HYPERHOMOCYSTEINEMIA LEAD TO TRANSMURAL INFLAMMATION OF COLON AND INCREASE SEVERITY OF DISEASE IN ACETIC ACID-INDUCED COLITIS IN RAT
Objective: The present study was designed to evaluate the effect of hyperhomocysteinemia (Hhcy) induced by feeding rats high methionine diet on the colon wall. Colonic damages caused by Hhcy were compared with those induced by acetic â€“acid induced colitis.
Methods: Sprague-Dawley rats (200-250g) were divided into four groups: group C (control), group M (received 1 g/kg methionine p. o. during 15 d), group A (colitis was induced by transrectal administration of acetic acid 4% on 8th day) and group MA (received methionine and acetic acid). At the end of the study, plasma homocysteine, C-reactive protein (CRP) and leukocytes (WBC) count were evaluated, all rats were sacrificed and distal 8 cm of the colon was dissected. Colon was weighed for disease activity index (DAI) and injuries were assessed macroscopically and histologically.
Results: High methionine diet induced significant (P<0.001) increase of homocysteine (hcy), CRP levels and WBC count compared to control. Acetic acid rats showed a significant decrease of WBC count. Mixed treatment caused a significant increase of hcy, CRP and a significant decrease of WBC count. Our results showed that Hhcy causes significant damages and immune cells infiltration in all layers of the colonic wall.
Conclusion: The present investigation demonstrated that Hhcy increased the major inflammatory markers as CRP and leukocytes count and produced transmural colitis in rats. Effect of Hhcy is more toxic on the colonic wall than acetic acid indeed while acetic acid lesions are localized in mucosa and submucosa the lesions of hcy extend to the all layers (mucosa, submucosa and muscularis propria). Acetic acid induced colitis in hyperhomocysteinemic rats increased the severity of colitis.
2. Medzhitov R. Origin and physiological roles of inflammation. Nature 2008;454:428-35.
3. Jiminez JA, Uwiera TC, Inglis DG, Uwiera RR. Animal models to study acute and chronic intestinal inflammation in mammals. Gut Pathog 2015;7:29.
4. Raiten DJ, Ashour FAS, Ross AC, Meydani SN, Dawson HD, Stephensen CB, Brabin BJ, Suchdev PS, van Ommen B. Inflammation and nutritional science for programs/policies and interpretation of research evidence (inspire). J Nutr 2015;145:1039Sâ€“1108S.
5. Murthy SN, Obregon DF, Chattergoon NN, Fonseca NA, Mondal D, Dunne JB, et al. Rosiglitazone reduces serum homocysteine levels, smooth muscle proliferation, and intimal hyperplasia in sprague-dawley rats fed a high methionine diet. Metabology 2005;54:645-52.
6. Wu JT. Circulating homocysteine is an inflammation marker and a risk factor of life-threatening inflammatory diseases. J Biomed Lab Sci 2007;19:107-11.
7. Cashman KD. Homocysteine and osteoporotic fracture risk: a potential role for B vitamins. Nutr Rev 2005;63:29-36.
8. Erzin Y, Uzun H, Celik AF, Aydin S, Dirican A, Uzunismail H. Hyperhomocysteinemia in inflammatory bowel disease patients without past intestinal resections: correlations with cobalamin, pyridoxine, folate concentrations, acute phase reactants, disease activity, and prior thromboembolic complications. J Clin Gastroenterol 2008;42:481-6.
9. Shivappa N, HÃ©bert JR, Rietzschel ER, De Buyzere ML, Langlois M, Debruyne E, et al. Associations between the dietary inflammatory index and inflammatory markers in the asklepios study. B J Nut 2015;113:665-71.
10. Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat MM, et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol 2014;7:4557â€“76.
11. Kapoor P, Ansari MN, Bhandari U. Modulatory effect of curcumin on methionine-induced hyperlipidemia and hyperhomocysteinemia in albino rats. Indian J Exp Biol 2008;46:534-40.
12. Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Gosavi TP, Badole SL, Bodhankar SL. Effect of hydroalcoholic extract of Hibiscus rosa sinensis Linn. Leaves in experimental colitis in rats. Asian Pac J Trop Biomed 2012;2:337-44.
13. Al-Rejaie SS, Abuohashish HM, Al-Enazi MM, Al-Assaf AH, Parmar MY, Ahmed MM. Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats. World J Gastroenterol 2013;19:5633-44.
14. Ueland PM, Refsum H, Stabler SP. Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem 1993;39:1764-79.
15. Ko JK, Lam FY, Cheung AP. Amelioration of experimental colitis by Astragalus membranaceus through anti-oxidation and inhibition of adhesion molecule synthesis. World J Gastroenterol 2005;11:5787-94.
16. Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterol 1989;96:795-803.
17. Ackerman Z, Karmeli F, Cohen P, Rachmilewitz D. Experimental colitis in rats with portal hypertension and liver disease. Inflammatory Bowel Dis 2003;9:18-24.
18. Colin M, Arkhurst G, Lebas F. Effets de lâ€™addition de mÃ©thionine au rÃ©gime alimentaire sur les performances de croissance chez le Lapin. Annal Zootech 1973;22:485-91.
19. Saunderson CL, Mackinlay J. Changes in body weight, composition and hepatic enzyme activities in response to dietary methionine, betaine and choline levels in growing chicks. Br J Nut 1990;63:339-49.
20. Toue S, Kodama R, Amao M, Kawamata Y, Kimura T, Sakai R. Screening of toxicity biomarkers for methionine excess in rats. J Nutr 2006;136:1716S-21S.
21. Kim SY, Kim H, Min H. Effects of excessive dietary methionine on oxidative stress and dyslipidemia in chronic ethanol-treated rats. Nutr Res Pract 2015;9:144-9.
22. Bastaki SMA, Al Ahmed MM, Al Zaabi A, Amir N, Adeghate E. Effect of turmeric on colon histology, body weight, ulcer, IL-23, MPO and glutathione in acetic-acid-induced inflammatory bowel disease in rats. BMC Complementary Altern Med 2016;16:72.
23. Braun TP, Marks DL. Pathophysiology and treatment of inflammatory anorexia in chronic disease. J Cachex Sarc Muscl 2010;1:135-45.
24. Munro HN. Nutritional consequences of excess amino acid intake. In: Nutritional Improvement of Food and Feed Proteins: Springer US; 1978. p. 119-29.
25. Gautron L, LayÃ© S. Neurobiology of inflammation-associated anorexia. Front Neurosci 2010;3:3.
26. Bottiglieri T. Homocysteine and folate metabolism in depression. Prog Neuro Psycho Pharmacol Biol Psychiatry 2005;29:1103-12.
27. Matthias D, Becker CH, Riezler R, Kindling PH. Homocysteine-induced arteriosclerosis-like alterations of the aorta in normotensive and hypertensive rats following application of high doses of methionine. Atherosclerosis 1996;122:201â€“16.
28. Bonaventura D, Tirapelli CR, De Oliveira AM. Chronic methionine load-induced hyperhomocysteinemia impairs the relaxation induced by bradykinin in the isolated rat carotid. Amin Acid 2009;37:617â€“27.
29. Bhandari U, Pathan RA, Kumar V, Khanna N. Ameliorative role of atorvastatin on methionine-induced hyperhomocysteinemia and hematological changes in albino rats. Indian J Exp Biol 2011;49:132-9.
30. MacPherson BR, Pfeiffer CJ. Experimental production of diffuse colitis in rats. Digest 1978;17:135-50.
31. Shalaby A, Shatta A. Potential antioxidant and anti-inflammatory effects of Hyphaenathebaica in experimentally induced inflammatory bowel disease. Int J Pharm Res 2013;9:51-60.
32. Patil MVK, Kandhare AD, Bhise SD. Effect of aqueous extract of cucumis sativus Linn. fruit in ulcerative colitis in laboratory animals. Asian Pac J Trop Biomed 2012;2:S962-S9.
33. Schroecksnadel K, Winkler C, Wirleitner B. Anti-inflammatory compound resveratrol suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells in vitro. Clin Chem Lab Med 2005;43:1084-8.
34. Lampinen M, Carlson M, Hakansson LD, Venge P. Cytokine-regulated accumulation of eosinophils in inflammatory disease. Allerg 2004;59:793-805.
35. Vermeire S, Van Assche G, Rutgeerts P. Câ€reactive protein as a marker for inflammatory bowel disease. Inflammatory Bowel Dis 2004;10:661-705.
36. Chandrashekara S. C-reactive protein: an inflammatory marker with a specific role in physiology, pathology, and diagnosis. Int J Rheumatol ClinImmunol 2014;2(S1):SR3.
37. Verma S, Yeh ETH. C-reactive protein and atherothrombosisâ€”Beyond a biomarker: an actual partaker of lesion formation. Am J Physiol Regul Integr Comp Physiol 2003;285:1253â€“306.
38. Tyagi N, Sedoris KC, Steed M, Ovechkin AV, Moshal KS, Tyagi SC. Mechanisms of homocysteine-induced oxidative stress. Am J Physiol-Heart Circulat Physiol 2005;289:H2649-H56.
39. Ansari MN, Nigam GK, Bhandari U. Effect of folic acid on hematological changes in methionine-induced hyperhomocysteinemia in rats. Indian J Pharmaceut Sci 2009;71:270-305.
40. Carru C, Zinellu A, Sotgia S, Serra R, Usai MF, Pintus G, et al. A new HPLC method for serum neopterin measurement and relationships with plasma thiols levels in healthy subjects. Biomed Chrom 2004;18:360-1.
41. Carru C, Deiana L, Sotgia S, Usai MF, Zinellu A. Relationships between white blood cell count and levels of serum homocysteine and cysteine in healthy subjects. Br J Haematol 2005;90:136-207.
42. Alfadda AA, Storr MA, Shaffer EA. Eosinophilic colitis: an update on pathophysiology and treatment. Br Med Bull 2011;100:59-72.
43. Cibor D, Domagala-Rodacka R, Rodacki T, Jurczyszyn A, Mach T, Owczarek D. Endothelial dysfunction in inflammatory bowel diseases: Pathogenesis, assessment and implications. World J Gastroenterol 2016;22:1067-77.
44. Ding H, Mei Q, Gan HZ, Cao LY, Liu XC, Xu JM. Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism. Gastroenterol Report (Oxf) 2014;2:215-20.
45. Zhang C, Cai Y, Adachi MT, Oshiro S, Aso T, Kaufman RJ, et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem 2001;276:35867-74.
46. Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen DW. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells implications for vascular disease. Circulat 2001;103:2717-23
47. Oldenburg B, Van Tuyl BA, van der Griend R, Fijnheer R, van Berge henigouwen GP. Risk factors for thromboembolic complications in inflammatory bowel disease: the role of hyperhomocysteinaemia. Diges Diseas Sci 2005;50:235-40.
48. Faraci FM, Lentz SR. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Strok 2004;35:345-7.
49. EL Oudi M, Aouni Z, Mazigh C, Khochkar R, Gazoueni E, Haouela H, et al. Homocysteine and markers of inflammation in acute coronary syndrome. Exp Clin Cardiol 2010;15:25â€“8.
50. MÅ±zes G, MolnÃ¡r B, Tulassay Z, Sipos F. Changes of the cytokine profile in inflammatory bowel diseases. World J Gastroenterol 2012;18:5848-61.
51. Danese S, Sans M, de la Motte C, Graziani C, West G, Phillips MH, et al. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterol 2006;130:2060-73.
52. Roybal CN, Yang S, Sun CW, Hurtado D, Vander Jagt DL, Townes TM, et al. Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem 2004;279:14844-52.
53. Peyrin-Biroulet L. Lâ€™homocystÃ©inÃ©mie, un nouveau marqueur de sÃ©vÃ©ritÃ© dans les MICI? HÃ©pato Gastro Oncol Digest 2007;14:149-56.