Reelin levels in inflammatory bowel disease: A case-control study

Abstract

Background/Aim: Crohn's Disease (CD) and Ulcerative Colitis (UC) are grouped as Inflammatory Bowel Diseases (IBD). There are many similarities between these two diseases, and CD and UC cases cannot be separated at a rate varying between 5% and 10%. Reelin is an extracellular matrix protein first known for its vital role in neuronal migration. Studies in rodent small intestine suggested that reelin protects the organism from intestinal pathologies. In a 5-year retrospective case-control study, we aimed to detect the effectiveness of serum reelin level in patients with IBD in determining the severity and activation of the disease and compare healthy volunteers with patients in terms of inactivation and remission. Methods: The data of all 194 IBD patients diagnosed at Beyazit Training and Research Hospital between 2011-2015 were retrospectively reviewed. The patients were matched with 30 healthy volunteers. Risk factors were assessed by multivariate logistic regression analysis. Results: The serum reelin levels were similar between UC and CD patients, the control group, UC and CD groups (P=0.067), and those with active disease or disease in remission, and did not differ according to disease behavior or location of involvement. Conclusions: Our study shows that Reelin cannot be used as an activation/remission marker in IBD. In addition, it does not differentiate between UC and CD.

Keywords

• Reelin
• Inflammatory bowel diseases
• Crohn
• Ulcerative colitis

Öz

ÖZET İnflamatuvar barsak hastalıkları aktivasyon ve remisyon ile giden ve etiyolojisi bilinmeyen kronik intestinal hastalıklardır. Aktiviteyi belirlemek inflamatuvar barsak hastalığında tedavinin düzenlenmesi ve prognozu göstermesi açısından büyük önem taşır. Aktiviteyi belirlemek için halen ortak bir konsensüs oluşmamıştır. Reelin de nörolojik gelişim ve sinaptik plastisite önemli roller oynamaktadır. Reelinin şizofreni patogenezinde rolü bulunmaktadır. Araştırma Ankara Dışkapı Yıldırım Beyazıt Eğitim ve Araştırma Hastanesi Gastroenteroloji – İBH Polikliniği’nde gerçekleştirilmiştir. Takip ve tedavisi yapılan İBH vakası 194 hasta ve 30 sağlıklı kontrol dâhil edilmiştir. Hastaların verileri poliklinik dosya ve hastane bilgi işlem sisteminden elde edilmiştir. CH aktivite indeksi ile UC True Love aktivite indeksi kullanılmış ve serumda Reelin düzeyi çalışılmıştır. Çalışma retrospektif olup hastalara ek herhangi bir işlem uygulanmamıştır. Araştırmada da; Reelin düzeyleri ÜK total: 0,6216 +/- 1,0835 aktif:0,3846 +/- 0,4850 remisyon:0,4354 +/- 0,4354 idi. CD’da Reelin total:0,3993 +/-0,5101 aktif: 0,3675 +/- 0,5789 remisyon: 0,4354 +/- 0,5789 idi ve kontrol grubunda: 0,5576 +/- 0,6142 olarak saptandı. ÜK ve CH arasında serum Reelin düzeyi ile anlamlı fark saptanmamış, ÜK ve CH ile ayrı ayrı kontrol grubu ile olan karşılaştırma sonucu anlamlı fark bulunmamıştır. (p > 0,05). Bu bağlamda da görülmektedir ki, serum Reelin düzeyinin ÜK ve CH vakalarını etkileme düzeyi farklılık içermemektedir. Araştırma kapsamında, ÜK ve CH aktif ve kontrol grubu arasında istatistik bakımdan anlamlı bulunmamıştır (p > 0,05). ÜK reelin düzeyleri:0,6216 +/- 1,0835 (X2 = 0,109; p > 0,05) ve aktif ÜK reelin düzeyleri: 0,3846 +/- 0,4850 (X2 = 0,820; p > 0,05) tutulum görülen lokasyona göre anlamlı farklılık göstermemektedir. Gruplar bazında genel olarak değerlendirildiğinde de görülmektedir ki, Reelin düzeyleri tutulum görülen lokasyona göre anlamlı farklılık göstermemektedir (X2 = 1,007; p> 0,05). Sonuç olarak çalışmamız; Reelinin, İBH’da aktivasyon remisyon markerı olarak kullanılamayacağını ve ayrıca ÜK-Crohn arasında ayrıcı tanıda belirteç olmadığını göstermektedir

Anahtar Kelimeler

• Reelin, İnflamatuvar Barsak Hastalığı, Crohn Hastalığı, Ülseratif Kolit.

Kaynakça

1. 1. Valdovinos-García R, Martínez-Vázquez M. Diagnostic approach to inflammatory bowel. IBD Reviews. 2018;4:30-8.
2. 2. Kim DH, Cheon JH. Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies. Immune Netw. 2017 Feb;17(1):25- 40. doi: 10.4110/in.2017.17.1.25.
3. 3. Danese S, Fiorino G, Peyrin-Biroulet L, Lucenteforte E, Virgili G, Moja L, Bonovas S. Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis. Ann Intern Med. 2014 May 20;160(10):704-11. doi: 10.7326/M13-2403.
4. 4. Ökten A. Gastroenterohepatoloji. İstanbul: Nobel Medicine Publication. 2001
5. 5. Baumgart DC, Sandborn WJ. Crohn's disease. Lancet. 2012 Nov 3;380(9853):1590-605. doi: 10.1016/S0140-6736(12)60026-9.
6. 6. Hendrickson BA, Gokhale R, Cho JH. Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev. 2002 Jan;15(1):79-94. doi: 10.1128/CMR.15.1.79-94.2002.
7. 7. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012 Jan;142(1):46-54.e42; quiz e30. doi: 10.1053/j.gastro.2011.10.001.
8. 8. Kurata JH, Kantor-Fish S, Frankl H, Godby P, Vadheim CM. Crohn's disease among ethnic groups in a large health maintenance organization. Gastroenterology. 1992;102:1940–8.

9. 9. Malik TA. Inflammatory Bowel Disease: Historical Perspective, Epidemiology, and Risk Factors. Surg Clin North Am. 2015 Dec;95(6):1105-22. doi: 10.1016/j.suc.2015.07.006
10. 10. Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015 Apr;12(4):205-17. doi: 10.1038/nrgastro.2015.34.
11. 11. Andres PG, Friedman LS. Epidemiology and the natural course of inflammatory bowel disease. Gastroenterology Clinics of North America. 1999;28(2):255-81.
12. 12. Taleban S. Challenges in the Diagnosis and Management of Inflammatory Bowel Disease in the Elderly. Curr Treat Options Gastroenterol. 2015 Sep;13(3):275-86. doi: 10.1007/s11938-015-0059-6
13. 13. Foxworthy DM, Wilson JA. Crohn's disease in the elderly. Prolonged delay in diagnosis. J Am Geriatr Soc. 1985 Jul;33(7):492-5. doi: 10.1111/j.1532-5415.1985.tb05462.x.
14. 14. Russel MGVM. Changes in the incidence of inflammatory bowel disease: what does it mean? European Journal of Internal Medicine. 2000;11(4):191-6.
15. 15. Ekbom, A. The changing faces of Crohn's disease and ulcerative colitis. In: Targan SR, Shanahan F, Karp LC. Inflammatory bowel disease: from bench to bedside (pp. 5-20) New York: Springer. 2005.
16. 16. Kirsner JB. The historical basis of the idiopathic inflammatory bowel diseases. Inflammatory Bowel Diseases. 1995;1(1):2-26.
17. 17. Korzenik JR. Past and current theories of etiology of IBD: toothpaste, worms, and refrigerators. J Clin Gastroenterol. 2005 Apr;39(4 Suppl 2):S59-65. doi: 10.1097/01.mcg.0000155553.28348.fc.
18. 18. Kirsner JB. Historical origins of current IBD concepts. World J Gastroenterol. 2001 Apr;7(2):175-84. doi: 10.3748/wjg.v7.i2.175.
19. 19. Lomer MC, Thompson RP, Powell JJ. Fine and ultrafine particles of the diet: influence on the mucosal immune response and association with Crohn's disease. Proc Nutr Soc. 2002 Feb;61(1):123-30. doi: 10.1079/pns2001134.
20. 20. Carbonnel F, Jantchou P, Monnet E, Cosnes J. Environmental risk factors in Crohn's disease and ulcerative colitis: an update. Gastroenterol Clin Biol. 2009 Jun;33 Suppl 3:S145-57. doi: 10.1016/S0399-8320(09)73150-1.
21. 21. Kefalakes H, Stylianides TJ, Amanakis G, Kolios G. Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality? Eur J Clin Pharmacol. 2009 Oct;65(10):963-70. doi: 10.1007/s00228-009-0719-3.
22. 22. Patel B, Schutte R, Sporns P, Doyle J, Jewel L, Fedorak RN. Potato glycoalkaloids adversely affect intestinal permeability and aggravate inflammatory bowel disease. Inflammatory Bowel Dis. 2002 Sep;8(5):340-6. doi: 10.1097/00054725-200209000-00005.
23. 23. Hugot JP, Alberti C, Berrebi D, Bingen E, Cézard JP. Crohn's disease: the cold chain hypothesis. Lancet. 2003 Dec 13;362(9400):2012-5. doi: 10.1016/S0140-6736(03)15024-6.
24. 24. Yamamoto-Furusho JK, Sarmiento-Aguilar A, Toledo-Mauriño JJ, Bozada-Gutiérrez KE, Bosques-Padilla FJ, Martínez-Vázquez MA, et al.; EPIMEX Study Group. Incidence and prevalence of inflammatory bowel disease in Mexico from a nationwide cohort study in a period of 15 years (2000-2017). Medicine (Baltimore). 2019 Jul;98(27):e16291. doi: 10.1097/MD.0000000000016291.
25. 25. Santana J, Marzolo MP. The functions of Reelin in membrane trafficking and cytoskeletal dynamics: implications for neuronal migration, polarization and differentiation. Biochem J. 2017 Sep 7;474(18):3137-65. doi: 10.1042/BCJ20160628.
26. 26. Byrne DJ, Harmon MJ, Simpson JC, Blackstone C, O'Sullivan NC. Roles for the VCP co-factors Npl4 and Ufd1 in neuronal function in Drosophila melanogaster. J Genet Genomics. 2017 Oct 20;44(10):493-501. doi: 10.1016/j.jgg.2017.06.003.
27. 27. Fatemi SH, Earle JA, McMenomy T. Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry. 2000 Nov;5(6):654-63, 571. doi: 10.1038/sj.mp.4000783.
28. 28. Fatemi SH, Snow AV, Stary JM, Araghi-Niknam M, Reutiman TJ, Lee S, Brooks AI, Pearce DA. Reelin signaling is impaired in autism. Biol Psychiatry. 2005 Apr 1;57(7):777-87. doi: 10.1016/j.biopsych.2004.12.018.
29. 29. Haas CA, Frotscher M. Reelin deficiency causes granule cell dispersion in epilepsy. Exp Brain Res. 2010 Jan;200(2):141-9. doi: 10.1007/s00221-009-1948-5.
30. 30. Özkul T , Gölgeli A . Deneysel şizofreni modellerinin oluşturulması ve deneysel yöntemlerle şizofreni belirtilerinin değerlendirilmesi. Mersin Üniversitesi Sağlık Bilimleri Dergisi. 2019;12(2):351-9.
31. 31. Carvajal AE, Vázquez Carretero MD, García Miranda P, Peral Rubio MJ, Calonge Castrillo ML, Ilundáin Larrañeta MA. A. Reelin expression is up-regulated in mice colon in response to acute colitis and provides resistance against colitis. Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids. 2017;1863(2):462-73.
32. 32. Carvajal AE, Serrano-Morales JM, Vázquez-Carretero MD, García-Miranda P, Calonge ML, Peral MJ, et al. Reelin protects from colon pathology by maintaining the intestinal barrier integrity and repressing tumorigenic genes. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2017;1863(9):2126-34.
33. 33. Groeger SE, Meyle J. Epithelial barrier and oral bacterial infection. Periodontol 2000. 2015 Oct;69(1):46-67. doi: 10.1111/prd.12094.
34. 34. García-Miranda P, Vázquez-Carretero MD, Sesma P, Peral MJ, Ilundain AA. Reelin is involved in the crypt-villus unit homeostasis. Tissue Eng Part A. 2013 Jan;19(1-2):188-98. doi: 10.1089/ten.TEA.2012.0050.
35. 35. Schulenburg H, Kurz CL, Ewbank JJ. Evolution of the innate immune system: the worm perspective. İmmunology Rev. 2004 Apr;198:36-58. doi: 10.1111/j.0105-2896.2004.0125.x
36. 36. Cader MZ, Kaser A. Recent advances in inflammatory bowel disease: mucosal immune cells in intestinal inflammation. Gut. 2013 Nov;62(11):1653-64. doi: 10.1136/gutjnl-2012-303955.
37. 37. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011 Jun 15;474(7351):298-306. doi: 10.1038/nature10208.
38. 38. Viggiano D, Ianiro G, Vanella G, Bibbò S, Bruno G, Simeone G, Mele G. Gut barrier in health and disease: focus on childhood. Eur Rev Med Pharmacol Sci. 2015;19(6):1077-85.
39. 39. García-Miranda P, Peral MJ, Ilundain AA. Rat small intestine expresses the reelin-Disabled-1 signalling pathway. Exp Physiol. 2010 Apr;95(4):498-507. doi: 10.1113/expphysiol.2009.050682.
40. 40. García-Miranda P, Vázquez-Carretero MD, Sesma P, Peral MJ, Ilundain AA. Reelin is involved in the crypt-villus unit homeostasis. Tissue Eng Part A. 2013 Jan;19(1-2):188-98. doi: 10.1089/ten.TEA.2012.0050.
41. 41. Carvajal A, Vázquez-Carretero M, Peral M, Ilundáin A, Calonge M. (2015). DSS-induced inflammation and regulation of reelin gene expression in mouse colon: P4-4. Acta Physiologica. 2015.
42. 42. Gökden Y , Hot S , Gönen C , Kalyon S , Akkan Çetinkaya Z . The value of adenosine deaminase level in assessing activation of inflammatory bowel disease. Journal of Surgery and Medicine. 2020;4(8):654-59. doi: 10.28982/josam.769877
43. 43. Kalyon S, Gökden Y, Oyman F. A new biological marker in inflammatory bowel disease: Pentraxin 3. Journal of Surgery and Medicine. 2020;4(10):875-8. doi: 10.28982/josam.791156.