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Whey protein concentrate enhances intestinal integrity and influences transforming growth factor-β1 and mitogen-activated protein kinase signalling pathways in piglets after lipopolysaccharide challenge

  • Kan Xiao (a1), Lefei Jiao (a1), Shuting Cao (a1), Zehe Song (a1), Caihong Hu (a1) and Xinyan Han (a1)...

Abstract

Whey protein concentrate (WPC) has been reported to have protective effects on the intestinal barrier. However, the molecular mechanisms involved are not fully elucidated. Transforming growth factor-β1 (TGF-β1) is an important component in the WPC, but whether TGF-β1 plays a role in these processes is not clear. The aim of this study was to investigate the protective effects of WPC on the intestinal epithelial barrier as well as whether TGF-β1 is involved in these protection processes in a piglet model after lipopolysaccharide (LPS) challenge. In total, eighteen weanling pigs were randomly allocated to one of the following three treatment groups: (1) non-challenged control and control diet; (2) LPS-challenged control and control diet; (3) LPS+5 %WPC diet. After 19 d of feeding with control or 5 %WPC diets, pigs were injected with LPS or saline. At 4 h after injection, pigs were killed to harvest jejunal samples. The results showed that WPC improved (P<0·05) intestinal morphology, as indicated by greater villus height and villus height:crypt depth ratio, and intestinal barrier function, which was reflected by increased transepithelial electrical resistance and decreased mucosal-to-serosal paracellular flux of dextran (4 kDa), compared with the LPS group. Moreover, WPC prevented the LPS-induced decrease (P<0·05) in claudin-1, occludin and zonula occludens-1 expressions in the jejunal mucosae. WPC also attenuated intestinal inflammation, indicated by decreased (P<0·05) mRNA expressions of TNF-α, IL-6, IL-8 and IL-1β. Supplementation with WPC also increased (P<0·05) TGF-β1 protein, phosphorylated-Smad2 expression and Smad4 and Smad7 mRNA expressions and decreased (P<0·05) the ratios of the phosphorylated to total c-jun N-terminal kinase (JNK) and p38 (phospho-JNK:JNK and p-p38:p38), whereas it increased (P<0·05) the ratio of extracellular signal-regulated kinase (ERK) (phospho-ERK:ERK). Collectively, these results suggest that dietary inclusion of WPC attenuates the LPS-induced intestinal injury by improving mucosal barrier function, alleviating intestinal inflammation and influencing TGF-β1 canonical Smad and mitogen-activated protein kinase signalling pathways.

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      Whey protein concentrate enhances intestinal integrity and influences transforming growth factor-β1 and mitogen-activated protein kinase signalling pathways in piglets after lipopolysaccharide challenge
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      Whey protein concentrate enhances intestinal integrity and influences transforming growth factor-β1 and mitogen-activated protein kinase signalling pathways in piglets after lipopolysaccharide challenge
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Corresponding author

* Corresponding authors: Dr C. Hu, email chhu@zju.edu.cn; Dr X. Han, email xyhan@zju.edu.cn

References

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1. Sprong, RC, Schonewille, AJ & van der Meer, R (2010) Dietary cheese whey protein protects rats against mild dextran sulfate sodium-induced colitis: role of mucin and microbiota. J Dairy Sci 93, 13641371.
2. Playford, RJ, Macdonald, CE & Johnson, WS (2000) Colostrum and milk-derived peptide growth factors for the treatment of gastrointestinal disorders. Am J Clin Nutr 72, 514.
3. Marshall, K (2004) Therapeutic applications of whey protein. Altern Med Rev 9, 136156.
4. Hering, NA, Andres, S, Fromm, A, et al. (2011) Transforming growth factor-β, a whey protein component, strengthens the intestinal barrier by upregulating claudin-4 in HT-29/B6 cells. J Nutr 141, 783789.
5. Penttila, IA (2010) Milk-derived transforming growth factor-beta and the infant immune response. J Pediatr 156, S21S25.
6. Cross, ML & Gill, HS (1999) Modulation of immune function by a modified bovine whey protein concentrate. Immunol Cell Biol 77, 345350.
7. Penttila, IA, van Sprie, AB, Zhang, MF, et al. (1998) Transforming growth factor-beta levels in maternal milk and expression in postnatal rat duodenum and ileum. Pediatr Res 44, 524531.
8. Barnard, JA, Warick, GJ & Gold, LI (1993) Localisation of transforming growth factor β in the normal murine small intestine and colon. Gastroenterology 105, 6773.
9. Mei, J & Xu, RJ (2005) Transient changes of transforming growth factor-β expression in the small intestine of the pig in association with weaning. Br J Nutr 93, 3745.
10. Godlewski, MM, Hallay, N, Bierła, JB, et al. (2007) Molecular mechanism of programmed cell death in the gut epithelium of neonatal piglets. J Physiol Pharmacol 3, Suppl., 97113.
11. van’t Land, B, Meijer, HP, Frerichs, J, et al. (2002) Transforming growth factor-beta2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling. Br J Cancer 87, 113118.
12. Xiao, K, Song, ZH, Jiao, LF, et al. (2014) Developmental changes of TGF-β1 and smads signaling pathway in intestinal adaption of weaned pigs. PLOS ONE 9, e104589.
13. Weiss, A & Attisano, L (2013) The TGF beta superfamily signaling pathway. Wiley Interdiscip Rev Dev Biol 2, 4763.
14. Derynck, R & Zhang, YE (2003) Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425, 577584.
15. Association of Official Analytical Chemists (2002) Official Methods of Analysis, Association of Official Analytical Chemists, 17th ed. Washington, DC: AOAC.
16. Liu, YL, Huang, JJ, Hou, YQ, et al. (2008) Dietary arginine supplementation alleviates intestinal mucosal disruption induced by Escherichia coli lipopolysaccharide in weaned pigs. Br J Nutr 100, 552560.
17. Liu, YL, Chen, F, Odle, J, et al. (2012) Fish oil enhances intestinal integrity and inhibits TLR4 and NOD2 signaling pathways in weaned pigs after LPS challenge. J Nutr 142, 20172024.
18. Pi, DA, Liu, YL, Shi, HF, et al. (2014) Dietary supplementation of aspartate enhances intestinal integrity and energy status in weanling piglets after lipopolysaccharide challenge. J Nutr Biochem 25, 456462.
19. Mercer, DW, Smith, GS, Cross, JM, et al. (1996) Effects of lipopolysaccharide on intestinal injury: potential role of nitric oxide and lipid peroxidation. J Surg Res 63, 185192.
20. Alscher, KT, Phang, PT, McDonald, TE, et al. (2001) Enteral feeding decreases gut apoptosis, permeability, and lung inflammation during murine endotoxemia. Am J Physiol Gastrointest Liver Physiol 281, G569G576.
21. Touchette, KJ, Carroll, JA, Allee, GL, et al. (2002) Effect of spray-dried plasma and lipopolysaccharide exposure on weaned pigs: I. Effects on the immune axis of weaned pigs. J Anim Sci 80, 494501.
22. Ewaschuk, J, Endersby, R, Thiel, D, et al. (2007) Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis. Hepatology 46, 841850.
23. Wallace, JL, Steel, G, Whittle, B, et al. (1987) Evidence for platelet-activating factor as a mediator of endotoxin-induced gastrointestinal damage in the rat: effects of three platelet-activating factor antagonists. Gastroenterology 93, 765773.
24. Hu, CH, Xiao, K, Luan, ZS, et al. (2013) Early weaning increases intestinal permeability, alters expression of cytokine and tight junction proteins, and activates mitogen- activated protein kinases in pigs. J Anim Sci 91, 10941101.
25. Moeser, AJ, Ryan, KA, Nighot, PK, et al. (2007) Gastrointestinal dysfunction induced by early weaning is attenuated by delayed weaning and mast cell blockade in pigs. Am J Physiol Gastrointest Liver Physiol 293, G413G421.
26. Verhasselt, V, Milcent, V, Cazareth, J, et al. (2008) Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 14, 170175.
27. Hsieh, CC, Hernández-Ledesma, B, Fernández-Tomé, S, et al. (2015) Milk proteins, peptides, and oligosaccharides: effects against the 21st century disorders. Biomed Res Int 2015, 146840.
28. Hou, YQ, Wang, L, Zhang, W, et al. (2012) Protective effects of N-acetylcysteine on intestinal functions of piglets challenged with lipopolysaccharide. Amino Acids 43, 12331242.
29. Li, YQ, Mette, VQ, Jiang, PP, et al. (2013) Whey protein processing influences formula-induced gut maturation in preterm pigs. J Nutr 143, 19341942.
30. Mei, J, Zhang, YQ, Wang, T, et al. (2006) Oral ingestion of colostrum altersintestinal transforming growth factor-beta receptor intensity in newborn pigs. Livest Sci 105, 214222.
31. Ozawa, T, Miyata, M, Nishimura, M, et al. (2009) Transforming growth factor-β activity in commercially available pasteurized cow milk provides protection against inflammation in mice. J Nutr 139, 6975.
32. Clark, JA, Doelle, SM, Halpern, MD, et al. (2006) Intestinal barrier failure during experimental necrotizing enterocolitis: protective effect of EGF treatment. Am J Physiol Gastrointest Liver Physiol 291, G938G949.
33. Kuhara, T, Tanaka, A, Yamauchi, K, et al. (2014) Bovine lactoferrin ingestion protects against inflammation via IL-11 induction in the small intestine of mice with hepatitis. Br J Nutr 111, 18011810.
34. Buccigrossi, V, de Marco, G, Bruzzese, E, et al. (2007) Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatr Res 61, 410414.
35. Xu, R, Liu, N, Xu, X, et al. (2011) Antioxidative effects of whey protein on peroxide -induced cytotoxicity. J Dairy Sci 94, 37393746.
36. Suzuki, T (2013) Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci 70, 631659.
37. Visser, JT, Lammers, K, Hoogendijk, A, et al. (2010) Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat. Diabetologia 53, 26212628.
38. Al-Sadi, R, Boivin, M & Ma, T (2009) Mechanism of cytokine modulation of epithelial tight junction barrier. Front Biosci (Landmark Ed) 14, 27652778.
39. Pié, S, Lallès, JP, Blazy, F, et al. (2004) Weaning is associated with an upregulation of expression of inflammatory cytokines in the intestine of piglets. J Nutr 134, 641647.
40. Ma, TY, Boivin, MA, Ye, D, et al. (2005) Mechanism of TNF-α modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Am J Physiol Gastrointest Liver Physiol 288, G422G430.
41. Blikslager, AT, Moeser, AJ, Gookin, JL, et al. (2007) Restoration of barrier function in injured intestinal mucosa. Physiol Rev 87, 545564.
42. Beaulieu, J, Girard, D, Dupont, C, et al. (2009) Inhibition of neutrophil infiltration by a malleable protein matrix of lactic acid bacteria-fermented whey proteins in vivo . Inflamm Res 58, 133138.
43. McKaig, BC, Hughes, K, Tighe, PJ, et al. (2002) Differential expression of TGF-β isoforms by normal and inflammatory bowel disease intestinal myofibroblasts. Am J Physiol Cell Physiol 282, C172C182.
44. Andújar, I, Ríos, JL, Giner, RM, et al. (2013) Shikonin promotes intestinal wound healing in vitro via induction of TGF-β release in IEC-18 cells. Eur J Pharm Sci 49, 637641.
45. Hahm, KB, Im, YH, Parks, TW, et al. (2001) Loss of transforming growth factor-β signalling in the intestine contributes to tissue injury in inflammatory bowel disease. Gut 49, 190198.
46. McCartney-Francis, N, Jin, W & Wahl, SM (2004) Aberrant toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-β1 signaling pathway. J Immunol 172, 38143821.
47. Ando, T, Hatsushika, K, Wako, M, et al. (2007) Orally administered TGF-beta is biologically active in the intestinal mucosa and enhances oral tolerance. J Allergy Clin Immunol 120, 916923.
48. Penttila, IA, Flesch, IE, McCue, AL, et al. (2003) Maternal milk regulation of cell infiltration and interleukin 18 in the intestine of suckling rat pups. Gut 52, 15791586.
49. Shiou, SR, Yu, YY, Guo, Y, et al. (2013) Oral administration of transforming growth factor-β1 (TGF-β1) protects the immature gut from injury via smad protein-dependent suppression of epithelial nuclear factor κB (NF-κB) signaling and proinflammatory cytokine production. J Biol Chem 288, 3475734766.
50. Howe, KL, Reardon, C, Wang, A, et al. (2005) Transforming growth factor-β regulation of epithelial tight junction proteins enhances barrier function and blocks enterohemorrhagic Escherichia coli O157:H7-induced increased permeability. Am J Pathol 167, 15871597.
51. Chen, X, Yang, X, Liu, T, et al. (2012) Kaempferol regulates MAPKs and NF-kappaB signaling pathways to attenuate LPS-induced acute lung injury in mice. Int Immunopharmacol 14, 209216.
52. Rusu, D, Drouin, R, Pouliot, Y, et al. (2010) A bovine whey protein extract stimulates human neutrophils to generate bioactive IL-1Ra through a NF-kappa B- and MAPK-dependent mechanism. J Nutr 140, 382391.
53. Benhar, M, Dalyot, I, Engelberg, D, et al. (2001) Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol Cell Biol 21, 69136926.
54. Ku, BM, Lee, YK, Jeong, JY, et al. (2007) Ethanol-induced oxidative stress is mediated by p38 MAPK pathway in mouse hippocampal cells. Neurosci Lett 419, 6467.
55. Zhu, LH, Xu, JX, Zhu, SW, et al. (2014) Gene expression profiling analysis reveals weaning-induced cell cycle arrest and apoptosis in the small intestine of pigs. J Anim Sci 92, 9961006.
56. Song, ZH, Xiao, K, Ke, YL, et al. (2014) Zinc oxide enhances intestinal barrier partially through the mitogen-activated protein kinases and transforming growth factor-β1 signaling pathways in weaned pigs. Innate Immun 0, 18.
57. Ma, ZJ, Misawa, H & Yamaguchi, M (2001) Stimulatory effect of zinc on insulin-like growth factor-I and transforming growth factor-beta1 production with bone growth of newborn rats. Int J Mol Med 8, 623628.
58. Rautava, S, Nanthakumar, NN, Dubert-Ferrandon, A, et al. (2011) Breast milk-transforming growth factor-β2 specifically attenuates IL-1β-induced inflammatory responses in the immature human intestine via an SMAD6-and ERK-dependent mechanism. Neonatology 99, 192201.
59. Khailova, L, Dvorak, K, Arganbright, KM, et al. (2009) Changes in hepatic cell junctions structure during experimental necrotizing enterocolitis: effect of EGF treatment. Pediatr Res 66, 140144.
60. Haedo, W, Gonzalez, T, Mas, JA, et al. (1996) Oral human recombinant epidermal growth factor in the treatment of patients with duodenal ulcer. Rev Esp Enferm Dig 88, 409418.
61. Tarnawski, A, Stachura, J, Durbin, T, et al. (1992) Increased expression of epidermal growth factor receptor during the gastric ulcer healing in rats. Gastroenterology 102, 695698.
62. Wu, J, Chen, J, Wu, W, et al. (2014) Enteral supplementation of bovine lactoferrin improves gut barrier function in rats after massive bowel resection. Br J Nutr 112, 486492.

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Whey protein concentrate enhances intestinal integrity and influences transforming growth factor-β1 and mitogen-activated protein kinase signalling pathways in piglets after lipopolysaccharide challenge

  • Kan Xiao (a1), Lefei Jiao (a1), Shuting Cao (a1), Zehe Song (a1), Caihong Hu (a1) and Xinyan Han (a1)...

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