The effect of zinc supplementation on pro-inflammatory cytokines (TNF-α, IL-1 AND IL-6) in mice with Escherichia coli LPS-induced diarrhea
Background and Objectives: Inflammation in the intestine causes diarrhea due to an increased release of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6. These are triggered by the exposure of E. coli-LPS to epithelial cells of the intestinal mucosa as well as low concentration of zinc in plasma such as in infants or children who are experiencing diarrhea. This paper aims to determine the effects of zinc supplementation on pro-inflammatory cytokines (TNF-α, IL-1 and IL-6) in mice with E. coli-LPS-induced diarrhea.
Materials and Methods: This study used a controlled trial experimental design in the laboratory. A sample size of 20 mice were randomly divided into 4 groups: 1) Control group was given standard foods, 2) Trial group was given E. coli-LPS 2.5 mg/kg/oral once on day1, 3) Prevention group was given E. coli-LPS + 30 mg/kg/oral of zinc once daily for 12 days, 4) Therapeutic group was given E. coli-LPS, and were then given 30 mg/kg/oral of zinc once daily for 12 days if diarrhea occurred. Blood samples of mice were taken through the orbital sinus on the 0, 5th, 10th hour, and on the 4th, 8th and 12th days.
Results: Positive effects of zinc supplementation on levels of pro-inflammatory cytokines were observed, in which the higher levels of zinc were present, the lower levels of pro-inflammatory cytokines, especially TNF-α were observed. However, there was an increase of IL-1 and IL-6 levels on the 8th day in the prevention and therapeutic groups.
Conclusion: Oral zinc supplementation had a significant positive effect on the levels of pro-inflammatory cytokines. Where there were higher levels of zinc, lower levels of pro-inflammatory cytokines TNF-α were present.
2. King JC (2003). Specific nutrient requirements. In: Nutrition And Immunology Principles And Practice. Humana Press Inc. New Jersey, USA, pp. 65-73.
3. Roy SK, Behrens RH, Haider R, Akramuzzaman SM, Mahalanabis D, Wahed MA, et al. Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhea and persistent diarrhea syndrome. J Pediatr Gastroenterol Nutr 1992; 15:289-296.
4. Kikkawa I, Saito S, Tominaga K, Hoshino Y, Ooi Y, Nakano M. Lippopolysaccharide (LPS) stimulates the production of tumor necrosis factor (TNF)-alpha and expression of inducible nitric oxide synthase (iNOS) by osteoclasts (OCL) in muribe bone marrow cell culture. Microbiol Immunol 1998; 42:591-598.
5. Baratawidjaja KG, Rengganis I (2009). Cytokines in Basic Immunology. University of Indonesia Press, 8th ed. Jakarta, Indonesia, pp. 219-55.
6. Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young North Indian children. Pediatrics 2002; 109(6):e86.
7. Fenwick PK, Aggett PJ, Macdonald DC, Huber C, Wakelin D. Zinc deprivation and zinc repletion: effect on the response of rats to infection with strongyloides ratti. Am J Clin Nutr 1990; 52:173-177.
8. Madiono B, Moeslichan S, Sastroasmoro S, Budiman I, and Purwanto SH. (2002). Sample Size Estimation in Basic Clinical Research Methods. Sagung Seto Press, 2nd ed. Jakarta, Indonesia, pp. 259-87.
9. Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol 1993; 11:165-190.
10. Sturniolo GC. The many functions of zink in inflammatory conditions of the gastrointestinal tract. Trace Elem Exp Med 2000; 13: 33-39.
11. Gammoh NZ, Lothar Rin. Zinc in infection and inﬂammation. Nutrients 2017; 9(6): E624.
12. Nishida K, Ryota Uchid. Role of zinc signaling in the regulation of mast cell, Basophil, and T cell-mediated allergic responses. J Immunol Res 2018;2018: 1-9.
13. Prasad AS. Zinc in human health: Effect of Zinc on immune cells. Mol Med 2008, 14: 353-357.
14. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr 1998, 68(2 Suppl):447S-463S.
15. Janeway CA, Travers P, Walport M, Shlomchik M (2005). Innate Immunity. In: Immunobiology: The Immune System in Health & Disease. Garland Science Publishing, 6th ed. New York, USA, pp.
16. Olechnowicz J, Tinkov A, Skalny A, Suliburska J. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism.. J Physiol Sci 2018; 68:19-31.
17. Rosalina I (2007), The efficacy of Zinc administration on diarrhea, in the Proceeding of The 3rd National Meeting of Indonesian Pediatric Gastroenterology Coordination Board: A Comprehensive Management of Gastroenterohepatic Problems in Children. BKGAI, 1st ed. Surabaya, Indonesia, pp. 159-67.
18. Wong CP, Nicole AR, Emily Ho. Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation. Mol Nutr Food Res 2015; 59: 991-999.
19. Helge K, Rink L. Zink-altered immune function. J Nutr 2003; 133(5 Suppl 1):1452S-1456S.
20. Bires J, Bajova V, Vrzgula L, Strojny L, Kovarova E, Levkutova M, et al. Humoral immunity response to zinc injectible zindep inj a.u.v. biotika in pregnant cows. Biopharm 1991;1: 103-109.
21. Linder, M.C (1992) Nutritional Biochemistry and Metabolism. Translated version. Penerbit Universitas Indonesia, Jakarta, Indonesia.
22. Aggarwal R, Sentz J, Miler MA. Role of zink administration in prevention of childhood diarrhea and respiratory illness: a meta analysis. Pediatrics 2007; 119;1120-1130.
23. Subowo (1993): Cytokines in Immunology. Angkasa Press, 1st ed. Bandung, Indonesia, pp. 187-206.
24. Scrimshaw NS, SanGiovanni JP. Synergism of nutrition, infection, and immunity: an overview. Am J Clin Nutr 1997; 66: 464S-477S.