肠碱性磷酸酶保护肠道健康的分子机制及其畜禽生产应用

摘要

肠碱性磷酸酶(IAP)在维持肠道稳态中具有关键作用。动物 IAP 功能失调与肠道屏障完整性被破坏、肠道免疫反应调控及肠道菌群紊乱密切相关,其分子机制涉及紧密连接蛋白、黏蛋白、模式识别受体等关键因子的调控与肠道微生物群平衡的维持。文章系统综述了 IAP 在肠屏障保护领域的最新研究进展,重点阐述了 IAP 的营养调控措施及改善肠屏障功能的具体作用机制,旨在为开发靶向改善肠道屏障功能的治疗策略提供理论依据,探讨 IAP 作为饲料添加剂在畜禽生产领域中的应用前景。

关键词

肠碱性磷酸酶 / 肠道屏障 / 脂多糖 / 畜禽生产应用

参考文献

[1] Dong L J, Xie J W, Wang Y Y, et al. Mannose ameliorates experimental colitis by protecting intestinal barrier integrity[J]. Nature Communications, 2022, 13. DOI:10.1038/s41467—022—32505—8.

[2] Zaher D M, El—Gamal M I, Omar H A, et al. Recent advances with alkaline phosphatase isoenzymes and their inhibitors[J]. Archiv der Pharmazie, 2020, 353(5). DOI:10.1002/ardp.202000011.

[3] Van Dongen J M, Kooyman J, Visser W J, et al. The effect of increased crypt cell proliferation on the activity and subcellular localization of esterases and alkaline phosphatase in the rat small intestine[J]. The Histochemical Journal, 1977, 9(1): 61-75.

[4] 王梦竹 . 京尼平苷对 LPS 诱导小鼠肠道损伤时 NF—κB/IAP 的影响[D]. 大庆: 黑龙江八一农垦大学, 2020.

[5] Malo M S, Moaven O, Muhammad N, et al. Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates[J]. American Journal of Physiology. Gastrointestinal and Liver Physiology, 2014, 306(10): G826-G838.

[6] 张春垒, 蒙洪娇, 朱世馨, 等. 碱性磷酸酶对断奶仔猪肠道健康作用机制的研究[J]. 养猪, 2017(6): 13-16.

[7] 杨红, 谢智鑫, 刘丹怡, 等. 猪小肠粘膜碱性磷酸酶的分离纯化及性质研究[J]. 食品工业科技, 2020, 41(20): 122—126, 141.

[8] Deng Q H, Jia G, Zhao H, et al. The prolonged effect of glucagon—like peptide 2 pretreatment on growth performance and intestinal development of weaned piglets[J]. Journal of Animal Science and Biotechnology, 2016, 7. DOI:10.1186/s40104—016—0087—7.

[9] Yang H S, Xiong X, Li J Z, et al. Effects of chito—oligosaccharide on intestinal mucosal amino acid profiles and alkaline phosphatase activities, and serum biochemical variables in weaned piglets[J]. Livestock Science, 2016, 190: 141-146. DOI:10.1016/j.livsci.2016.06.008.

[10] Leforestier G, Blais A, Blachier F, et al. Effects of galacto—oligosaccharide ingestion on the mucosa—associated mucins and sucrase activity in the small intestine of mice[J]. European Journal of Nutrition, 2009, 48(8): 457-464.

[11] Okazaki Y, Katayama T. Glucomannan consumption elevates colonic alkaline phosphatase activity by up—regulating the expression of IAP—I, which is associated with increased production of protective factors for gut epithelial homeostasis in high—fat diet—fed rats[J]. Nutrition Research, 2017, 43: 43-50. DOI:10.1016/j.nutres.2017.05.012.

[12] Wang T T, Yang J Z, Lin G, et al. Effects of dietary mannan oligosaccharides on Non—specific immunity, intestinal health, and antibiotic resistance genes in pacific white shrimp Litopenaeus vannamei [J]. Front Immunol, 2021, 12. DOI:10.3389/fimmu.2021.772570.

[13] 王语聪, 谢智鑫, 张学艳, 等. 阿拉伯半乳聚糖对 2 型糖尿病大鼠肠道碱性磷酸酶、细菌内毒素和肠道中细胞因子的影响[J]. 食品工业科技, 2021, 42(14): 334-340.

[14] Alvarenga L, Cardozo L F M F, Lindholm B, et al. Intestinal alkaline phosphatase modulation by food components: Predictive, preventive, and personalized strategies for novel treatment options in chronic kidney disease[J]. EPMA Journal, 2020, 11(4): 565-579.

[15] 肖英平, 洪奇华, 刘秀婷, 等. 谷氨酰胺对断奶仔猪生长性能、营养物质表观消化率、空肠碱性磷酸酶活性及与肠道健康相关因子基因表达的影响[J]. 动物营养学报, 2012, 24(8): 1438-1446.

[16] Zhao X, Xu X X, Liu Y, et al. The in vitro protective role of bovine lactoferrin on intestinal epithelial barrier[J]. Molecules, 2019, 24(1). DOI:10.3390/molecules24010148.

[17] Amigo—Benavent M, Clemente A, Caira S, et al. Use of phytochemomics to evaluate the bioavailability and bioactivity of antioxidant peptides of soybean β—conglycinin[J]. Electrophoresis, 2014, 35(11): 1582-1589.

[18] Takeuchi A, Hisamatsu K, Okumura N, et al. IIAEK targets intestinal alkaline phosphatase (IAP) to improve cholesterol metabolism with a specific activation of IAP and downregulation of ABCA1[J]. Nutrients, 2020, 12(9). DOI:10.3390/nu12092859.

[19] Nakaoka K, Yamada A, Noda S, et al. Vitamin D—restricted high—fat diet down—regulates expression of intestinal alkaline phosphatase isozymes in ovariectomized rats[J]. Nutrition Research, 2018, 53: 23-31.

[20] Haarhaus M, Cianciolo G, Barbuto S, et al. Alkaline phosphatase: an old friend as treatment target for cardiovascular and mineral bone disorders in chronic kidney disease[J]. Nutrients, 2022, 14(10). DOI:10.3390/nu14102124.

[21] Melo A D B, Silveira H, Bortoluzzi C, et al. Intestinal alkaline phosphatase and sodium butyrate may be beneficial in attenuating LPS—induced intestinal inflammation[J]. Genetics and Molecular Research, 2016, 15(4). DOI:10.4238/gmr15048875.

[22] Goldberg R F, Austen W G Jr, Zhang X B, et al. Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition[J]. Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(9): 3551-3556.

[23] Shin J, Carr A, Corner G A, et al. The intestinal epithelial cell differentiation marker intestinal alkaline phosphatase (ALPi) is selectively induced by histone deacetylase inhibitors (HDACi) in colon cancer cells in a Kruppel—like factor 5 (KLF5)—dependent manner[J]. Journal of Biological Chemistry, 2014, 289(36): 25306-25316.

[24] Chen L Y, Yang P C, Hu L L, et al. Modulating phenylalanine metabolism by L. acidophilus alleviates alcohol—related liver disease through enhancing intestinal barrier function [J]. Cell & Bioscience, 2023, 13(1). DOI:10.1186/s13578—023—00974—z.

[25] 魏清甜, 李平华, 汪涵, 等. 粪肠球菌替代抗生素对保育仔猪生长性能、腹泻率、体液免疫指标和肠道微生物数量的影响[J]. 南京农业大学学报, 2014, 37(6): 143-148.

[26] Bokharaeian M, Toghdory A, Ghoorchi T. Effects of dietary curcumin nano—micelles on performance, biological responses, and thermal stress resilience in heat—stressed fattening lambs across varying temperature—humidity index conditions: implications for climate change[J]. Journal of Thermal Biology, 2024, 123. DOI:10.1016/j.jtherbio.2024.103905.

[27] Foster M T, Gentile C L, Cox—York K, et al. Fuzhuan tea consumption imparts hepatoprotective effects and alters intestinal microbiota in high saturated fat diet—fed rats[J]. Molecular Nutrition & Food Research, 2016, 60(5): 1213-1220.

[28] Chen J L, Li Y, Yu B, et al. Dietary chlorogenic acid improves growth performance of weaned pigs through maintaining antioxidant capacity and intestinal digestion and absorption function[J]. Journal of Animal Science, 2018, 96(3): 1108-1118.

[29] Bibi S, Du M, Zhu M J. Dietary red raspberry reduces colorectal inflammation and carcinogenic risk in mice with dextran sulfate sodium—induced colitis[J]. The Journal of Nutrition, 2018, 148(5): 667-674.

[30] Lassenius M I, Fogarty C L, Blaut M, et al. Intestinal alkaline phosphatase at the crossroad of intestinal health and disease—a putative role in type 1 diabetes[J]. Journal of Internal Medicine, 2017, 281(6): 586-600.

[31] Chen G C, Huang T Y, Dai Y F, et al. Effects of POPs—induced SIRT6 alteration on intestinal mucosal barrier function: A comprehensive review[J]. Ecotoxicology and Environmental Safety, 2025, 289. DOI:10.1016/j.ecoenv.2025.117705.

[32] Hamarneh S R, Kim B M, Kaliannan K, et al. Intestinal alkaline phosphatase attenuates alcohol—induced hepatosteatosis in mice[J]. Digestive Diseases and Sciences, 2017, 62(8): 2021-2034.

[33] Hamarneh S R, Mohamed M M R, Economopoulos K P, et al. A novel approach to maintain gut mucosal integrity using an oral enzyme supplement[J]. Annals of Surgery, 2014, 260(4): 706-714.

[34] Liu W, Hu D, Huo H Z, et al. Intestinal alkaline phosphatase regulates tight junction protein levels[J]. Journal of the American College of Surgeons, 2016, 222(6): 1009-1017.

[35] Ghosh S S, He H L, Wang J, et al. Intestine—specific expression of human chimeric intestinal alkaline phosphatase attenuates Western diet—induced barrier dysfunction and glucose intolerance[J]. Physiological Reports, 2018, 6(14). DOI:10.14814/phy2.13790.

[36] 毛文姣, 张红梅 . 基于肠道碱性磷酸酶相关信号通路探讨针灸维持肠道菌群—免疫稳定作用的机制[J]. 中国医药导报, 2019, 16(28): 126-129.

[37] Ghosh S S, Wang J, Yannie P J, et al. Over—expression of intestinal alkaline phosphatase attenuates atherosclerosis[J]. Circulation Research, 2021, 128(11): 1646-1659.

[38] Zarepour M, Bhullar K, Montero M, et al. The mucin Muc2 limits pathogen burdens and epithelial barrier dysfunction during Salmonella enterica serovar Typhimurium colitis [J]. Infection and Immunity, 2013, 81(10): 3672-3683.

[39] Okazaki Y, Katayama T. Consumption of non—digestible oligosaccharides elevates colonic alkaline phosphatase activity by up—regulating the expression of IAP—I, with increased mucins and microbial fermentation in rats fed a high—fat diet[J]. The British Journal of Nutrition, 2019, 121(2): 146-154.

[40] Patel K K, Miyoshi H, Beatty W L, et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production[J]. The EMBO Journal, 2013, 32(24): 3130-3144.

[41] Danielak A, Wojcik D, Mazur—Bialy A, et al. Intestinal alkaline phosphatase combined with voluntary physical activity alleviates experimental colitis in obese mice. involvement of oxidative stress, myokines, adipokines and proinflammatory biomarkers[J]. Antioxidants, 2021, 10(2). DOI:10.3390/antiox10020240.

[42] Ghosh S S, Wang J, Yannie P J, et al. Intestinal barrier dysfunction, LPS translocation, and disease development[J]. Journal of the Endocrine Society, 2020, 4(2). DOI:10.1210/jendso/bvz039.

[43] Estaki M, Decoffe D, Gibson D L. Interplay between intestinal alkaline phosphatase, diet, gut microbes and immunity[J]. World Journal of Gastroenterology, 2014, 20(42): 15650-15656.

[44] Bates J M, Akerlund J, Mittge E, et al. Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota[J]. Cell Host & Microbe, 2007, 2(6): 371-382.

[45] Chen K T, Malo M S, Beasley—Topliffe L K, et al. A role for intestinal alkaline phosphatase in the maintenance of local gut immunity[J]. Digestive Diseases and Sciences, 2011, 56(4): 1020-1027.

[46] Chen K T, Malo M S, Moss A K, et al. Identification of specific targets for the gut mucosal defense factor intestinal alkaline phosphatase[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2010, 299(2): G467-G475.

[47] Moss A K, Hamarneh S R, Mohamed M M R, et al. Intestinal alkaline phosphatase inhibits the proinflammatory nucleotide uridine diphosphate[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2013, 304(6): G597-G604.

[48] Proietti M, Perruzza L, Scribano D, et al. ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens[J]. Nature Communications, 2019, 10. DOI:10.1038/s41467—018—08156—z.

[49] Khounlotham M, Kim W, Peatman E, et al. Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis[J]. Immunity, 2012, 37(3): 563-573.

[50] Le Bourgot C, Ferret—Bernard S, Apper E, et al. Perinatal short—chain fructooligosaccharides program intestinal microbiota and improve enteroinsular axis function and inflammatory status in high—fat diet—fed adult pigs[J]. The FASEB Journal, 2019, 33(1): 301-313.

[51] Leikeim L, Li H, An L Y, et al. Adenosine signalling in T—cell activation favours development of IL—17 positive cells with suppressive properties[J]. Immunology, 2023, 169(1): 42-56.

[52] Huang H, Huang J, Huang W D, et al. Breast milk jaundice affects breastfeeding: From the perspective of intestinal flora and SCFAs—GPR41/43[J]. Frontiers in Nutrition, 2023, 10. DOI:10.3389/fnut.2023.1121213.

[53] Mendonca A F, Amoroso T L, Knabel S J. Destruction of gram—negative food—borne pathogens by high pH involves disruption of the cytoplasmic membrane[J]. Applied and Environmental Microbiology, 1994, 60(11): 4009-4014.

[54] Alam S N, Yammine H, Moaven O, et al. Intestinal alkaline phosphatase prevents antibiotic—induced susceptibility to enteric pathogens[J]. Annals of Surgery, 2014, 259(4): 715-722.

[55] Yang W H, Heithoff D M, Aziz P V, et al. Recurrent infection progressively disables host protection against intestinal inflammation[J]. Science, 2017, 358(6370). DOI:10.1126/science.aao5610.

[56] 毕景成, 王新颖, 黎介寿 . 肠碱性磷酸酶在肠屏障中作用的研究进展[J]. 肠外与肠内营养, 2015, 22(4): 244-247.

[57] 李湘, 王敏成, 郑金, 等. 一株产碱性磷酸酶奇异虚构芽孢杆菌的分离鉴定及其产酶条件优化[J/OL]. 饲料工业, 1-12[2026—01—16]. https://link.cnki.net/urlid/21.1169.S.20250520.1406.002.

[58] Escobar J, Dobbs M, Ellenberger C, et al. Oral supplementation of alkaline phosphatase in poultry and swine[J]. Translational Animal Science, 2022, 6(3). DOI:10.1093/tas/txac079.

[59] Genova J L, Rupolo P E, Melo A D B, et al. Biological response of piglets challenged with Escherichia coli F4 (K88) when fed diets containing intestinal alkaline phosphatase [J]. Czech Journal of Animal Science, 2021, 66(10): 391-402.

[60] Beumer C, Wulferink M, Raaben W, et al. Calf intestinal alkaline phosphatase, a novel therapeutic drug for lipopolysaccharide (LPS)—mediated diseases, attenuates LPS toxicity in mice and piglets[J]. The Journal of Pharmacology and Experimental Therapeutics, 2003, 307(2): 737-744.

[61] Rodrigues L A, Wellington M O, González—Vega J C, et al. Ileal alkaline phosphatase is upregulated following functional amino acid supplementation in Salmonella Typhimurium—challenged pigs [J]. Journal of Animal Science, 2022, 100(2). DOI:10.1093/jas/skab376.

[62] Zong E Y, Huang P F, Zhang W, et al. The effects of dietary sulfur amino acids on growth performance, intestinal morphology, enzyme activity, and nutrient transporters in weaning piglets[J]. Journal of Animal Science, 2018, 96(3): 1130-1139.

[63] Yang C W, Zhu X, Liu N, et al. Lactoferrin up—regulates intestinal gene expression of brain—derived neurotrophic factors BDNF UCHL1 and alkaline phosphatase activity to alleviate early weaning diarrhea in postnatal piglets[J]. The Journal of Nutritional Biochemistry, 2014, 25(8): 834-842.

[64] Mccaffrey C, Corrigan A, Moynagh P, et al. Effect of yeast cell wall supplementation on intestinal integrity, digestive enzyme activity and immune traits of broilers[J]. British Poultry Science, 2021, 62(5): 771-782.

[65] Ji F J, Yang H S, Wang Q Y, et al. Porcine intestinal antimicrobial peptide as an in—feed antibiotic alternative improves intestinal digestion and immunity by shaping the gut microbiota in weaned piglets[J]. Animal Nutrition, 2023, 14: 43-55. DOI:10.1016/j.aninu.2023.04.001.

[66] Hu F, Gao X, She R, et al. Effects of antimicrobial peptides on growth performance and small intestinal function in broilers under chronic heat stress[J]. Poultry Science, 2017, 96(4): 798-806.

基金资助

国家自然科学基金区域创新发展联合基金重点项目(U21A20252)

大学生创新创业训练计划项目“东北农业大学 2024 年大学生 SIPT 省级项目”(S202410224181X)