risk of Inflammatory Bowel Disease. Am J Gastroenterol. 2016;111(12):1851. DOI: 10.1038/ajg.2016.412
37. Golomb B.A., Evans M.A. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008;8:373–418. DOI: 10.2165/0129784-200808060-00004
38. Hammer G.P., du Prel J.B., Blettner M. Avoiding bias in observational studies: part 8 in a series of articles on evaluation of scientific publications. Dtsch Arztebl Int. 2009;106(41):664–8. DOI: 10.3238/arztebl.2009.0664
39. Mansi I., Mortensen E. The controversy of a wider statin utilization: why? Expert Opin Drug Saf. 2013;12:327–37. DOI: 10.1517/14740338.2013.779667
40. Karlson B.W., Palmer M.K., Nicholls S.J., et al. Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis. Eur J Prev Cardiol. 2016;23(7):744–7. DOI: 10.1177/2047487315598710
41. Sathyapalan T., Atkin S.L., Kilpatrick E.S. Disparate effects of atorvastatin compared with simvastatin on C-reactive protein concentrations in patients with type 2 diabetes. Diabetes Care. 2010;33(9):1948–50. DOI: 10.2337/dc10-0201
42. van der Meij E., Koning G.G., Vriens P.W., et al. A clinical evaluation of statin pleiotropy: statins selectively and dose-dependently reduce vascular inflammation. PLoS One. 2013;8(1):e53882. DOI: 10.1371/journal.pone.0053882
43. Fujita M., Morimoto T., Ikemoto M., et al. Dose-dependency in pleiotropic effects of atorvastatin. Int J Angiol. 2007;16(3):89–91.
44. Dobrzycka M., Spychalski P., Łachiński A.J., et al. Statins and Colorectal Cancer — A Systematic Review. Exp Clin Endocrinol Diabetes. 2018 Aug 27. DOI: 10.1055/a-0668-5692
45. Mamtani R., Lewis J.D., Scott F.I., et al. Disentangling the Association between Statins, Cholesterol, and Colorectal Cancer: A Nested Case-Control Study. PLoS Med. 2016;13(4):e1002007. DOI: 10.1371/journal.pmed.1002007
46. Sopková J., Vidomanová E., Strnádel J., et al. The role of statins as therapeutic agents in cancer. Gen Physiol Biophys. 2017;36(5):501–11. DOI: 10.4149/gpb_2017045
47. Ehrlich A.C., Patel S., Meillier A., et al. Chemoprevention of colorectal cancer in inflammatory bowel disease. Expert Rev Anticancer Ther. 2017;17(3):247–55. DOI: 10.1080/14737140.2017.1283987
Review
For citations:
Genkel V.V., Shaposhnik I.I. Inflammatory Bowel Disease and Statins. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2020;30(1):7-13. (In Russ.) https://doi.org/10.22416/1382-4376-2020-30-1-7-13
Views:
8282
Email this article 
