Skip to main content Accessibility help
×
Home

Consumption of transgenic milk containing the antimicrobials lactoferrin and lysozyme separately and in conjunction by 6-week-old pigs improves intestinal and systemic health

  • Caitlin A Cooper (a1), Elizabeth A Maga (a1) and James D Murray (a1) (a2)

Abstract

Lactoferrin and lysozyme are antimicrobial and immunomodulatory proteins produced in high quantities in human milk that aid in gastrointestinal (GI) health and have beneficial effects when supplemented separately and in conjunction in human and animal diets. Ruminants produce low levels of lactoferrin and lysozyme; however, there are genetically engineered cattle and goats that respectively secrete recombinant human lactoferrin (rhLF-milk), and human lysozyme (hLZ-milk) in their milk. Effects of consumption of rhLF-milk, hLZ-milk and a combination of rhLF-and hLZ-milk were tested on young pigs as an animal model for the GI tract of children. Compared with control milk-fed pigs, pigs fed a combination of rhLF and hLZ (rhLF+hLZ) milk had a significantly deeper intestinal crypts and a thinner lamina propria layer. Pigs fed hLZ-milk, rhLF-milk and rhLF+hLZ had significantly reduced mean corpuscular volume (MCV) and red blood cells (RBCs) were significantly increased in pigs fed hLZ-milk and rhLF-milk and tended to be increased in rhLF+hLZ-fed pigs, indicating more mature RBCs. These results support previous research demonstrating that pigs fed milk containing rhLF or hLZ had decreased intestinal inflammation, and suggest that in some parameters the combination of lactoferrin and lysozyme have additive effects, in contrast to the synergistic effects reported when utilising in-vitro models.

Copyright

Corresponding author

* For correspondence; e-mail: Jdmurray@ucdavis.edu

References

Hide All
Actor, JK, Hwang, SA & Kruzel, ML 2009 Lactoferrin as a natural immune modulator. Current Pharmaceutical Design 15 19561973
Brundige, DR, Maga, EA, Klasing, KC & Murray, JD 2008 Lysozyme transgenic goats' milk influences gastrointestinal morphology in young pigs. Journal of Nutrition 138 921926
Brundige, DR, Maga, EA, Klasing, KC & Murray, JD 2010 Consumption of pasteurized human lysozyme transgenic goats' milk alters serum metabolite profile in young pigs. Transgenic Research 19 563574
Cerven, D, DeGeorge, G & Bethell, D 2008 28-day repeated dose oral toxicity of recombinant human holo-lactoferrin in rats. Regulatory Toxicology and Pharmacology 52 174179
Cetin, E, Silici, S, Cetin, N & Güçlü, BK 2010 Effects of diets containing different concentrations of propolis on hematological and immunological variables in laying hens. Poultry Science 89 17031708
Cooper, CA, Brundige, DR, Reh, WA, Maga, EA & Murray, JD 2011 Lysozyme transgenic goats' milk positively impacts intestinal cytokine expression and morphology. Transgenic Research 20 12351243
Cooper, CA, Nelson, KM, Maga, EA & Murray, JD 2013 Consumption of transgenic cows' milk containing human lactoferrin results in beneficial changes in the gastrointestinal tract and systemic health of young pigs. Transgenic Research 22 571578
Drakesmith, H & Prentice, AM 2012 Hepcidin and the iron-infection axis. Science 338 768772
Ellison, RTJ & Giehl, TJ 1991 Killing of Gram-negative bacteria by lactoferrin and lysozyme. Journal of Clinical Investigation 88 10801091
Evans, GO 2009 Animal Hematoxicology: a Practical Guild for Toxicologist and Biomedical Researchers, 1st edition. Boca Raton, FL: Taylor and Francis Group
Fonseca, AM, Pereira, CF, Porto, G & Arosa, FA 2003 Red blood cells upregulate cytoprotective proteins and the labile iron pool in dividing human T cells despite a reduction in oxidative stress. Free Radical Biology and Medicine 35 14041416
Ginsburg, I 2002 Role of lipoteichoic acid in infection and inflammation. Lancet Infectious Disease 2 171179
Goldman, AS, Thorpe, LW, Goldblum, RM & Hanson, LA 1986 Anti-inflammatory properties of human milk. Acta Paediatrica Scandinavica 75 689695
Harikrishnan, R, Balasundaram, C & Heo, MS 2010 Effect of probiotics enriched diet on Paralichthys olivaceus infected with lymphocystis disease virus (LCDV). Fish and Shellfish Immunology 29 868874
Harikrishnan, R, Kim, JS, Kim, MC, Balasundaram, C & Heo, MS 2012 Pomegranate enriched diet enhances the hematology, innate immune response, and disease resistance in olive flounder against Philasterides dicentrarchi. Veterinary Parasitology 187 147156
Hettinga, K, van Valenberg, H, de Vries, S, Boeren, S, van Hooijdonk, T, van Arendonk, J & Vervoort, J 2011 The host defense proteome of human and bovine milk. PLoS ONE 6 e19433
Hu, W, Zhao, J, Wang, J, Yu, T, Wang, J & Li, N 2012 Transgenic milk containing recombinant human lactoferrin modulates the intestinal flora in piglets. Biochemistry and Cell Biology 90 485496
Humphrey, BD, Huang, N & Klasing, KC 2002 Rice expressing lactoferrin and lysozyme has antibiotic-like properties when fed to chicks. Journal of Nutrition 132 12141218
Ita, SO, Etim, OE, Ben, EE & Ekpo, OF 2007 Haematopoietic properties of ethanolic extract of Ageratum conyzoides (goat weed) in albino rats. Niger Journal of Physiological Science 22 8387
Jacobs, A & Summers, MR 1981 Iron uptake and ferritin synthesis by peripheral blood leucocytes in patients with primary idiopathic haemochromatosis. British Journal of Haematology 49 649652
Kruzel, ML, Actor, JK, Boldogh, I & Zimecki, M 2007 Lactoferrin in health and disease. Postepy higieny i medycyny doswiadczalnej 61 261267
Kuang, SY, Xiao, WW, Feng, L, Liu, Y, Jiang, J, Jiang, WD, Hu, K, Li, SH, Tang, L & Zhou, XQ 2012 Effects of graded levels of dietary methionine hydroxy analogue on immune response and antioxidant status of immune organs in juvenile Jian carp (Cyprinus carpio var. Jian). Fish and Shellfish Immunology 32 629636
Kurasawa, T, Takada, K, Ohno, N & Yadomae, T 1996 Effects of murine lysozyme on lipopolysaccharide-induced biological activities. Federation of European Microbiological Societies: Immunology and Medical Microbiology 13 293301
Lee, M, Kovacs-Nolan, J, Yang, C, Archibold, T, Fan, MZ & Mine, Y 2009 Hen egg lysozyme attenuates inflammation and modulates local gene expression in a porcine model of dextran sodium sulfate (DSS)-induced colitus. Journal of Agricultural Food Chemistry 57 22332240
Leitch, EC & Wilcox, MD 1999 Elucidation of the antistaphylococcal action of lactoferrin and lysozyme. Journal of Medical Microbiology 48 867871
Liao, Y, Lopez, V, Shafizadeh, TB, Halsted, CH & Lonnerdal, B 2007 Cloning of a pig homologue of the human lactoferrin receptor: expression and localization during intestinal maturation in piglets. Comparative Biochemistry and Physiology Part A: Molecular and Integrative Physiology 148 584590
Liao, Y, Jiang, R & Lonnerdal, B 2012 Biochemical and molecular impacts of lactoferrin on small intestinal growth and development during early life. Biochemistry and Cell Biology 90 476484
Liu, D, Guo, Y, Wang, Z & Yuan, J 2010 Exogenous lysozyme influences Clostridium perfringens colonization and intestinal barrier function in broiler chickens. Avian Pathology 39 1724
Ljungh, A & Wadström, T 2006 Lactic acid bacteria as probiotics. Current Issues in Intestinal Microbiology 7 7389
Maga, EA, Shoemaker, CF, Rowe, JD, Bondurant, RH, Anderson, GB & Murray, JD 2006a Production and processing of milk from transgenic goats expressing human lysozyme in the mammary gland. Journal of Dairy Science 89 518524
Maga, EA, Cullor, JS, Smith, W, Anderson, GB & Murray, JD 2006b Human lysozyme expressed in the mammary gland of transgenic dairy goats can inhibit the growth of bacteria that cause mastitis and the cold-spoilage of milk. Foodborne Pathology and Disease 3 384392
Maga, EA, Walker, RL, Anderson, GB & Murray, JD 2006c Consumption of milk from transgenic goats expressing human lysozyme in the mammary gland results in the modulation of intestinal microflora. Transgenic Research 15 515519
Maga, EA, Desai, PT, Weimer, BC, Dao, N, Kültz, D & Murray, JD 2012 Consumption of lysozyme-rich milk can alter microbial fecal populations. Applied and Environmental Microbiology 78 61536160
Mahmoud, KZ & Edens, FW 2012 Breeder age affects small intestine development of broiler chicks with immediate or delayed access to feed. British Poultry Science 53 3241
Moore, G, Knight, G & Blann, A 2010 Fundamentals of Biomedical Science: Haematology. New York, NY: Oxford University Press
Moriguchi, R, Otaki, Y, Hazeki, S, Shimada, T, Matsumoto, A, Kakita, N, Kaibe, S, Kuragano, T, Nonoguchi, H, Masayoshi, N, Hasuike, Y & Nakanishi, T 2012 High levels of tumor necrosis factor-α downregulate antimicrobial iron transport protein, Nramp1, in chronic hemodialysis patients: a key factor for infection risk. American Journal of Nephrology 35 372378
Mountzouris, KC, McCartney, AL & Gibson, GR 2002 Intestinal microflora of human infants and current trends for its nutritional modulation. British Journal of Nutrition 87 405420
Newburg, DS & Walker, WA 2007 Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatric Research 61 28
Nielsen, SM, Hansen, GH & Danielsen, EM 2010 Lactoferrin targets T cells in the small intestine. Journal of Gastroenterology 45 11211128
Ohno, N & Morrison, DC 1989a Lipopolysaccharide interaction with lysozyme. Binding of lipopolysaccharide to lysozyme and inhibition of lysozyme enzymatic activity. Journal of Biological Chemistry 264 44344441
Ohno, N & Morrison, DC 1989b Lipopolysaccharide interactions with lysozyme differentially affect lipopolysaccharide immunostimulatory activity. European Journal of Biochemistry 186 629636
Pfaffl, MW, Horgan, GW & Dempfle, L 2002 Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Research 30 36
Scharfen, EC, Mills, DA & Maga, EA 2007 Use of human lysozyme transgenic goat milk in cheese making: effects on lactic acid bacteria performance. Journal of Dairy Science 90 40844091
Takada, K, Ohno, N & Yadomae, T 1994a Binding of lysozyme to lipopolysaccharide suppresses tumor necrosis factor production in vivo. Infection and Immunity 62 11711175
Takada, K, Ohno, N & Yadomae, T 1994b Detoxification of lipopolysaccharide (LPS) by egg white lysozyme. Federation of European Microbiological Societies: Immunology and Medical Microbiology 9 255263
Thomassen, EA, van Veen, HA, van Berkel, PH, Nuijens, JH & Abrahams, JP 2005 The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin. Transgenic Research 14 397405
van Berkel, PH, Welling, MM, Geerts, M, van Veen, HA, Ravensbergen, B, Salaheddine, M, Pauwels, EK, Pieper, F, Nuijens, JH & Nibbering, PH 2002 Large scale production of recombinant human lactoferrin in the milk of transgenic cows. Nature Biotechnology 20 484487
van der Linden, DS, Short, D, Dittmann, A & Yu, PL 2009 Synergistic effects of ovine-derived cathelicidins and other antimicrobials against Escherichia coli O157:H7 and Staphylococcus aureus 1056 MRSA. Biotechnology Letters 31 12651267
Wang, L, Trebicka, E, Fu, Y, Ellenbogen, S, Hong, CC, Babitt, JL, Lin, HY & Cherayil, BJ 2012 The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease. Inflammatory Bowel Disease 18 112119
Wu, X, Yung, LM, Cheng, WH, Yu, PB, Babitt, JL, Lin, HY & Xia, Y 2012 Hepcidin regulation by BMP signaling in macrophages is lipopolysaccharide dependent. PLoS ONE 7 e44622
Yang, B, Wang, J, Tang, B, Liu, Y, Guo, C, Yang, P, Yu, T, Li, R, Zhao, J, Zhang, L, Dai, Y & Li, N 2011 Characterization of bioactive recombinant human lysozyme expressed in milk of cloned transgenic cattle. PLoS ONE 16 e17593
Yen, CC, Lin, CY, Chong, KY, Tsai, TC, Shen, CJ, Lin, MF, Su, CY, Chen, HL & Chen, CM 2009 Lactoferrin as a natural regimen for selective decontamination of the digestive tract: recombinant porcine lactoferrin expressed in the milk of transgenic mice protects neonates from pathogenic challenge in the gastrointestinal tract. Journal of Infectious Disease 199 590598
Zhang, P, Sawicki, V, Lewis, A, Hanson, L, Nuijens, JH & Neville, MC 2001 Human lactoferrin in the milk of transgenic mice increases intestinal growth in ten-day-old suckling neonates. Advances in Experimental Medicine and Biology 501 107113

Keywords

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed