Abstract
The intestinal epithelial barrier plays a crucial role in the health and growth of weaned piglets. Proper epithelial function mainly depends on tight junctions (TJs), which act as both ion channels and a barrier against noxious molecules. TJs are multiprotein complexes consisting of transmembrane and membrane-associated proteins. Because the intestine in piglets is immature and incomplete, its structure and function are easily impaired by various stresses, infections, and food-related factors. Certain nutrients have been demonstrated to participate in intestinal TJ regulation. Probiotics, amino acids, fibers, oligosaccharide, and certain micronutrients can enhance barrier integrity and counteract infections through elevated TJ protein expression and distribution. In this review, the distribution and classification of intestinal TJs is described, the factors influencing TJs after weaning are summarized, and the regulation of weaning piglet intestinal TJs by nutrients is discussed.
Keywords: Tight junction proteins, intestinal barrier impairment, weaned piglet, structure and distribution, influencing factor, nutrition regulation.
Graphical Abstract
[1]
Farquhar, M.G.; Palade, G.E. Junctional complexes in various epithelia. J. Cell Biol., 1963, 17, 375-412.
[2]
Suzuki, T. Regulation of intestinal epithelial permeability by tight junctions. Cell. Mol. Life Sci., 2013, 70, 631-659.
[3]
Clayburgh, D.R.; Shen, L.; Turner, J.R. A porous defense: The leaky epithelial barrier in intestinal disease. Lab. Invest., 2004, 84, 282-291.
[4]
Marchiando, A.M.; Graham, W.V.; Turner, J.R. Epithelial barriers in homeostasis and disease. Annu. Rev. Pathol., 2010, 5, 119-144.
[5]
Nusrat, A.; Turner, J.R.; Madara, J.L. Molecular physiology and pathophysiology of tight junctions. IV. Regulation of tight junctions by extracellular stimuli: nutrients, cytokines, and immune cells. Am. J. Physiol. Gastrointest. Liver Physiol., 2000, 279, G851-G857.
[6]
Ulluwishewa, D.; Anderson, R.C.; Mcnabb, W.C.; Moughan, P.J.; Wells, J.M.; Roy, N.C. Regulation of tight junction permeability by intestinal bacteria and dietary components. J. Nutr., 2011, 141, 769-776.
[7]
Turner, J.R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol., 2009, 9, 799-809.
[8]
Nagasawa, K.; Chiba, H.; Fujita, H.; Kojima, T.; Saito, T.; Endo, T.; Sawada, N. Possible involvement of gap junctions in the barrier function of tight junctions of brain and lungendothelial cells. J. Cell. Physiol., 2006, 208, 123-132.
[9]
Szaszi, K.; Amoozadeh, Y. New insights into functions, regulation, and pathological roles of tight junctions in kidney tubular epithelium. Int. Rev. Cell Mol. Biol., 2014, 308, 205-271.
[10]
Xu, S.; Lee, J.; Miyake, M. Expression of ZO-1 and occludin at mRNA and protein level during preimplantation development of the pig parthenogenetic diploids. Zygote, 2011, 20, 147-158.
[11]
Furuse, M.; Fujita, K.; Hiiragi, T.; Fujimoto, K.; Tsukita, S. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J. Cell Biol., 1998, 141, 1539-1550.
[12]
Martin-Padura, I.; Lostaglio, S.; Schneemann, M.; Williams, L.; Romano, M.; Fruscella, P.; Panzeri, C.; Stoppacciaro, A.; Ruco, L.; Villa, A.; Simmons, D.; Dejana, E. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J. Cell Biol., 1998, 142, 117-127.
[13]
Raleigh, D.R.; Marchiando, A.M.; Zhang, Y.; Shen, L.; Sasaki, H.; Wang, Y. Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Mol. Biol. Cell, 2010, 21, 1200-1213.
[14]
Liang, G.H.; Weber, C.R. Molecular aspects of tight junction barrier function. Curr. Opin. Pharmacol., 2014, 19, 84-89.
[15]
Boudry, G.; Péron, V.; Le Huërou-Luron, I.; Lallès, J.P.; Sève, B. Weaning induces both transient and long-lasting modifications of absorptive, secretory, and barrier properties of piglet intestine. J. Nutr., 2004, 134, 2256-2262.
[16]
Moeser, A.J.; Klok, C.V.; Ryan, K.A. Stress signaling pathways activated by weaning mediate intestinal dysfunction in the pig. Am. J. Physiol. Gastrointest. Liver Physiol., 2007, 292, G173-G181.
[17]
Pluske, J.R. Feed and feed additives-related aspects of gut health and development in weanling pigs. J. Anim. Sci. Biotechnol., 2013, 4, 1.
[18]
Smith, F.; Clark, J.E.; Overman, B.L.; Tozel, C.C.; Huang, J.H.; Rivier, J.E.; Blisklager, A.T.; Moeser, A.J. Early weaning stress impairs development of mucosal barrier function in the porcine intestine. Am. J. Physiol. Gastrointest. Liver Physiol., 2010, 298, G352-G363.
[19]
Moeser, A.J.; Ryan, K.A.; Nighot, P.K.; Blikslager, A.T. Gastrointestinal dysfunction induced by early weaning is attenuated by delayed weaning and mast cell blockade in pigs. Am. J. Physiol. Gastrointest. Liver Physiol., 2007, 293, G413-G421.
[20]
Hu, C.H.; Xiao, K.; Luan, Z.S.; Song, J. Early weaning increases intestinal permeability, alters expression of cytokine and tight junction proteins, and activates mitogen-activated protein kinases in pigs. J. Anim. Sci., 2013, 91, 1094-1101.
[21]
Wijtten, P.J.; van der Meulen, J.; Verstegen, M.W. Intestinal barrier function and absorption in pigs after weaning: A review. Br. J. Nutr., 2011, 105, 967-981.
[22]
Gareau, M.G.; Jury, J.; Perdue, M.H. Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability. Am. J. Physiol. Gastrointest. Liver Physiol., 2007, 293, G198-G203.
[23]
Takahashi, A.; Kondoh, M.; Suzuki, H.; Watari, A.; Yagi, K. Pathological changes in tight junctions and potential applications into therapies. Drug Discov. Today, 2012, 17, 727-732.
[24]
Spitz, J.; Yuhan, R.; Koutsouris, A.; Blatt, C.; Alverdy, J.; Hecht, G. Enteropathogenic Escherichia coli adherence to intestinal epithelial monolayers diminishes barrier function. Am. J. Physiol., 1995, 268, G374-G379.
[25]
Roselli, M.A.; Finamore, A. Britti, M.S.; Konstantinov, S.R.; Smidt, H.; de Vos, W.M.; Mengheri, E. The novel porcine Lactobacillus sobrius strain protects intestinal cells from enterotoxigenic Escherichia coli K88 infection and prevents membrane barrier damage. J. Nutr., 2007, 137, 2709-2716.
[26]
Lodemann, U.; Amasheh, S.; Radloff, J.; Kern, M.; Bethe, A.; Wieler, L.H.; Pieper, R.; Zentek, J.; Aschenbach, J.R. Effects of ex vivo Infection with ETEC on jejunal barrier properties and cytokine expression in probiotic-supplemented pigs. Dig. Dis. Sci., 2017, 62, 922-933.
[27]
Yang, K.M.; Jiang, Z.Y.; Zheng, C.T.; Wang, L.; Yang, X.F. Effect of Lactobacillus plantarum on diarrhea and intestinal barrier function of young piglets challenged with enterotoxigenic Escherichia coli K88. J. Anim. Sci., 2014, 92, 1496-1503.
[28]
Gibson, D.L.; Ma, C.; Rosenberger, C.M.; Bergstrom, K.S.; Valdez, Y.; Huang, J.T.; Khan, M.A.; Vallance, B.A. Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis. Cell. Microbiol., 2008, 10, 388-403.
[29]
Che, P.; Tang, H.; Li, Q. The interaction between claudin-1 and dengue viral prM/M protein for its entry. Virology, 2013, 446, 303-313.
[30]
Ploss, A.; Evans, M.J.; Gaysinskaya, V.A.; Panis, M.; You, H.; De Jong, Y.P.; Rice, C.M. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature, 2009, 457, 882-886.
[31]
Dickman, K.G.; Hempson, S.J.; Anderson, J.; Lippe, S.; Zhao, L.; Burakoff, R.; Shaw, R.D. Rotavirus alters paracellular permeability and energy metabolism in Caco-2 cells. Am. J. Physiol. Gastrointest. Liver Physiol., 2000, 279, G757-G766.
[32]
Coyne, C.B.; Shen, L.; Turner, J.R.; Bergelson, J.M. Coxsackie virus entry across epithelial tight junctions requires occludin and the small GTPases Rab34 and Rab5. Cell Host Microbe, 2007, 2, 181-192.
[33]
Saif, L.J.; Pensaert, M.B.; Sestak, K.; Yeo, S.G.; Jung, K. Coronaviruses. In: Zimmerman, J.J.; Karriker, L.A.; Ramirez, A.;
Schwartz, K.J.; Steven-son, G.W.; Eds. Diseases of swine. Wiley-
Blackwell, Iowa State University,; , 2012; pp. 501-524.
[34]
Jung, K.; Eyerly, B.; Annamalai, T.; Lu, Z.; Saif, L.J. Structural alteration of tight and adherens junctions in villous and crypt epithelium of the small and large intestine of conventional nursing piglets infected with porcine epidemic diarrhea virus. Vet. Microbiol., 2015, 177, 373-378.
[35]
Luo, X.; Guo, L.; Zhang, J.; Xu, Y.; Gu, W.; Feng, L.; Wang, Y. Tight junction protein occludin is a porcine epidemic diarrhea virus entry factor. J. Virol., 2017, 91, e00202-e00217.
[36]
Wang, J.; Zhao, P.; Guo, L.; Liu, Y.; Du, Y.; Ren, S.; Li, J.; Zhang, Y.; Fan, Y.; Huang, B.; Liu, S.; Wu, J. Porcine epidemic diarrhea virus variants with high pathogenicity, China. Emerg. Infect. Dis., 2013, 19, 2048-2049.
[37]
Zhao, S.; Gao, J.; Zhu, L.; Yang, Q. Transmissible gastroenteritis virus and porcine epidemic diarrhoea virus infection induces dramatic changes in the tight junctions and microfilaments of polarized IPEC-J2 cells. Virus Res., 2014, 192, 34-45.
[38]
Horn, N.; Ruch, F.; Miller, G.; Ajuwon, K.M.; Adeola, O. Impact of acute water and feed deprivation events on growth performance, intestinal characteristics, and serum stress markers in weaned pigs. J. Anim. Sci., 2014, 92, 4407-4416.
[39]
Yang, Y.; Li, W.; Sun, Y.; Han, F.; Hu, C.A.; Wu, Z. Amino acid deprivation disrupts barrier function and induces protective autophagy in intestinal porcine epithelial cells. Amino Acids, 2015, 47, 2177-2184.
[40]
Gu, M.J.; Song, S.K.; Park, S.M.; Lee, I.K.; Yun, C.H. Bacillus subtilis protects porcine intestinal barrier from deoxynivalenol via improved zonula occludens-1 expression. Asian-Australas. J. Anim. Sci., 2014, 27, 580-586.
[41]
Gu, M.J.; Song, S.K.; Lee, I.K.; Ko, S.; Han, S.E.; Bae, S.; Ji, S.Y.; Park, B.C.; Song, K.D.; Lee, H.K.; Han, S.H.; Yun, C.H. Barrier protection via Toll-like receptor 2 signaling in porcine intestinal epithelial cells damaged by deoxynivalnol. Vet. Res. , 2016, 47, 25.
[42]
Lessard, M.; Savard, C.; Deschene, K.; Lauzon, K.; Pinilla, V.A.; Gagnon, C.A.; Lapointe, J.; Guay, F.; Chorfi, Y. Impact of deoxynivalenol (DON) contaminated feed on intestinal integrity and immune response in swine. Food Chem. Toxicol., 2015, 80, 7-16.
[43]
Springler, A.; Hessenberger, S.; Schatzmayr, G.; Mayer, E. Early activation of MAPK p44/42 is partially involved in DON-induced disruption of the intestinal barrier function and tight junction network. Toxins , 2016, 8, 264.
[44]
Bouhet, S.; Hourcade, E.; Loiseau, N.; Fikry, A.; Martinez, S.; Roselli, M.; Galtier, P.; Mengheri, E.; Oswald, I.P. The mycotoxin fumonisin B1 alters the proliferation and the barrier function of porcine intestinal epithelial cells. Toxicol. Sci., 2004, 77, 165-171.
[45]
Tossou, M.C.; Liu, H.; Bai, M.; Chen, S.; Cai, Y.; Duraipandiyan, V.; Liu, H.; Adebowale, T.O.; Al-Dhabi, N.A.; Long, L.; Tarique, H.; Oso, A.O.; Liu, G.; Yin, Y. Effect of high dietary tryptophan on intestinal morphology and tight junction protein of weaned pig. BioMed Res. Int., 2016, 20162912418
[46]
Chapman, J.C.; Liu, Y.; Zhu, L.; Rhoads, J.M. Arginine and citrulline protect intestinal cell monolayer tight junctions from hypoxia-induced injury in piglets. Pediatr. Res., 2012, 72, 576-582.
[47]
Di Lorenzo, M.; Bass, J.; Krantis, A. Use of L-arginine in the treatment of experimental enterocolitis. J. Pediatr. Surg., 1995, 30, 235-240.
[49]
Wang, H.; Zhang, C.; Wu, G.; Sun, Y.; Wang, B.; He, B.; Dai, Z.; Wu, Z. Glutamine enhances tight junction protein expression and modulates corticotropin-releasing factor signaling in the jejunum of weanling piglets. J. Nutr., 2015, 145, 25-31.
[50]
Wang, B.; Wu, Z.; Ji, Y.; Sun, K.; Dai, Z.; Wu, G. L-Glutamine enhances tight junction integrity by activating CaMK Kinase 2-AMP-activated protein kinase signaling in intestinal porcine epithelial cells. J. Nutr., 2016, 146, 501-508.
[51]
Wang, J.; Li, G.R.; Tan, B.E.; Xiong, X.; Kong, X.F.; Xiao, D.F.; Xu, L.W.; Wu, M.M.; Huang, B.; Kim, S.W.; Yin, Y.L. Oral administration of putrescine and proline during the suckling period improves epithelial restitution after early weaning in piglets. J. Anim. Sci., 2015, 93, 1679-1688.
[52]
Li, W.; Sun, K.; Ji, Y.; Wu, Z.; Wang, W.; Dai, Z.; Wu, G. Glycine regulates expression and distribution of claudin-7 and ZO-3 proteins in intestinal porcine epithelial cells. J. Nutr., 2016, 146, 964-969.
[53]
Anderson, R.C.; Cookson, A.; McNabb, W.; Park, Z.; McCann, M.; Kelly, W. Lactobacillus plantarum MB452 enhances the function of the intestinal barrier by increasing the expression levels of genes involved in tight junction formation. BMC Microbiol., 2010, 10, 316.
[54]
Eun, C.S.; Kim, Y.S.; Han, D.S.; Choi, J.H.; Lee, A.R.; Park, Y.K. Lactobacillus casei prevents impaired barrier function in intestinal epithelial cells. APMIS, 2011, 119, 49-56.
[55]
Patel, R.M.; Myers, L.S.; Kurundkar, A.R.; Maheshwari, A.; Nusrat, A.; Lin, P.W. Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. Am. J. Pathol., 2010, 180, 626-635.
[56]
Wu, Y.; Zhu, C.; Chen, Z.; Chen, Z.; Zhang, W.; Ma, X. Protective effects of Lactobacillus plantarum on epithelial barrier disruption caused by enterotoxigenic Escherichia coli in intestinal porcine epithelial cells. Vet. Immunol. Immunopathol., 2016, 172, 55-63.
[57]
Yang, F.; Wang, A.; Zeng, X.; Hou, C.; Liu, H.; Qiao, S. Lactobacillus reuteri I5007 modulates tight junction protein expression in IPEC-J2 cells with LPS stimulation and in newborn piglets under normal conditions. BMC Microbiol., 2015, 15, 32.
[58]
Xiao, Z.; Liu, L.; Tao, W.; Pei, X.; Wang, G.; Wang, M. Clostridium tyrobutyricum protect intestinal barrier function from LPS-induced apoptosis via p38/JNK signaling pathway in IPEC-J2 cell. Cell. Physiol. Biochem., 2018, 46, 1779-1792.
[59]
Blaut, M.; Clavel, T. Metabolic diversity of the intestinal microbiota: implications for health and disease. J. Nutr., 2007, 137, 751-755.
[60]
Chen, H.; Mao, X.; He, J.; Yu, B.; Huang, Z.; Yu, J.; Zheng, P.; Chen, D. Dietary fibre affects intestinal mucosal barrier function and regulates intestinal bacteria in weaning piglets. Br. J. Nutr., 2013, 110, 1837-1848.
[61]
Richter, J.F.; Pieper, R.; Zakrzewski, S.S.; Günzel, D.; Schulzke, J.D.; Van Kessel, A.G. Diets high in fermentable protein and fibre alter tight junction protein composition with minor effects on barrier function in piglet colon. Br. J. Nutr., 2014, 111, 1040-1049.
[62]
Jiao, L.F.; Ke, Y.L.; Xiao, K.; Song, Z.H.; Hu, C.H.; Shi, B. Effects of cello-oligosaccharide on intestinal microbiota and epithelial barrier function of weanling pigs. J. Anim. Sci., 2015, 93, 1157-1164.
[63]
Chen, H.; Hu, H.; Chen, D.; Tang, J.; Yu, B.; Luo, J.; He, J.; Luo, Y.; Yu, J.; Mao, X. Dietary pectic oligosaccharide administration improves growth performance and immunity in weaned pigs infected by rotavirus. J. Agric. Food Chem., 2017, 65, 2923-2929.
[64]
Mao, X.; Xiao, X.; Chen, D.; Yu, B.; He, J.; Chen, H.; Xiao, X.; Luo, J.; Luo, Y.; Tian, G.; Wang, J. Dietary apple pectic oligosaccharide improves gut barrier function of rotavirus-challenged weaned pigs by increasing antioxidant capacity of enterocytes. Oncotarget, 2017, 8, 92420-92430.
[65]
Zhou, X.L.; Kong, X.F.; Lian, G.Q.; Blachier, F.; Geng, M.M.; Yin, Y.L. Dietary supplementation with soybean oligosaccharides increases short-chain fatty acids but decreases protein-derived catabolites in the intestinal luminal content of weaned Huanjiang mini-piglets. Nutr. Res., 2014, 34, 780-788.
[66]
Zhu, C.; Lv, H.; Chen, Z.; Wang, L.; Wu, X.; Chen, Z.; Zhang, W.; Liang, R.; Jiang, Z. Dietary zinc oxide modulates antioxidant capacity, small intestine development, and jejunal gene expression in weaned piglets. Biol. Trace Elem. Res., 2017, 175, 331-338.
[67]
Xia, T.; Lai, W.; Han, M.; Han, M.; Ma, X.; Zhang, L. Dietary ZnO nanoparticles alters intestinal microbiota and inflammation response in weaned piglets. Oncotarget, 2017, 8, 64878-64891.
[68]
Wang, C.; Zhang, L.; Su, W.; Ying, Z.; He, J.; Zhang, L.; Zhong, X.; Wang, T. Zinc oxide nanoparticles as a substitute for zinc oxide or colistin sulfate: Effects on growth, serum enzymes, zinc deposition, intestinal morphology and epithelial barrier in weaned piglets. PLoS One, 2017, 12e0181136
[69]
Grilli, E.; Tugnoli, B.; Vitari, F.; Domeneghini, C.; Morlacchini, M.; Piva, A.; Prandini, A. Low doses of microencapsulated zinc oxide improve performance and modulate the ileum architecture, inflammatory cytokines and tight junctions expression of weaned pigs. Animal, 2015, 9, 1760-1768.
[70]
Hu, C.; Song, J.; Li, Y.; Luan, Z.; Zhu, K. Diosmectite-zinc oxide composite improves intestinal barrier function, modulates expression of pro-inflammatory cytokines and tight junction protein in early weaned pigs. Br. J. Nutr., 2013, 110, 681-688.
[71]
Yan, H.; Ajuwon, K.M. Butyrate modifies intestinal barrier function in IPEC-J2 cells through a selective upregulation of tight junction proteins and activation of the Akt signaling pathway. PLoS One, 2017, 12e0179586
[72]
Suzuki, T.; Hara, H. Role of flavonoids in intestinal tight junction regulation. J. Nutr. Biochem., 2011, 22, 401-408.
[73]
Zhu, C.; Wu, Y.; Jiang, Z.; Zheng, C.; Wang, L.; Yang, X.; Ma, X.; Gao, K.; Hu, Y. Dietary soy isoflavone attenuated growth performance and intestinal barrier functions in weaned piglets challenged with lipopolysaccharide. Int. Immunopharmacol., 2015, 28, 288-294.
[74]
Sun, K.; Lei, Y.; Wang, R.; Wu, Z.; Wu, G. Cinnamicaldehyde regulates the expression of tight junction proteins and amino acid transporters in intestinal porcine epithelial cells. J. Anim. Sci. Biotechnol., 2017, 8, 66.
[75]
Mercado, J.; Valenzano, M.C.; Jeffers, C.; Sedlak, J.; Cugliari, M.K.; Papanikolaou, E.; Clouse, J.; Miao, J.; Wertan, N.E.; Mullin, J.M. Enhancement of tight junctional barrier function by micronutrients: compound-specific effects on permeability and claudin composition. PLoS One, 2013, 8e78775
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