氨基酸在炎症性肠病中的作用及其信号通路

doi:10.11843/j.issn.0366-6964.2020.10.003

摘要/Abstract

摘要： 肠道是营养物质消化、吸收的主要器官，但易受外界环境刺激，导致炎症性肠病（inflammatory bowel disease，IBD）的发生，严重危害动物肠道健康。膳食氨基酸在促进肠道发育、维持肠道健康方面发挥重要作用，其主要通过调控腺苷酸活化蛋白激酶（AMP-activated kinase，AMPK）、雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）、丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）、Toll样受体（Toll-like receptors，TLRs）、核苷酸结合寡聚化结构域（nucleotide binding oligomerization domain，NOD）/核因子-κB（nuclear factor kappa-B，NF-κB）等信号通路影响肠上皮细胞生理活动、改善肠道屏障功能、减轻肠道氧化损伤、调节炎性因子的产生、提高内源抗菌肽表达，进而预防和治疗IBD。本文综述了IBD的基本特征、氨基酸在IBD中的作用及其信号通路，以及氨基酸在畜禽生长中维持肠道健康的作用与应用，为膳食营养素防治IBD提供有效线索与策略。

关键词: 氨基酸, 炎症性肠病, 作用, 信号通路

Abstract: The intestine is the primary organ responsible for digestion and absorption of nutrients and is frequently subjected to external environmental stimulations leading to the development of inflammatory bowel disease (IBD), which can cause serious harm to intestinal health in animals. Dietary amino acids play important roles in promoting intestinal development and maintaining intestinal health and exert diverse effects through multiple signaling pathways on the prevention and treatment of IBD, including affecting the physiological activities of intestinal epithelial cells, improving intestinal barrier function, reducing intestinal oxidative damage, regulating the production of inflammatory cytokines, and promoting the expression of endogenous antimicrobial peptides, and involved in main signaling pathways including AMP-activated kinase (AMPK), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), Toll-like receptors (TLRs), nucleotide binding oligomerization domain (NOD)/nuclear factor kappa-B (NF-κB). In this review, basic characteristics of IBD, effects and involved signaling pathways of the amino acids on IBD, and effects and applications of amino acids in maintaining intestinal health in livestock and poultry production were reviewed, so as to provide effective clues and strategies for dietary nutrients in the prevention and treatment of IBD.

Key words: amino acids, inflammatory bowel disease, function, signaling pathways

中图分类号:

S811
S856.4

高楠, 窦秀静, 杨洋, 单安山. 氨基酸在炎症性肠病中的作用及其信号通路[J]. 畜牧兽医学报, 2020, 51(10): 2349-2358.

GAO Nan, DOU Xiujing, YANG Yang, SHAN Anshan. Effects of Amino Acids on Inflammatory Bowel Disease and Its Signaling Pathways[J]. Acta Veterinaria et Zootechnica Sinica, 2020, 51(10): 2349-2358.

参考文献 74

[1]	KIM C J,KOVACS-NOLAN J A,YANG C B,et al.L-tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis[J].J Nutr Biochem,2010,21(6):468-475.
[2]	TANAKA S,NEMOTO Y,TAKEI Y,et al.High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage[J].Biochem Biophys Res Commun,2020,522(4):971-977.
[3]	WANG X C,ZHANG Y F,CAO L,et al.Deoxynivalenol induces intestinal damage and inflammatory response through the nuclear factor-κB signaling pathway in piglets[J].Toxins,2019,11(11):663.
[4]	WANG H B,LIU Y L,SHI H F,et al.Aspartate attenuates intestinal injury and inhibits TLR4 and NODs/NF-κB and p38 signaling in weaned pigs after LPS challenge[J].Eur J Nutr,2017,56(4):1433-1443.
[5]	SONG Z H,TONG G,XIAO K,et al.L-cysteine protects intestinal integrity,attenuates intestinal inflammation and oxidant stress,and modulates NF-κB and Nrf2 pathways in weaned piglets after LPS challenge[J].Innate Immun,2016,22(3):152-161.
[6]	KASER A,ZEISSIG S,BLUMBERG R S.Inflammatory bowel disease[J].Annu Rev Immunol,2010,28:573-621.
[7]	RAVINDRAN R,LOEBBERMANN J,NAKAYA H I,et al.The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation[J].Nature,2016,531(7595):523-527.
[8]	HU X M,DENG J L,YU T M,et al.ATF4 deficiency promotes intestinal inflammation in mice by reducing uptake of glutamine and expression of antimicrobial peptides[J].Gastroenterology,2019,156(4):1098-1111.
[9]	ANANTHAKRISHNAN A N,BERNSTEIN C N,ILIOPOULOS D,et al.Environmental triggers in IBD:a review of progress and evidence[J].Nat Rev Gastroenterol Hepatol,2018,15(1):39-49.
[10]	LIU Y L,WANG X Y,HU C A A,et al.Therapeutic potential of amino acids in inflammatory bowel disease[J].Nutrients,2017,9(9):920.
[11]	LAN J,DOU X J,LI J W,et al.L-arginine ameliorates lipopolysaccharide-induced intestinal inflammation through inhibiting the TLR4/NF-κB and MAPK pathways and stimulating β-defensin expression in vivo and in vitro[J].J Agric Food Chem,2020,68(9):2648-2663.
[12]	QIN Q,XU X,WANG X Y,et al.Glutamate alleviates intestinal injury,maintains mTOR and suppresses TLR4 and NOD signaling pathways in weanling pigs challenged with lipopolysaccharide[J].Sci Rep,2018,8(1):15124.
[13]	YI D,HOU Y Q,XIAO H,et al.N-Acetylcysteine improves intestinal function in lipopolysaccharides-challenged piglets through multiple signaling pathways[J].Amino Acids,2017,49(12):1915-1929.
[14]	LIU H N,TAN B,HUANG B,et al.Involvement of calcium-sensing receptor activation in the alleviation of intestinal inflammation in a piglet model by dietary aromatic amino acid supplementation[J].Br J Nutr,2018,120(12):1321-1331.
[15]	ZHANG H,PENG A L,YU Y,et al.L-arginine protects ovine intestinal epithelial cells from lipopolysaccharide-induced apoptosis through alleviating oxidative stress[J].J Agric Food Chem,2019,67(6):1683-1690.
[16]	王蕾,刘坚,侯永清,等.α-酮戊二酸对LPS慢性应激仔猪小肠黏膜形态与功能的影响[J].畜牧兽医学报,2010,41(1):46-52.WANG L,LIU J,HOU Y Q,et al.The effects of α-Ketogluarate on intestinal mucosal morphology and function in piglets chronically challenged with lipopolysaccharide[J].Acta Veterinaria et Zootechnica Sinica,2010,41(1):46-52.(in Chinese)
[17]	XIA Z F,HUANG L Q,YIN P,et al.L-arginine alleviates heat stress-induced intestinal epithelial barrier damage by promoting expression of tight junction proteins via the AMPK pathway[J].Mol Biol Rep,2019,46(6):6435-6451.
[18]	NUNES T,BERNARDAZZI C,DE SOUZA H S.Cell death and inflammatory bowel diseases:apoptosis,necrosis,and autophagy in the intestinal epithelium[J].Biomed Res Int,2014,2014:218493.
[19]	LI X G,SUI W G,GAO C Q,et al.L-glutamate deficiency can trigger proliferation inhibition via down regulation of the mTOR/S6K1 pathway in pig intestinal epithelial cells[J].J Anim Sci,2016,94(4):1541-1549.
[20]	CHEN S Y,XIA Y Y,ZHU G Q,et al.Glutamine supplementation improves intestinal cell proliferation and stem cell differentiation in weanling mice[J].Food Nutr Res,2018,62:1439,doi:10.29219/fnr.v62.1439.
[21]	PI D G,LIU Y L,SHI H F,et al.Dietary supplementation of aspartate enhances intestinal integrity and energy status in weanling piglets after lipopolysaccharide challenge[J].J Nutr Biochem,2014,25(4):456-462.
[22]	WANG T X,YAO W L,HE Q Y,et al.L-leucine stimulates glutamate dehydrogenase activity and glutamate synthesis by regulating mTORC1/SIRT4 pathway in pig liver[J].Anim Nutr,2018,4(3):329-338.
[23]	MAO X B,REN M,CHEN D W,et al.Leucine modulates the IPEC-J2 cell proteome associated with cell proliferation,metabolism and phagocytosis[J].Anim Nutr,2018,4(3):316-321.
[24]	QIU Y Q,YANG X F,WANG L,et al.L-arginine inhibited inflammatory response and oxidative stress induced by lipopolysaccharide via arginase-1 signaling in IPEC-J2 cells[J].Int J Mol Sci,2019,20(7):1800.
[25]	LEE S I,KANG K S.N-acetylcysteine modulates lipopolysaccharide-induced intestinal dysfunction[J].Sci Rep,2019,9(1):1004.
[26]	JIANG J,YIN L,LI J Y,et al.Glutamate attenuates lipopolysaccharide-induced oxidative damage and mRNA expression changes of tight junction and defensin proteins,inflammatory and apoptosis response signaling molecules in the intestine of fish[J].Fish Shellfish Immunol,2017,70:473-484.
[27]	CHEN S K,LIU Y L,WANG X Y,et al.Asparagine improves intestinal integrity,inhibits TLR4 and NOD signaling,and differently regulates p38 and ERK1/2 signaling in weanling piglets after LPS challenge[J].Innate Immun,2016,22(8):577-587.
[28]	WANG W W,WU Z L,LIN G,et al.Glycine stimulates protein synthesis and inhibits oxidative stress in pig small intestinal epithelial cells[J].J Nutr,2014,144(10):1540-1548.
[29]	HSIEH C Y,OSAKA T,MORIYAMA E,et al.Strengthening of the intestinal epithelial tight junction by Bifidobacterium bifidum[J].Physiol Rep,2015,3(3):e12327.
[30]	CITI S.Intestinal barriers protect against disease[J].Science,2018,359(6380):1097-1098.
[31]	CHEN Y P,ZHANG H,CHENG Y F,et al.Dietary L-threonine supplementation attenuates lipopoly-saccharide-induced inflammatory responses and intestinal barrier damage of broiler chickens at an early age[J].Br J Nutr,2018,119(11):1254-1262.
[32]	CHEN M D,LIU Y Y,XIONG S B,et al.Dietary L-tryptophan alleviated LPS-induced intestinal barrier injury by regulating tight junctions in a Caco-2 cell monolayer model[J].Food Funct,2019,10(5):2390-2398.
[33]	TANG Z R,LIU J Y,SUN Z H,et al.Protective effects of taurine on growth performance and intestinal epithelial barrier function in weaned piglets challenged without or with lipopolysaccharide[J].Anim Prod Sci,2018,58(11):2011-2020.
[34]	JI S Y,QI X,MA S X,et al.A deficient or an excess of dietary threonine level affects intestinal mucosal integrity and barrier function in broiler chickens[J].J Anim Physiol Anim Nutr,2019,103(6):1792-1799.
[35]	CHEN Y,LI D F,DAI Z L,et al.L-methionine supplementation maintains the integrity and barrier function of the small-intestinal mucosa in post-weaning piglets[J].Amino Acids,2014,46(4):1131-1142.
[36]	LI W,SUN K J,JI Y,et al.Glycine regulates expression and distribution of claudin-7 and ZO-3 proteins in intestinal porcine epithelial cells[J].J Nutr,2016,146(5):964-969.
[37]	WANG J,LI G R,TAN B E,et al.Oral administration of putrescine and proline during the suckling period improves epithelial restitution after early weaning in piglets[J].J Anim Sci,2015,93(4):1679-1688.
[38]	ZHU H L,PI D A,LENG W B,et al.Asparagine preserves intestinal barrier function from LPS-induced injury and regulates CRF/CRFR signaling pathway[J].Innate Immun,2017,23(6):546-556.
[39]	LIU G,YU L,FANG J,et al.Methionine restriction on oxidative stress and immune response in DSS-induced colitis mice[J].Oncotarget,2017,8(27):44511-44520.
[40]	FENG L,LI W,LIU Y,et al.Dietary phenylalanine-improved intestinal barrier health in young grass carp (Ctenopharyngodon idella) is associated with increased immune status and regulated gene expression of cytokines,tight junction proteins,antioxidant enzymes and related signalling molecules[J].Fish Shellfish Immunol,2015,45(2):495-509.
[41]	LIU N,MA X S,LUO X,et al.L-glutamine attenuates apoptosis in porcine enterocytes by regulating glutathione-related redox homeostasis[J].J Nutr,2018,148(4):526-534.
[42]	ZHOU X H,ZHANG Y M,HE L Q,et al.Serine prevents LPS-induced intestinal inflammation and barrier damage via p53-dependent glutathione synthesis and AMPK activation[J].J Funct Foods,2017,39:225-232.
[43]	MARTINEZ Y,LI X,LIU G,et al.The role of methionine on metabolism,oxidative stress,and diseases[J].Amino Acids,2017,49(12):2091-2098.
[44]	SCHREINER P,NEURATH M F,NG S C,et al.Mechanism-based treatment strategies for IBD:cytokines,cell adhesion molecules,JAK inhibitors,gut flora,and more[J].Inflamm Intest Dis,2019,4(3):79-96.
[45]	RENZ H,BRANDTZAEG P,HORNEF M,et al.The impact of perinatal immune development on mucosal homeostasis and chronic inflammation[J].Nat Rev Immunol,2012,12(1):9-23.
[46]	ZHANG B B,GAN L P,SHAHID M S,et al.In vivo and in vitro protective effect of arginine against intestinal inflammatory response induced by Clostridium perfringens in broiler chickens[J].J Anim Sci Biotechnol,2019,10(1):73.
[47]	COBURN L A,GONG X,SINGH K,et al.L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis[J].PLoS One,2012,7(3):e33546.
[48]	LIU S Q,WANG L Y,LIU G H,et al.Leucine alters immunoglobulin a secretion and inflammatory cytokine expression induced by lipopolysaccharide via the nuclear factor-κB pathway in intestine of chicken embryos[J].Animal,2018,12(9):1903-1911.
[49]	LIU D,ZONG E Y,HUANG P F,et al.The effects of dietary sulfur amino acids on serum biochemical variables,mucosal amino acid profiles,and intestinal inflammation in weaning piglets[J].Livest Sci,2019,220:32-36.
[50]	ANDOU A,HISAMATSU T,OKAMOTO S,et al.Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages[J].Gastroenterology,2009,136(2):564-574.E2.
[51]	MINE Y,ZHANG H.Calcium-sensing receptor (CaSR)-mediated anti-inflammatory effects of L-amino acids in intestinal epithelial cells[J].J Agric Food Chem,2015,63(45):9987-9995.
[52]	MENG Q H,COONEY M,YEPURI N,et al.L-arginine attenuates Interleukin-1β (IL-1β) induced Nuclear Factor Kappa-Beta (NF-κB) activation in Caco-2 cells[J].PLoS One,2017,12(3):e0174441.
[53]	ANDRADE M E R,DE BARROS P A V,DOS REIS MENTA P L,et al.Arginine supplementation reduces colonic injury,inflammation and oxidative stress of DSS-induced colitis in mice[J].J Funct Foods,2019,52:360-369.
[54]	VARASTEH S,BRABER S,KRANEVELD A D,et al.L-arginine supplementation prevents intestinal epithelial barrier breakdown under heat stress conditions by promoting nitric oxide synthesis[J].Nutr Res,2018,57:45-55.
[55]	KIM H,ZHAO Q J,ZHENG H,et al.A novel crosstalk between TLR4-and NOD2-mediated signaling in the regulation of intestinal inflammation[J].Sci Rep,2015,5(1):12018.
[56]	CHENG S X,LIGHTFOOT Y L,YANG T,et al.Epithelial CaSR deficiency alters intestinal integrity and promotes proinflammatory immune responses[J].FEBS Lett,2014,588(22):4158-4166.
[57]	ZHANG H,KOVACS-NOLAN J,KODERA T,et al.γ-Glutamyl cysteine and γ-glutamyl valine inhibit TNF-α signaling in intestinal epithelial cells and reduce inflammation in a mouse model of colitis via allosteric activation of the calcium-sensing receptor[J].Biochim Biophys Acta,2015,1852(5):792-804.
[58]	WANG J J,DOU X J,SONG J,et al.Antimicrobial peptides:promising alternatives in the post feeding antibiotic era[J].Med Res Rev,2019,39(3):831-859.
[59]	HAN F F,ZHANG H W,XIA X,et al.Porcine β-defensin 2 attenuates inflammation and mucosal lesions in dextran sodium sulfate-induced colitis[J].J Immunol,2015,194(4):1882-1893.
[60]	CORETTI L,NATALE A,CUOMO M,et al.The interplay between defensins and microbiota in Crohn's disease[J].Mediators Inflamm,2017,2017:8392523.
[61]	HASHIMOTO T,PERLOT T,REHMAN A,et al.ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation[J].Nature,2012,487(7408):477-481.
[62]	SORGDRAGER F J H,NAUDÉ P J W,KEMA I P,et al.Tryptophan metabolism in inflammaging:from biomarker to therapeutic target[J].Front Immunol,2019,10:2565.
[63]	SU Y N,WU P,FENG L,et al.The improved growth performance and enhanced immune function by DL-methionyl-DL-methionine are associated with NF-κB and TOR signalling in intestine of juvenile grass carp (Ctenopharyngodon idella)[J].Fish Shellfish Immunol,2018,74:101-118.
[64]	REN M,ZHANG S H,LIU X T,et al.Different lipopolysaccharide branched-chain amino acids modulate porcine intestinal endogenous β-defensin expression through the Sirt1/ERK/90RSK pathway[J].J Agric Food Chem,2016,64(17):3371-3379.
[65]	REN M,CAI S,ZHOU T,et al.Isoleucine attenuates infection induced by E. coli challenge through the modulation of intestinal endogenous antimicrobial peptide expression and the inhibition of the increase in plasma endotoxin and IL-6 in weaned pigs[J].Food Funct,2019,10(6):3535-3542.
[66]	ZHENYUKH O,CIVANTOS E,RUIZ-ORTEGA M,et al.High concentration of branched-chain amino acids promotes oxidative stress,inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation[J].Free Radic Biol Med,2017,104:165-177.
[67]	HE F,WU C L,LI P,et al.Functions and signaling pathways of amino acids in intestinal inflammation[J].Biomed Res Int,2018,2018:9171905.
[68]	王晶,许丽,齐广海,等.家禽肠道健康及其营养调控措施[J].动物营养学报,2019,31(6):2479-2486.WANG J,XU L,QI G H,et al.Intestinal health and its nutritional modulation measures of poultry[J].Chinese Journal of Animal Nutrition,2019,31(6):2479-2486.(in Chinese)
[69]	WANG X Y,LIU Y L,LI S,et al.Asparagine attenuates intestinal injury,improves energy status and inhibits AMP-activated protein kinase signalling pathways in weaned piglets challenged with Escherichia coli lipopolysaccharide[J].Br J Nutr,2015,114(4):553-565.
[70]	XU X,WANG X Y,WU H T,et al.Glycine relieves intestinal injury by maintaining mTOR signaling and suppressing AMPK,TLR4,and NOD signaling in weaned piglets after Lipopolysaccharide challenge[J].Int J Mol Sci,2018,19(7):1980.
[71]	黄牛,李欢,何流琴,等.谷氨酰胺干预断奶仔猪肠道黏膜受损中免疫能力的作用[J].畜牧兽医学报,2017,48(4):752-760.HUANG N,LI H,HE L Q,et al.The effects of glutamine on the immunity in the intestinal mucosa of weaned piglets with lipopolysaccharide challenge[J].Acta Veterinaria et Zootechnica Sinica,2017,48(4):752-760.(in Chinese)
[72]	CHANG Y L,CAI H Y,LIU G H,et al.Effects of dietary leucine supplementation on the gene expression of mammalian target of rapamycin signaling pathway and intestinal development of broilers[J].Anim Nutr,2015,1(4):313-319.
[73]	ZHANG B B,LV Z P,LI Z,et al.Dietary L-arginine supplementation alleviates the intestinal injury and modulates the gut microbiota in broiler chickens challenged by Clostridium perfringens[J].Front Microbiol,2018,9:1716.
[74]	YUE Y S,GUO Y M,YANG Y.Effects of dietary L-tryptophan supplementation on intestinal response to chronic unpredictable stress in broilers[J].Amino Acids,2017,49(7):1227-1236.