乳脂肪球膜的研究进展
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摘要
乳脂肪球膜(milk fat globule membrane,MFGM)是包裹乳脂肪球的薄膜,由于其含有蛋白质和极性脂质的特殊组成被广泛用作食品或非食品领域中的乳化剂、稳定剂及营养物质载体等。此外,MFGM被证明具有丰富的营养价值。本文综述MFGM的结构、组成成分、分离制备及营养功能的研究进展,介绍MFGM制备脂质体包埋生物活性物质的新技术,为开发利用MFGM提供一定的参考依据。
Milk fat globule membrane (MFGM), the membrane surrounding fat globules in milk, is particularly interesting due to its specific composition of proteins and polar lipids which makes it an excellent candidate to develop a wide range of innovative applications such as emulsifiers, stabilizers, and health promoters in both food and non-food fields. In addition, MFGM has been proven to be rich in nutrients. This review focuses on current studies on the structure, composition, preparation and nutritional aspects of MFGM. Furthermore, new technologies for preparing MFGM-derived phospholipids liposomes entrapping bioactive compounds are described. We hope that this review can provide a rationale for the application of MFGM.
Milk fat globule membrane (MFGM), the membrane surrounding fat globules in milk, is particularly interesting due to its specific composition of proteins and polar lipids which makes it an excellent candidate to develop a wide range of innovative applications such as emulsifiers, stabilizers, and health promoters in both food and non-food fields. In addition, MFGM has been proven to be rich in nutrients. This review focuses on current studies on the structure, composition, preparation and nutritional aspects of MFGM. Furthermore, new technologies for preparing MFGM-derived phospholipids liposomes entrapping bioactive compounds are described. We hope that this review can provide a rationale for the application of MFGM.
引文
[1]陆淳,黄龙,张列兵.乳制品中脂肪上浮的机理及影响因素[J].中国乳品工业,2009,37(4):42-45.DOI:10.3969/j.issn.1001-2230:2009.04.012.
[2]BOURLIEU C,MICHALSKI M C.Structure-function relationship of the milk fat globule[J].Current Opinion in Clinical Nutrition and Metabolic Care,2015,18(2):118-127.DOI:10.1097/MCO.0000000000000138.
[3]RUEDA R,MALDONADO J,NARBONA E,et al.Neonatal dietary gangliosides[J].Early Human Development,1998,53(Suppl 1):S135-S147.DOI:10.1016/S0378-3782(98)00071-1.
[4]SINGH H,GALLIER S.Nature's complex emulsion:the fat globules of milk[J].Food Hydrocolloids,2016,68:81-89.DOI:10.1016/j.foodhyd.2016.10.011.
[5]FONG B Y,NORRIS C S,MACGIBBON A K H.Protein and lipid composition of bovine milk-fat-globule membrane[J].International Dairy Journal,2007,17(4):275-288.DOI:10.1016/j.idairyj.2006.05.004.
[6]秦书云,于景华.脂肪球膜中脂类的组成及测定方法[J].中国乳品工业,2018,46(2):37-40.DOI:10.3969/j.issn.1001-2230.2018.02.010.
[7]SPITSBERG V L.Invited review:bovine milk fat globule membrane as a potential nutraceutical[J].Journal of Dairy Science,2005,88(7):2289-2294.DOI:10.3168/j ds.s0022-0302(05)72906-4.
[8]KUCHTA A M,KELLY P M,STANTON C,et al.Milk fat globule membrane:a source of polar lipids for colon health?a review[J].International Journal of Dairy Technology,2012,65(3):315-333DOI:10.11 11/j.1471-0307.201 1.00759.x.
[9]FULLER K L,KUHLENSCHMIDT T B,KUHLENSCHMIDT M S,et al.Milk fat globule membrane isolated from buttermilk or whey cream and their lipid components inhibit infectivity of rotavirus in vitro[J].Journal of Dairy Science,2013,96:3488-3497.DOI:10.3168/jds.2012-6122.
[10]JEONG J,LISINSKI I,KADEGOWDA A K G,et al.A test of current models for the mechanism of milk-lipid droplet secretion[J].Traffic,2013,14(9):974-986.DOI:10.1111/tra.12087.
[11]EVERS J M,HAVERKAMP R G,HOLROYD S E,et al.Heterogeneity of milk fat globule membrane structure and composition as observed using fluorescence microscopy techniques[J].International Dairy Journal,2008,18(12):1081-1089.DOI:10.1016,j.idairyj.2008.06.001.
[12]SANCHEZJUANES F,ALONSO J M,ZANCADA L,et al.Distribution and fatty acid content of phospholipids from bovine milk and bovine milk fat globule membranes[J].International Dairy Journal,2009,19(5):273-278.DOI:10.1016/j.idairyj.2008.11.006.
[13]ZHANG Ping,LI Baixiang,GAO Shuying,et al.Dietary sphingomyelin inhibits colonic tumorigenesis with an upregulation of alkaline sphingomyelinase expression in ICR mice[J].Anticancer Research,2008,28(6A):3631-3635.DOI:10.1097/CAD-0b013e328312c0e5.
[14]MAZZEI J C,ZHOU H,BRAYFIELD B P,et al.Suppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin:importance of peroxisome proliferator-activated receptor y expression[J].Journal of Nutritional Biochemistry,2011,22(12):1160-1 171.DOI:10.1016/j.jnutbio.20 10.09.0 17.
[15]HERNELL O,TIMBY N,DOMELLOF M,et al.Clinical benefits of milk fat globule membranes for infants and children[J].Journal of Pediatrics,2016,173:S60-S65.DOI:10.1016/j.jpeds.2016.02.077.
[16]NORRIS G H,JIANG C,RYAN J,et al.Milk sphingomyelin improves lipid metabolism and alters gut microbiota in high fat dietfed mice[J].Journal of Nutritional Biochemistry,2016,30(38):93-101.DOI:10.1016/j.j nutbio.2015.12.003.
[17]KINGSLEY M.Effects of phosphatidylserine supplementation on exercising humans[J].Sports Medicine,2006,36(8):657-669.DOI:10.2165/00007256-200636080-00003.
[18]VANDERGHEM C,BODSON P,DANTHINE S,et al.Milk fat globule membrane and buttermilks:from composition tovalorization[J].Biotechnologie Agronomie Societe Et Environnement,2010,14(3):354-362.DOI:10.1016/S0891-5849(00)00480-9.
[19]ELIAS-ARGOTE X,LAUBSCHER A,JIMENEZ-FLORES R.Advances in dairy ingredients[M].New Jersey:Wiley-Blackwell,2013:71-98.DOI:10.1002/978 1118448205.ch3.
[20]韩立强,杨国宇,王月影,等.乳中黄嘌呤氧化还原酶的研究进展[J].乳业科学与技术,2006,29(5):212-214.
[21]NG G Z,MENHENIOTT T R,EVERY A L,et al.The MUC1mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome[J].Gut,2015,65:1087-1099.DOI:10.113 6/gutj nl-2014-307175.
[22]FONG B Y,NORRIS C S,AKH M G.Protein and lipid composition of bovine milk-fat-globule membrane[J].International Dairy Journal,2007,17(4):275-288.DOI:10.1016/j.idairyj.2006.05.004.
[23]VOJDANI A,ANYANWU E,KASHANIAN A,et al.Antibodies to neuron-specific antigens in children with autism:possible cross-reaction with encephalitogenic proteins from milk,Chlamydia pneumoniae,and Streptococcus,group A[J].Journal of Neuroimmunology,2002,129(1):168-177.DOI:10.1016/S0165-5728(02)00180-7.
[24]MARTIN H M,HANCOCK J T,SALISBURY V,et al.Role of xanthine oxidoreductase as an antimicrobial agent[J].Infection and Immunity,2004,72(9):4933-4939.DOI:10.1 128/IAI.72.9.4933-4939.2004.
[25]KANKAINEN M,PAULIN L,TYNKKYNEN S,et al.Comparative genomic analysis of Lactobacillus rhamnosus GG reveals pili containing a human-mucus binding protein[J].Proceedings of the National Academy of Sciences of the United States of America,2009,106(40):17193-17198.DOI:10.1073/pnas.0908876106.
[26]SMOCZYNSKI M,STANIEWSKI B,KIELCZEWSKA K.Biological activities of milk fat globule membrane proteins[J].Medycyna Weterynaryjna,201 1,67(5):313-317.DOI:10.5326/JAAHA-MS-55 17.
[27]WU Jingjing,WANG Yini,LI Lanjuan.Functional significance of exosomes applied in sepsis:a novel approach to therapy[J].BBAMolecular Basis of Disease,20 17,1863(1):292-297.DOI:10.1016/j.bbadis.2016.10.024.
[28]HE Shenghua,MA Ying,WANG Jiaqi,et al.Characterization of fat globules and milk fat globule membrane proteins in milk of different yak breeds[J].Dairy Science and Technology,2010,90(5):601-609.DOI:10.1051/dst/2010022.
[29]KOEN D,ROELAND R,NATACHA T,et al.Nutritional and technological aspects of milk fat globule membrane material[J].International Dairy Journal,2008,18(5):436-457.DOI:10.1016/j.idairyj.2007.10.014.
[30]SINGH H.The milk fat globule membrane:a biophysical system for food applications[J].Current Opinion in Colloid and Interface Science,2006,11(2):154-163.DOI:10.1016/j.cocis.2005.1 1.002.
[31]HOLZMULLER W,KULOZIK U.Isolation of milk fat globule membrane(MFGM)material by coagulation and diafiltration of buttermilk[J].International Dairy Journal,2016,63:88-91.DOI:10.101 6/j.idairyj.2016.08.002.
[32]THOMPSON A K,SINGH H.Preparation of liposomes from milk fat globule membrane phospholipids using a microfluidizer[J].Journal of Dairy Science,2006,89(2):410-419.DOI:10.3168/jds.s0022-0302(06)72105-1.
[33]NGUYEN H T H,MADEC M N,ONG L,et al.The dynamics of the biological membrane surrounding the buffalo milk fat globule investigated as a function of temperature[J].Food Chemistry,2016,204:343-35 1.DOI:10.1016/i,foodchem.2016.02.141.
[34]MAHERANI B,ARABTEHRANY E,MOZAFARI M R,et al.Liposomes:a review of manufacturing techniques and targeting strategies[J].Current Nanoscience,2011,7(3):436-452.DOI:10.2174/1573413 11795542453.
[35]THOMPSON A K,SINGH H.Preparation of liposomes from milk fat globule membrane phospholipids using a microfluidizer[J].Journal of Dairy Science,2006,89(2):410-419.DOI:10.3168/jds.s0022-0302(06)72105-1.
[36]JIN Honghao,LU Qun,JIANG Jianguo.Curcumin liposomes prepared with milk fat globule membrane phospholipids and soybean lecithin[J].Journal of Dairy Science,2016,99(3):1780-1790.DOI:10.3168,jds.2015-10391.
[37]LIU Weilin,YE Aiqian,LIU Wei,et al.Stability during in vitra digestion of lactoferrin-loaded liposomes prepared from milk fat globule membrane-derived phospholipids[J].Journal of Dairy Science,2013,96(4):2061-2070.DOI:10.3168/jds.2012-6072.
[38]GULSEREN I,CORREDIG M.Storage stability and physica:characteristics of tea-polyphenol-bearing nanoliposomes prepared with milk fat globule membrane phospholipids[J].Journal of Agricultural and Food Chemistry,2013,61(13):3242-3251.DOI:10.1021/jf3045439.
[39]DAVIES J,EL-DIB M,MASSARO A,et al.Renal function is impaired in small for gestational age premature infants[J].The Journal of Maternal-Fetal and Neonatal Medicine,2012,26(4):388-391.DOI:10.3109/14767058.2012.733767.
[40]HORTA B L,CHRISTIAN L D M,VICTORA C G.Long-term consequences of breastfeeding on cholesterol,obesity,systolic blood pressure and type 2 diabetes:a systematic review and meta-analysis[J].Acta Paediatrica,2015,104:30-37.DOI:10.1111/apa.13133.
[41]TIMBY N,DOMELLOF E,HERNELL O,et al.Neurodevelopment.nutrition,and growth until 12 mo of age in infants fed a lowenergy,low-protein formula supplemented with bovine milk fat globule membranes:a randomized controlled trial[J].Americar Journal of Clinical Nutrition,2014,99(4):860-868.DOI:10.3945,ajcn.1 13.064295.
[42]VEEREMAN-WAUTERS G,STAELENS S,ROMBAUT R,et al.Milk fat globule membrane(INPULSE)enriched formula milk decreases febrile episodes and may improve behavioral regulation in young children[J].Nutrition,2012,28(7/8):749-752.DOI:10.1016,j.nut.2011.10.011.
[43]NELLY Z,ANNE STAUDT K,GITTE G,et al.Efficacy of an MFGM-enriched complementary food in diarrhea,anemia,and micronutrient status in infants[J].Journal of Pediatric Gastroenterology and Nutrition,2015,53(5):561-568.DOI:10.1097/MPG.Ob013e318225cdaf.
[44]ZHENG Ping,SONG Yi,TIAN Yihang,et al.Dietary arginine supplementation affects intestinal function by enhancing antioxidant capacity of a nitric oxide-independent pathway in low-birthweight piglets[J].Journal of Nutrition,2018,148(11):1751-1759.DOI:10.1093/jn/nxy198.
[2]BOURLIEU C,MICHALSKI M C.Structure-function relationship of the milk fat globule[J].Current Opinion in Clinical Nutrition and Metabolic Care,2015,18(2):118-127.DOI:10.1097/MCO.0000000000000138.
[3]RUEDA R,MALDONADO J,NARBONA E,et al.Neonatal dietary gangliosides[J].Early Human Development,1998,53(Suppl 1):S135-S147.DOI:10.1016/S0378-3782(98)00071-1.
[4]SINGH H,GALLIER S.Nature's complex emulsion:the fat globules of milk[J].Food Hydrocolloids,2016,68:81-89.DOI:10.1016/j.foodhyd.2016.10.011.
[5]FONG B Y,NORRIS C S,MACGIBBON A K H.Protein and lipid composition of bovine milk-fat-globule membrane[J].International Dairy Journal,2007,17(4):275-288.DOI:10.1016/j.idairyj.2006.05.004.
[6]秦书云,于景华.脂肪球膜中脂类的组成及测定方法[J].中国乳品工业,2018,46(2):37-40.DOI:10.3969/j.issn.1001-2230.2018.02.010.
[7]SPITSBERG V L.Invited review:bovine milk fat globule membrane as a potential nutraceutical[J].Journal of Dairy Science,2005,88(7):2289-2294.DOI:10.3168/j ds.s0022-0302(05)72906-4.
[8]KUCHTA A M,KELLY P M,STANTON C,et al.Milk fat globule membrane:a source of polar lipids for colon health?a review[J].International Journal of Dairy Technology,2012,65(3):315-333DOI:10.11 11/j.1471-0307.201 1.00759.x.
[9]FULLER K L,KUHLENSCHMIDT T B,KUHLENSCHMIDT M S,et al.Milk fat globule membrane isolated from buttermilk or whey cream and their lipid components inhibit infectivity of rotavirus in vitro[J].Journal of Dairy Science,2013,96:3488-3497.DOI:10.3168/jds.2012-6122.
[10]JEONG J,LISINSKI I,KADEGOWDA A K G,et al.A test of current models for the mechanism of milk-lipid droplet secretion[J].Traffic,2013,14(9):974-986.DOI:10.1111/tra.12087.
[11]EVERS J M,HAVERKAMP R G,HOLROYD S E,et al.Heterogeneity of milk fat globule membrane structure and composition as observed using fluorescence microscopy techniques[J].International Dairy Journal,2008,18(12):1081-1089.DOI:10.1016,j.idairyj.2008.06.001.
[12]SANCHEZJUANES F,ALONSO J M,ZANCADA L,et al.Distribution and fatty acid content of phospholipids from bovine milk and bovine milk fat globule membranes[J].International Dairy Journal,2009,19(5):273-278.DOI:10.1016/j.idairyj.2008.11.006.
[13]ZHANG Ping,LI Baixiang,GAO Shuying,et al.Dietary sphingomyelin inhibits colonic tumorigenesis with an upregulation of alkaline sphingomyelinase expression in ICR mice[J].Anticancer Research,2008,28(6A):3631-3635.DOI:10.1097/CAD-0b013e328312c0e5.
[14]MAZZEI J C,ZHOU H,BRAYFIELD B P,et al.Suppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin:importance of peroxisome proliferator-activated receptor y expression[J].Journal of Nutritional Biochemistry,2011,22(12):1160-1 171.DOI:10.1016/j.jnutbio.20 10.09.0 17.
[15]HERNELL O,TIMBY N,DOMELLOF M,et al.Clinical benefits of milk fat globule membranes for infants and children[J].Journal of Pediatrics,2016,173:S60-S65.DOI:10.1016/j.jpeds.2016.02.077.
[16]NORRIS G H,JIANG C,RYAN J,et al.Milk sphingomyelin improves lipid metabolism and alters gut microbiota in high fat dietfed mice[J].Journal of Nutritional Biochemistry,2016,30(38):93-101.DOI:10.1016/j.j nutbio.2015.12.003.
[17]KINGSLEY M.Effects of phosphatidylserine supplementation on exercising humans[J].Sports Medicine,2006,36(8):657-669.DOI:10.2165/00007256-200636080-00003.
[18]VANDERGHEM C,BODSON P,DANTHINE S,et al.Milk fat globule membrane and buttermilks:from composition tovalorization[J].Biotechnologie Agronomie Societe Et Environnement,2010,14(3):354-362.DOI:10.1016/S0891-5849(00)00480-9.
[19]ELIAS-ARGOTE X,LAUBSCHER A,JIMENEZ-FLORES R.Advances in dairy ingredients[M].New Jersey:Wiley-Blackwell,2013:71-98.DOI:10.1002/978 1118448205.ch3.
[20]韩立强,杨国宇,王月影,等.乳中黄嘌呤氧化还原酶的研究进展[J].乳业科学与技术,2006,29(5):212-214.
[21]NG G Z,MENHENIOTT T R,EVERY A L,et al.The MUC1mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome[J].Gut,2015,65:1087-1099.DOI:10.113 6/gutj nl-2014-307175.
[22]FONG B Y,NORRIS C S,AKH M G.Protein and lipid composition of bovine milk-fat-globule membrane[J].International Dairy Journal,2007,17(4):275-288.DOI:10.1016/j.idairyj.2006.05.004.
[23]VOJDANI A,ANYANWU E,KASHANIAN A,et al.Antibodies to neuron-specific antigens in children with autism:possible cross-reaction with encephalitogenic proteins from milk,Chlamydia pneumoniae,and Streptococcus,group A[J].Journal of Neuroimmunology,2002,129(1):168-177.DOI:10.1016/S0165-5728(02)00180-7.
[24]MARTIN H M,HANCOCK J T,SALISBURY V,et al.Role of xanthine oxidoreductase as an antimicrobial agent[J].Infection and Immunity,2004,72(9):4933-4939.DOI:10.1 128/IAI.72.9.4933-4939.2004.
[25]KANKAINEN M,PAULIN L,TYNKKYNEN S,et al.Comparative genomic analysis of Lactobacillus rhamnosus GG reveals pili containing a human-mucus binding protein[J].Proceedings of the National Academy of Sciences of the United States of America,2009,106(40):17193-17198.DOI:10.1073/pnas.0908876106.
[26]SMOCZYNSKI M,STANIEWSKI B,KIELCZEWSKA K.Biological activities of milk fat globule membrane proteins[J].Medycyna Weterynaryjna,201 1,67(5):313-317.DOI:10.5326/JAAHA-MS-55 17.
[27]WU Jingjing,WANG Yini,LI Lanjuan.Functional significance of exosomes applied in sepsis:a novel approach to therapy[J].BBAMolecular Basis of Disease,20 17,1863(1):292-297.DOI:10.1016/j.bbadis.2016.10.024.
[28]HE Shenghua,MA Ying,WANG Jiaqi,et al.Characterization of fat globules and milk fat globule membrane proteins in milk of different yak breeds[J].Dairy Science and Technology,2010,90(5):601-609.DOI:10.1051/dst/2010022.
[29]KOEN D,ROELAND R,NATACHA T,et al.Nutritional and technological aspects of milk fat globule membrane material[J].International Dairy Journal,2008,18(5):436-457.DOI:10.1016/j.idairyj.2007.10.014.
[30]SINGH H.The milk fat globule membrane:a biophysical system for food applications[J].Current Opinion in Colloid and Interface Science,2006,11(2):154-163.DOI:10.1016/j.cocis.2005.1 1.002.
[31]HOLZMULLER W,KULOZIK U.Isolation of milk fat globule membrane(MFGM)material by coagulation and diafiltration of buttermilk[J].International Dairy Journal,2016,63:88-91.DOI:10.101 6/j.idairyj.2016.08.002.
[32]THOMPSON A K,SINGH H.Preparation of liposomes from milk fat globule membrane phospholipids using a microfluidizer[J].Journal of Dairy Science,2006,89(2):410-419.DOI:10.3168/jds.s0022-0302(06)72105-1.
[33]NGUYEN H T H,MADEC M N,ONG L,et al.The dynamics of the biological membrane surrounding the buffalo milk fat globule investigated as a function of temperature[J].Food Chemistry,2016,204:343-35 1.DOI:10.1016/i,foodchem.2016.02.141.
[34]MAHERANI B,ARABTEHRANY E,MOZAFARI M R,et al.Liposomes:a review of manufacturing techniques and targeting strategies[J].Current Nanoscience,2011,7(3):436-452.DOI:10.2174/1573413 11795542453.
[35]THOMPSON A K,SINGH H.Preparation of liposomes from milk fat globule membrane phospholipids using a microfluidizer[J].Journal of Dairy Science,2006,89(2):410-419.DOI:10.3168/jds.s0022-0302(06)72105-1.
[36]JIN Honghao,LU Qun,JIANG Jianguo.Curcumin liposomes prepared with milk fat globule membrane phospholipids and soybean lecithin[J].Journal of Dairy Science,2016,99(3):1780-1790.DOI:10.3168,jds.2015-10391.
[37]LIU Weilin,YE Aiqian,LIU Wei,et al.Stability during in vitra digestion of lactoferrin-loaded liposomes prepared from milk fat globule membrane-derived phospholipids[J].Journal of Dairy Science,2013,96(4):2061-2070.DOI:10.3168/jds.2012-6072.
[38]GULSEREN I,CORREDIG M.Storage stability and physica:characteristics of tea-polyphenol-bearing nanoliposomes prepared with milk fat globule membrane phospholipids[J].Journal of Agricultural and Food Chemistry,2013,61(13):3242-3251.DOI:10.1021/jf3045439.
[39]DAVIES J,EL-DIB M,MASSARO A,et al.Renal function is impaired in small for gestational age premature infants[J].The Journal of Maternal-Fetal and Neonatal Medicine,2012,26(4):388-391.DOI:10.3109/14767058.2012.733767.
[40]HORTA B L,CHRISTIAN L D M,VICTORA C G.Long-term consequences of breastfeeding on cholesterol,obesity,systolic blood pressure and type 2 diabetes:a systematic review and meta-analysis[J].Acta Paediatrica,2015,104:30-37.DOI:10.1111/apa.13133.
[41]TIMBY N,DOMELLOF E,HERNELL O,et al.Neurodevelopment.nutrition,and growth until 12 mo of age in infants fed a lowenergy,low-protein formula supplemented with bovine milk fat globule membranes:a randomized controlled trial[J].Americar Journal of Clinical Nutrition,2014,99(4):860-868.DOI:10.3945,ajcn.1 13.064295.
[42]VEEREMAN-WAUTERS G,STAELENS S,ROMBAUT R,et al.Milk fat globule membrane(INPULSE)enriched formula milk decreases febrile episodes and may improve behavioral regulation in young children[J].Nutrition,2012,28(7/8):749-752.DOI:10.1016,j.nut.2011.10.011.
[43]NELLY Z,ANNE STAUDT K,GITTE G,et al.Efficacy of an MFGM-enriched complementary food in diarrhea,anemia,and micronutrient status in infants[J].Journal of Pediatric Gastroenterology and Nutrition,2015,53(5):561-568.DOI:10.1097/MPG.Ob013e318225cdaf.
[44]ZHENG Ping,SONG Yi,TIAN Yihang,et al.Dietary arginine supplementation affects intestinal function by enhancing antioxidant capacity of a nitric oxide-independent pathway in low-birthweight piglets[J].Journal of Nutrition,2018,148(11):1751-1759.DOI:10.1093/jn/nxy198.
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