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Intestinal Alkaline Phosphatase: Potential Roles in Promoting Gut Health in Weanling Piglets and Its Modulation by Feed Additives - A Review
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 Title & Authors
Intestinal Alkaline Phosphatase: Potential Roles in Promoting Gut Health in Weanling Piglets and Its Modulation by Feed Additives - A Review
Melo, A.D.B.; Silveira, H.; Luciano, F.B.; Andrade, C.; Costa, L.B.; Rostagno, M.H.;
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The intestinal environment plays a critical role in maintaining swine health. Many factors such as diet, microbiota, and host intestinal immune response influence the intestinal environment. Intestinal alkaline phosphatase (IAP) is an important apical brush border enzyme that is influenced by these factors. IAP dephosphorylates bacterial lipopolysaccharides (LPS), unmethylated cytosine-guanosine dinucleotides, and flagellin, reducing bacterial toxicity and consequently regulating toll-like receptors (TLRs) activation and inflammation. It also desphosphorylates extracellular nucleotides such as uridine diphosphate and adenosine triphosphate, consequently reducing inflammation, modulating, and preserving the homeostasis of the intestinal microbiota. The apical localization of IAP on the epithelial surface reveals its role on LPS (from luminal bacteria) detoxification. As the expression of IAP is reported to be downregulated in piglets at weaning, LPS from commensal and pathogenic gram-negative bacteria could increase inflammatory processes by TLR-4 activation, increasing diarrhea events during this phase. Although some studies had reported potential IAP roles to promote gut health, investigations about exogenous IAP effects or feed additives modulating IAP expression and activity yet are necessary. However, we discussed in this paper that the critical assessment reported can suggest that exogenous IAP or feed additives that could increase its expression could show beneficial effects to reduce diarrhea events during the post weaning phase. Therefore, the main goals of this review are to discuss IAP`s role in intestinal inflammatory processes and present feed additives used as growth promoters that may modulate IAP expression and activity to promote gut health in piglets.
Feed Additives;Intestinal Alkaline Phosphatase;Intestinal Inflammation;Gut Health;Swine;
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Abasht, B., M. G. Kaiser, and S. J. Lamont. 2008. Toll-like receptor gene expression in cecum and spleen of advanced intercross line chicks infected with Salmonella enterica serovar Enteritidis. Vet. Immunol. Immunopathol. 123:314-323. crossref(new window)

Akira, S., K. Takeda, and T. Kaisho. 2001. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2:675-680. crossref(new window)

Alam, S. N., H. Yammine, O. Moaven, R. Ahmed, A. K. Moss, B. Biswas, N. Muhammad, R. Biswas, A. Raychowdhury, K. Kaliannan, S. Ghosh, M. Ray, S. R. Hamarneh, S. Barua, N. S. Malo, A. K. Bhan, M. S. Malo, and R. A. Hodin. 2014. Intestinal alkaline phosphatase prevents antibiotic-induced susceptibility to enteric pathogens. Ann. Surg. 259:715-722. crossref(new window)

Artis, D. 2008. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat. Rev. Immunol. 8:411-420. crossref(new window)

Bates, J. M., J. Akerlund, E. Mittge, and K. Guillemin. 2007. Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. Cell. Host. Microbe. 2:371-382. crossref(new window)

Bederska-Łojewska, D. and M. Pieszka. 2011. Modulating gastrointestinal microflora of pigs through nutrition using feed additives. Ann. Anim. Sci. 11:333-355.

Bentala, H., W. R. Verweij, A. Huizinga-Van der Vlag, A. M. van Loenen-Weemaes, D. K. Meijer, and K. Poelstra. 2002. Removal of phosphate from lipid A as a strategy to detoxify lipopolysaccharide. Shock. 18:561-566. crossref(new window)

Berkes, J., V. K. Viswanathan, S. D. Savkovic, and G. Hecht. 2003. Intestinal epithelial responses to enteric pathogens: Effects on the tight junction barrier, ion transport, and inflammation. Gut. 52:439-451. crossref(new window)

Beumer, C., M. Wulferink, W. Raaben, D. Fiechter, R. Brands, and W. Seinen. 2003. Calf intestinal alkaline phosphatase, a novel therapeutic drug for lipopolysaccharide (LPS)-mediated diseases, attenuates LPS toxicity in mice and piglets. J. Pharmacol. Exp. Ther. 307:737-744. crossref(new window)

Beutler, B. and E. T. Rietschel. 2003. Innate immune sensing and its roots: the story of endotoxin. Nat. Rev. Immunol. 3:169-176. crossref(new window)

Bevins, C. L., E. Martin-Porter, and T. Ganz. 1999. Defensins and innate host defence of the gastrointestinal tract. Gut. 45:911-915. crossref(new window)

Bol-Schoenmakers, M., D. Fiechter, W. Raaben, I. Hassing, R. Bleumink, D. Kruijswijk, K. Maijoor, M. Tersteeg-Zijderveld, R. Brands, and R. Pieters. 2010. Intestinal alkaline phosphatase contributes to the reduction of severe intestinal epithelial damage. Eur. J. Pharmacol. 633:71-77. crossref(new window)

Brun, L. R., M. L. Brance, M. Lombarte, M. Lupo, V. E. Di Loreto, and A. Rigalli. 2014. Regulation of intestinal calcium absorption by luminal calcium content: role of intestinal alkaline phosphatase. Mol. Nutr. Food. Res. 58:1546-1551. crossref(new window)

Burkey, T. E., K. A. Skjolaas, and J. E. Minton. 2009. Board-invited review: porcine mucosal immunity of the gastrointestinal tract. J. Anim. Sci. 87:1493-1501. crossref(new window)

Cario, E. 2005. Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut. 54:1182-1193. crossref(new window)

Chen, K. T., M. S. Malo, A. K. Moss, S. Zeller, P. Johnson, F. Ebrahimi, G. Mostafa, S. N. Alam, S. Ramasamy, H. S. Warren, E. L. Hohmann, and R. A. Hodin. 2010. Identification of specific targets for the gut mucosal defense factor intestinal alkaline phosphatase. Am. J. Physiol. Gastrointest. Liver Physiol. 299:G467-G475. crossref(new window)

Chen, K. T., M. S. Malo, L. K. Beasley-Topliffe, K. Poelstra, J. L. Millan, G. Mostafa, S. N. Alam, S. Ramasamy, H. S. Warren, E. L. Hohmann, and R. A. Hodin. 2011. A role for intestinal alkaline phosphatase in the maintenance of local gut immunity. Dig. Dis. Sci. 56:1020-1027. crossref(new window)

de Lange, C. F. M., J. Pluske, J. Gong, and C. M. Nyachoti. 2010. Strategic use of feed ingredients and feed additives to stimulate gut health and development in young pigs. Livest. Sci. 134:124-134. crossref(new window)

Eisenhut, M. 2006. Changes in ion transport in inflammatory disease. J. Inflamm (Lond). 3:5. crossref(new window)

Fairbrother, J. M., E. Nadeau, and C. L. Gyles. 2005. Escherichia coli in postweaning diarrhea in pigs: an update on bacterial types, pathogenesis, and prevention strategies. Anim. Health Res. Rev. 6:17-39. crossref(new window)

Gallois, M. and I. P. Oswald. 2008. Immunomodulators as efficient alternatives to in-feed antimicrobials in pig production. Arch. Zootech. 11:15-32.

Gao, M., N. London, K. Cheng, R. Tamura, J. Jin, O. Schueler-Furman, and H. Yin. 2014. Rationally designed macrocyclic peptides as synergistic agonists of LPS-induced inflammatory response. Tetrahedron. 70:7664-7668. crossref(new window)

Goldberg, R. F., W. G. Austen, Jr., X. Zhang, G. Munene, G. Mostafa, S. Biswas, M. McCormack, K. R. Eberlin, J. T. Nguyen, H. S. Tatlidede, H. S. Warren, S. Narisawa, J. L. Millán, and R. A. Hodin. 2008. Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition. Proc. Natl. Acad. Sci. USA 105:3551-3556. crossref(new window)

Goldstein, D. J., C. Rogers, and H. Harris. 1982. A search for trace expression of placental-like alkaline phosphatase in non-malignant human tissues: demonstration of its occurrence in lung, cervix, testis and thymus. Clin. Chim. Acta. 125:63-75. crossref(new window)

Heo, J. M., F. O. Opapeju, J. R. Pluske, J. C. Kim, D. J. Hampson, and C. M. Nyachoti. 2013. Gastrointestinal health and function in weaned pigs: a review of feeding strategies to control postweaning diarrhoea without using in-feed antimicrobial compounds. J. Anim. Physiol. Anim. Nutr (Berl). 97:207-237. crossref(new window)

Howe, L. M. 2000. Novel agents in the therapy of endotoxic shock. Expert. Opin. Investig. Drugs. 9:1363-1372. crossref(new window)

Hu, C. H., K. Xiao, J. Song, and Z. S. Luan. 2013. Effects of zinc oxide supported on zeolite on growth performance, intestinal microflora and permeability, and cytokines expression of weaned pigs. Anim. Feed. Sci. Technol. 181:65-71. crossref(new window)

Jang, I. S., Y. H. Ko, S. Y. Kang, and C. Y. Lee. 2007. Effect of a commercial essential oil on growth performance, digestive enzyme activity and intestinal microflora population in broiler chickens. Anim. Feed. Sci. Technol. 134:304-315. crossref(new window)

Kim, J. C., C. F. Hansen, B. P. Mullan, and J. R. Pluske. 2012. Nutrition and pathology of weaner pigs: Nutritional strategies to support barrier function in the gastrointestinal tract. Anim. Feed. Sci. Technol. 173:3-16. crossref(new window)

Koyama, I., T. Matsunaga, T. Harada, S. Hokari, and T. Komoda. 2002. Alkaline phosphatases reduce toxicity of lipopolysaccharides in vivo and in vitro through dephosphorylation. Clin. Biochem. 35:455-461. crossref(new window)

Lackeyram, D., C. Yang, T. Archbold, K. C. Swanson, and M. Z. Fan. 2010. Early weaning reduces small intestinal alkaline phosphatase expression in pigs. J. Nutr. 140:461-468. crossref(new window)

Lalles, J. P. 2010. Intestinal alkaline phosphatase: Multiple biological roles in maintenance of intestinal homeostasis and modulation by diet. Nutr. Rev. 68:323-332. crossref(new window)

Lalles, J. P. 2014. Intestinal alkaline phosphatase: Novel functions and protective effects. Nutr. Rev. 72:82-94. crossref(new window)

Levkut, M., A. Marcin, V. Revajova, L. Lenhardt, I. Danielovic, J. Hecl, J. Blanár, M. Levkutova, and J. Pistl. 2011. Influence of oregano extract on the intestine, some plasma parameters and growth performance in chickens. Acta. Vet. Brno. 61:215-225. crossref(new window)

Levkut, M., A. L. Marcin, L. Lenhardt, P. Porvaz, V. Revajova, B. Soltysova, J. Blanar, Z. Sevcikova, and J. Pistl. 2010. Effect of sage extract on alkaline phosphatase, enterocyte proliferative activity and growth performance in chickens. Acta. Vet. Brno. 79:177-183. crossref(new window)

Li, X., J. Yin, D. Li, X. Chen, J. Zang, and X. Zhou. 2006. Dietary supplementation with zinc oxide increases Igf-I and Igf-I receptor gene expression in the small intestine of weanling piglets. J. Nutr. 136:1786-1791. crossref(new window)

Malo, M. S., O. Moaven, N. Muhammad, B. Biswas, S. N. Alam, K. P. Economopoulos, S. S. Gul, S. R. Hamarneh, N. S. Malo, A. Teshager, M. M. Mohamed, Q. Tao, S. Narisawa, J. L. Millan, E. L. Hohmann, H. S. Warren, S. C. Robson, and R. A. Hodin. 2014. Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates. Am. J. Physiol. Gastrointest. Liver. Physiol. 306:G826-G838. crossref(new window)

Malo, M. S., S. Biswas, M. A. Abedrapo, L. Yeh, A. Chen, and R. A. Hodin. 2006. The pro-inflammatory cytokines, IL-1beta and TNF-alpha, inhibit intestinal alkaline phosphatase gene expression. DNA. Cell. Biol. 25:684-695. crossref(new window)

Martin, L., R. Pieper, N. Schunter, W. Vahjen, and J. Zentek. 2013. Performance, organ zinc concentration, jejunal brush border membrane enzyme activities and mRNA expression in piglets fed with different levels of dietary zinc. Arch. Anim. Nutr. 67:248-261. crossref(new window)

Martinez-Moya, P., M. Ortega-Gonzalez, R. Gonzalez, A. Anzola, B. Ocon, C. Hernandez-Chirlaque, R. Lopez-Posadas, M. D. Suarez, A. Zarzuelo, O. Martinez-Augustin, and F. Sanchez de Medina. 2012. Exogenous alkaline phosphatase treatment complements endogenous enzyme protection in colonic inflammation and reduces bacterial translocation in rats. Pharmacol. Res. 66:144-153. crossref(new window)

McGhee, J. R., M. E. Lamm, and W. Strober. 1999. Mucosal immune responses: an overview. In: Mucosal Immunology, 2nd Ed. (Eds. P. L. Ogra, J. Mestecky, and M. E. Lamm). Academic Press, San Diego, CA, USA. pp. 485-506.

Moss, A. K., S. R. Hamarneh, M. M. Mohamed, S. Ramasamy, H. Yammine, P. Patel, K. Kaliannan, S. N. Alam, N. Muhammad, O. Moaven, A. Teshager, N. S. Malo, S. Narisawa, J. L. Millán, H. S. Warren, E. Hohmann, M. S. Malo, and R. A. Hodin. 2013. Intestinal alkaline phosphatase inhibits the proinflammatory nucleotide uridine diphosphate. Am. J. Physiol. Gastrointest. Liver. Physiol. 304:G597-604. crossref(new window)

Mussa, T., M. Ballester, E. Silva-Campa, M. Baratelli, N. Busquets, M. P. Lecours, J. Dominguez, M. Amadori, L. Fraile, J. Hernandez, and M. Montoya. 2013. Swine, human or avian influenza viruses differentially activates porcine dendritic cells cytokine profile. Vet. Immunol. Immunopathol. 154:25-35. crossref(new window)

Oshiumi, H., M. Matsumoto, K. Funami, T. Akazawa, and T. Seya. 2003. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat. Immunol. 4:161-167. crossref(new window)

Perez, R., F. Stevenson, J. Johnson, M. Morgan, K. Erickson, N. E. Hubbard, L. Morand, S. Rudich, S. Katznelson, and J. B. German. 1998. Sodium butyrate upregulates Kupffer cell PGE2 production and modulates immune function. J. Surg. Res. 78:1-6. crossref(new window)

Pie, S., J. P. Lalles, F. Blazy, J. Laffitte, B. Seve, and I. P. Oswald. 2004. Weaning is associated with an upregulation of expression of inflammatory cytokines in the intestine of piglets. J. Nutr. 134:641-647. crossref(new window)

Poelstra, K., W. W. Bakker, P. A. Klok, J. A. Kamps, M. J. Hardonk, and D. K. Meijer. 1997a. Dephosphorylation of endotoxin by alkaline phosphatase in vivo. Am. J. Pathol. 151:1163-1169.

Poelstra, K., W. W. Bakker, P. A. Klok, M. J. Hardonk, and D. K. Meijer. 1997b. A physiologic function for alkaline phosphatase: endotoxin detoxification. Lab. Invest. 76:319-327.

Prakash, U. N. and K. Srinivasan. 2010. Beneficial influence of dietary spices on the ultrastructure and fluidity of the intestinal brush border in rats. Br. J. Nutr. 104:31-39. crossref(new window)

Roselli, M., A. Finamore, I. Garaguso, M. S. Britti, and E. Mengheri. 2003. Zinc oxide protects cultured enterocytes from the damage induced by Escherichia coli. J. Nutr. 133:4077-4082. crossref(new window)

Sang, Y., J. Yang, C. R. Ross, R. R. Rowland, and F. Blecha. 2008. Molecular identification and functional expression of porcine Toll-like receptor (TLR) 3 and TLR7. Vet. Immunol. Immunopathol. 125:162-167. crossref(new window)

Shelton, N. W., M. D. Tokach, J. L. Nelssen, R. D. Goodband, S. S. Dritz, J. M. DeRouchey, and G. M. Hill. 2011. Effects of copper sulfate, tri-basic copper chloride, and zinc oxide on weanling pig performance. J. Anim. Sci. 89:2440-2451. crossref(new window)

Shimosato, T., M. Tohno, H. Kitazawa, S. Katoh, K. Watanabe, Y. Kawai, H. Aso, T. Yamaguchi, and T. Saito. 2005. Toll-like receptor 9 is expressed on follicle-associated epithelia containing M cells in swine Peyer's patches. Immunol. Lett. 98:83-89. crossref(new window)

Shinkai, H., M. Tanaka, T. Morozumi, T. Eguchi-Ogawa, N. Okumura, Y. Muneta, T. Awata, and H. Uenishi. 2006a. Biased distribution of single nucleotide polymorphisms (SNPs) in porcine Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR5, and TLR6 genes. Immunogenetics 58:324-330. crossref(new window)

Shinkai, H., Y. Muneta, K. Suzuki, T. Eguchi-Ogawa, T. Awata, and H. Uenishi. 2006b. Porcine Toll-like receptor 1, 6, and 10 genes: complete sequencing of genomic region and expression analysis. Mol. Immunol. 43:1474-1480. crossref(new window)

Smith, F., J. E. Clark, B. L. Overman, C. C. Tozel, J. H. Huang, J. E. Rivier, A. T. Blikslager, and A. J. Moeser. 2010. Early weaning stress impairs development of mucosal barrier function in the porcine intestine. Am. J. Physiol. Gastrointest. Liver. Physiol. 298:G352-G363. crossref(new window)

Sussman, N. L., R. Eliakim, D. Rubin, D. H. Perlmutter, K. DeSchryver-Kecskemeti, and D. H. Alpers. 1989. Intestinal alkaline phosphatase is secreted bidirectionally from villous enterocytes. Am. J. Physiol. 257(1 Pt 1):G14-G23.

Takeda, K., and S. Akira. 2004. TLR signaling pathways. Semin. Immunol. 16:3-9. crossref(new window)

Taras, D., W. Vahjen, M. Macha, and O. Simon. 2006. Performance, diarrhea incidence, and occurrence of Escherichia coli virulence genes during long-term administration of a probiotic Enterococcus faecium strain to sows and piglets. J. Anim. Sci. 84:608-617. crossref(new window)

Tohno, M., T. Shimosato, H. Kitazawa, S. Katoh, I. D. Iliev, T. Kimura, Y. Kawai, K. Watanabe, H. Aso, T. Yamaguchi, and T. Saito. 2005. Toll-like receptor 2 is expressed on the intestinal M cells in swine. Biochem. Biophys. Res. Commun. 330:547-554. crossref(new window)

Tohno, M., T. Shimosato, M. Moue, H. Aso, K. Watanabe, Y. Kawai, T. Yamaguchi, T. Saito, and H. Kitazawa. 2006. Toll-like receptor 2 and 9 are expressed and functional in gutassociated lymphoid tissues of presuckling newborn swine. Vet. Res. 37:791-812. crossref(new window)

Tucci, F. M., M. C. Thomaz, L. S. O. Nakaghi, M. I. Hannas, A. J. Scandolera, and F. E. L. Budino. 2011. The effect of the addition of trofic agents in weaned piglet diets over the structure and ultra-structure of small intestine and over performance. Arq. Bras. Med. Vet. Zootec. 63:931-940. crossref(new window)

Tuin, A., A. Huizinga-Van der Vlag, A. M. van Loenen-Weemaes, D. K. Meijer, and K. Poelstra. 2006. On the role and fate of LPS-dephosphorylating activity in the rat liver. Am. J. Physiol. Gastrointest. Liver. Physiol. 290:G377-G385. crossref(new window)

Uenishi, H. and H. Shinkai. 2009. Porcine Toll-like receptors: the front line of pathogen monitoring and possible implications for disease resistance. Dev. Comp. Immunol. 33:353-361. crossref(new window)

Uysal, G., A. Sökmen, and S. Vidinlisan. 2000. Clinical risk factors for fatal diarrhea in hospitalized children. Indian. J. Pediatr. 67:329-333. crossref(new window)

Vaishnava, S. and L. V. Hooper. 2007. Alkaline phosphatase: keeping the peace at the gut epithelial surface. Cell. Host. Microbe. 2:365-367. crossref(new window)

van Veen, S. Q., A. K. van Vliet, M. Wulferink, R. Brands, M. A. Boermeester, and T. M. van Gulik. 2005. Bovine intestinal alkaline phosphatase attenuates the inflammatory response in secondary peritonitis in mice. Infect. Immun. 73:4309-4314. crossref(new window)

Weber, T. E. and B. J. Kerr. 2008. Effect of sodium butyrate on growth performance and response to lipopolysaccharide in weanling pigs. J. Anim. Sci. 86:442-450. crossref(new window)

Yamamoto, M., S. Sato, K. Mori, K. Hoshino, O. Takeuchi, K. Takeda, and S. Akira. 2002. Cutting edge: A novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J. Immunol. 169:6668-6672. crossref(new window)

Zhang, L., J. Liu, J. Bai, X. Wang, Y. Li, and P. Jiang. 2013. Comparative expression of Toll-like receptors and inflammatory cytokines in pigs infected with different virulent porcine reproductive and respiratory syndrome virus isolates. Virol. J. 10:135. crossref(new window)