在现代化养殖中，炎症性肠病(inflammatory bowel disease, IBD)可能导致肠道损伤和功能障碍，从而对动物的生长发育产生危害[1]。它的病因仍不明确，但相关研究表明，饮食结构不当[2]与饲料污染[3]等复杂因素的相互作用会促进IBD的发生与发展。越来越多的研究表明，氨基酸在维持肠道健康方面发挥着重要的作用，主要通过调节肠上皮细胞生理活动、改善肠道物理屏障功能、缓解肠道氧化损伤等进而缓解IBD[4-5]。本文对氨基酸在IBD的保护作用及相关信号通路做进一步阐述，为氨基酸在动物生产中的合理使用提供理论依据。
1 IBD的基本特征IBD是一种慢性、复发性肠道炎症反应，包括溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(Crohn’s disease, CD)，可影响整个胃肠道和黏膜层，导致肠道损伤和功能障碍，严重影响畜牧业发展[6]。目前，IBD的确切病因仍不清楚，但相关报道表明，其可能与遗传[7-8]、环境[9]等多种因素相关。在脂多糖(lipopolysaccharides, LPS)、葡聚糖硫酸钠(dextran sulfate sodium, DSS)、三硝基苯磺酸(trinitrobenzene sulfonic acid, TNBS)等建立的IBD模型中，主要表现为肠上皮细胞更替失衡、肠道物理屏障功能障碍、肠道氧化损伤、肠黏膜炎症反应和抗菌肽表达水平降低[10-11]。目前，免疫抑制剂及抗炎药物用于缓解IBD，可以缩短疾病的持续时间，但这些治疗方法长期使用均有较大副作用[6]。因此，需要新的辅助疗法来克服当前药理学治疗的局限性。
2 氨基酸在IBD中的作用及其信号通路近年来，越来越多的证据表明，氨基酸是维持肠道形态和功能的重要营养素，并在预防和治疗IBD方面扮演重要角色[12]，多种信号通路如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)等与氨基酸对肠道的保护作用密切相关[13-14]。
2.1 调控肠上皮细胞生理活动肠黏膜上皮是由不断分化和增殖的肠上皮细胞组成的单细胞层，是机体抵御外界环境的第一道防线，其结构稳态依赖于细胞增殖和凋亡的严格调控[15]。但是，炎症可能会导致肠黏膜能量缺乏进而造成肠道损伤和功能障碍，在IBD患者的肠黏膜中发现，正常的肠上皮细胞更替被扰乱[16]。因此，肠上皮细胞凋亡增加和增殖减少被认为是肠黏膜损伤的主要机制[17-18]。总之，维持肠上皮细胞正常生理活动对提高营养物质吸收效率和维持免疫调节功能至关重要。同时，大量研究表明，氨基酸在调节肠上皮细胞的生理活动中起重要作用。
研究发现，谷氨酸(glutamate, Glu)[19]、谷氨酰胺(glutamine, Gln)[20]、天冬氨酸(asparate, Asp)[21]通过线粒体氧化为哺乳动物肠上皮细胞提供能量，调节AMPK、mTOR通路活性促进肠上皮细胞增殖，对维持肠黏膜完整性起到重要作用。同时，亮氨酸(leucine, Leu)通过调节mTOR/沉默信息调节因子4(silent information regulator 4, SIRT4)通路为肠道中Glu的合成提供氨基，直接为营养物质的转运和细胞内蛋白质的转化提供能量[22]从而促进肠道发育，并可能通过调节仔猪空肠上皮细胞(porcine intestinal epithelial cell line-J2, IPEC-J2)增殖、凋亡、代谢和吞噬作用影响肠道屏障功能[23]。精氨酸(arginine, Arg)是一种条件性必需氨基酸，在细胞生理活动中扮演着关键角色[15]。研究表明，Arg能保护细胞免受LPS诱导的氧化损伤引起的凋亡[15]。同样，Arg能增加IPEC-J2活力，并促进细胞周期进入S期，加快细胞分裂进程[24]。细胞迁移对治疗CD、坏死性结肠炎(necrotic enteritis, NE)等多种疾病具有积极作用。膳食N-乙酰半胱氨酸(N-acetylcysteine, Nac)可以调节肠道伤口愈合过程，体外试验表明，Nac显著促进IPEC-J2增殖、迁移，缓解LPS引起的肠道损伤[25]。氨基酸在细胞生长、凋亡、迁移中发挥的重要作用也可能与MAPKs级联信号通路途径密切相关[26]。膳食天冬酰胺(asparagine, Asn)通过调节p38 MAPK、ERK磷酸化水平进而抑制LPS诱导的仔猪肠上皮细胞凋亡[27]。以IPEC-J1为实验模型，Wang等[28]发现，添加甘氨酸(glycine, Gly)能显著抑制氧化应激引起的IPEC-1凋亡，并抑制MAPK家族ERK、JNK、p38 MAPK的激活。由此可见，氨基酸对肠道上皮细胞的保护作用可能与AMPK、mTOR、MAPKs等多种信号通路途径密切相关。
2.2 维持肠道物理屏障功能肠道上皮由单层细胞排列组成，并与细胞间的紧密连接构成肠道物理屏障，可吸收营养物质，并在防止病原微生物从肠腔转移到体循环中起关键作用[29]。跨膜蛋白闭合蛋白(occludins)、封闭蛋白(claudins)与膜周蛋白胞浆蛋白(zonula occludens, ZOs)是紧密连接的重要组成部分[29-30]。肠上皮屏障功能障碍会导致细菌、毒素等有害物质侵入，这被认为是IBD的主要发病机制[29]。
研究发现，苏氨酸(threonine, Thr)[31]、色氨酸(tryptophan, Trp)[32]、牛磺酸(taurine, Tau)[33]均能调节紧密连接蛋白表达，改善LPS引起的肠道屏障功能障碍。然而，Ji等[34]发现，日粮中Thr水平不足或过量会对肉鸡肠黏膜的完整性和屏障功能造成不利影响，其中，添加125%NRC(nutrient requirements of poultry, 1994)水平的Thr更利于提高肉鸡的免疫力及肠道健康水平。Chen等[35]发现，膳食蛋氨酸(methionine, Met)显著促进仔猪空肠中occludin表达，并显著提高细胞单层跨膜电阻(TEER)，这表明，Met具有维持断奶仔猪小肠黏膜完整性和屏障功能的作用。同样，以IPEC-1为模型，生理浓度的Gly通过调节肠上皮细胞中claudin-7和ZO-3的表达和分布维持肠黏膜屏障功能[36]。膳食Glu[12]、Nac[13]显著提高仔猪小肠黏膜内claudin-1蛋白表达，同时激活mTOR蛋白磷酸化进而缓解LPS引起的断奶仔猪肠道损伤。口服脯氨酸(proline, Pro)可以改善早期断奶仔猪的黏膜增殖、肠道形态和紧密连接蛋白表达[37]。以上体内、体外研究共同提示，氨基酸对应激损伤后的肠上皮恢复和屏障功能具有重要意义。促肾上腺皮质激素释放因子(corticotrophin-releasing factor，CRF)/ CRF受体(CRFR)信号通路对应激性肠黏膜改变具有重要作用[38]。研究表明，膳食Asn抑制CRF/CRFR信号通路激活，从而减轻LPS对断奶仔猪肠道屏障功能的损害[38]。完整的肠上皮屏障对于肠道发挥正常的生理功能和机体对于疾病的预防至关重要[29]，以上研究表明，膳食氨基酸可为维持肠道完整性提供有效的营养策略。
2.3 缓解氧化应激损伤IBD与导致氧化应激的活性氧(reactive oxygen species, ROS)的过量产生、抗氧化酶的活性显著降低有关，氧化应激不仅会损伤肠道屏障也与IBD发生密切相关[39]。因此，抑制氧化应激是缓解IBD的有效策略之一[5]。
研究表明，Glu[26]、苯丙氨酸(phenylalanine, Phe)[40]均能通过激活核因子-E2相关因子2 (nuclear factor E2-related factor 2, Nrf2)信号通路，调节肠道内抗氧化酶活性，进而减轻肠道氧化损伤。谷胱甘肽(glutathione, GSH)作为一种内源性抗氧化清除剂，通过对ROS的防御，维持细胞氧化还原状态来保护细胞免受氧化应激[28]。Gln[41]、半胱氨酸(cystine, Cys)[5]、Nac[13]、丝氨酸(serine, Ser)[42]、Gly[28]在肠道内快速代谢参与GSH合成，主要通过与自由基反应和与ROS相互作用，进而调节肠道氧化还原状态，从而缓解LPS诱导的肠道氧化损伤。然而，有研究发现，Met能通过促进ROS的产生，造成线粒体DNA(mitochondrial DNA, mtDNA)氧化损伤[43]。Liu等[39]进一步报道，在DSS诱导的鼠结肠炎模型中，限制Met的摄入可以降低ROS的产生，减缓炎症反应过程，最终控制结肠炎的进程。综上，利用氨基酸的抗氧化功能来防止氧化应激的发生为防治IBD提供了另一个思路。
2.4 调节炎性介质与细胞因子表达IBD的发生与机体内的细胞因子应答息息相关，一旦机体内促炎因子与抗炎因子水平失衡，那么就会诱发IBD[44]。由免疫细胞分泌的细胞因子在炎症反应中起重要作用，一般而言，肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、白细胞介素-6(interleukin, IL-6)、IL-8、IL-1β等刺激炎症发生[11]，而IL-4、转化生长因子-β(transforming growth factor-β, TGF-β)等具有显著抗炎作用[45]。此外，已有研究证明, 促炎细胞因子会损害肠道紧密连接，导致肠道通透性增加，并引起肠上皮细胞凋亡[27]。同样，诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)、一氧化氮(nitric oxide, NO)、环氧化酶-2(cyclooxygenase-2, COX-2)是炎症发生的重要介质，在肠道黏膜炎症中表达明显升高[46-47]。因此，维持机体细胞因子动态平衡及调节炎症介质表达对治疗IBD至关重要[44]。
Liu等[48]发现，LPS提高了鸡胚肠内促炎细胞因子水平, 并显著促进MAPKs、NF-κB磷酸化，同时降低mTOR磷酸化水平进而促进炎症反应，但添加40 mmol·L-1 Leu逆转了这些变化。然而，Ravindran等[7]报道，饲喂2%蛋白质日粮或缺乏Leu日粮以一般性调控阻遏蛋白激酶2(general control nonderepressible 2, GCN2)以依赖性方式抑制炎症小体激活，进而抑制DSS诱导的结肠炎，以上研究提示，适宜浓度的Leu可对肠道炎症反应产生抑制作用。有研究发现，饲粮中添加0.63%以上含硫氨基酸(Met、Cys)能降低仔猪空肠黏膜内TNF-α、TGF-β和IL-1β表达[49]，表明饲粮中适当添加含硫氨基酸可缓解断奶仔猪空肠炎症。膳食组氨酸(histine, His)可通过抑制巨噬细胞产生的促炎细胞因子来改善IL-10缺乏细胞转移模型中的小鼠结肠炎症[50]。并且丙氨酸(alanine, Ala)、Thr能抑制TNF-α诱导的人结肠癌细胞(Caco-2 cells、HT-29 cells)内IL-8表达[51]。Arg作为iNOS和NO的底物，其对肠道的保护作用与降低iNOS和促炎细胞因子表达水平，促进NO产生密切相关[52-54]。同样，在iNOS基因表达缺失的C57BL/6鼠模型中，Arg的抗炎作用被消除，提示iNOS和NO在减轻肠道损伤中发挥重要作用[47]。
先天免疫系统对病原体的识别依赖于特异性受体的检测，其中，TLRs和NODs作为炎症信号通路的重要蛋白家族，受到广泛关注。TLRs和NODs与它们的特定病原相关分子相互作用将细胞外信号激活，传递到细胞内，引起NF-κB的释放和核转位与MAPKs通路活化，并启动下游炎症基因转录，进而诱导宿主体内发生炎症反应[52, 55]。NF-κB是由p65和p50组成的异源二聚体转录因子家族，可调节与免疫应答、炎症过程、细胞凋亡发生相关的基因表达[52]。LPS通过与细胞膜上TLR4受体结合，激活细胞内的炎症信号通路，从而引起IBD的发生，而补充Arg可阻断LPS与TLR4受体结合，抑制下游NF-κB和MAPKs信号通路激活进而缓解IBD[11]。Jiang等[26]首次证明，预处理Glu可抑制NF-κB和p38 MAPK活性，同时降低LPS诱导的TNF-α、IL-1β、IL-6、COX-2表达水平，减轻LPS造成的鱼肠道炎症反应。在LPS诱导的断奶仔猪IBD模型中，Asn与Asp介导细胞内炎症信号转导通路TLR4、NODs/NF-κB、MAPKs，进一步抑制促炎细胞因子产生，阻断IBD的发生[4, 27]。同样，在LPS诱导的断奶仔猪IBD模型中，膳食Cys抑制NF-κB核易位，显著降低结肠、空肠中TNF-α、IL-1β、IL-6浓度[5]。
钙离子敏感受体(calcium-sensing receptor, CaSR)是G蛋白偶联受体(G-protein coupled receptor, GPCR)家族的成员，是参与细胞内信号转导的次级信号分子，在维持和恢复肠道稳态中起着关键作用[56]。然而，肠道上皮CaSR缺失可损坏肠屏障功能，改变肠道微生物群组成，促进肠道发生炎性免疫反应[56]，这表明，CaSR可能成为一种潜在的IBD治疗靶点。研究发现，芳香族氨基酸(aromatic amino acids)(Trp、Phe、酪氨酸(tyrosine, Tyr)和γ-谷氨酰二肽(γ-glutamyl dipeptide)通过与细胞膜上CaSR受体结合，阻断炎症信号MAPK、NF-κB转导，调控炎性细胞因子的表达，从而发挥抗炎作用[45, 51, 57]。因此，膳食氨基酸和肽可能通过与细胞膜受体相互作用或被转运到细胞后，调节细胞信号转导和炎性基因表达，发挥其有益作用。
2.5 诱导内源抗菌肽表达抗菌肽(包括β-防御素)是肠道先天免疫系统的重要组成部分，它能增强肠道屏障功能，保护肠道免受外来病原体的侵袭，有可能提高动物生长性能和营养物质消化率[58-59]。肠道中的β-防御素水平降低或功能障碍可能引起体内平衡紊乱，从而导致肠道疾病，例如CD和UC[60]。在DSS诱导的小鼠结肠炎模型中，Han等[59]发现，在饲粮中添加猪β-防御素2(porcine beta defensin-2, pBD-2)可降低炎症介质iNOS、COX-2等的产生，提高紧密连接蛋白、黏蛋白转录水平，进而减轻炎症反应，改善黏膜病变。这表明，抗菌肽具有缓解IBD的潜力[59]，通过营养物质提高内源抗菌肽的表达水平或将成为防治IBD的策略之一[11]。
大量研究发现，多种氨基酸具有调控内源抗菌肽表达、增强机体先天免疫的能力。Lan等[11]发现，Arg具有通过激活mTOR途径刺激IPEC-J2表达β-防御素的能力。此外，过表达pBD-1基因后，IPEC-J2中由LPS刺激的TNF-α水平显著降低。这表明，Arg可能通过诱导体内防御素表达进而缓解LPS诱导的IBD。血管紧张素转换酶2(angiotensin-converting enzyme2, ACE2)是肾素-血管紧张素系统的重要酶，在氨基酸平衡、先天免疫反应和肠道菌群中起重要作用[61]。Hashimoto等[61]发现，在小鼠结肠炎模型中，ACE2基因缺失和变异小鼠肠道对Trp的摄取下降，导致小鼠对IBD高度敏感。相反，添加Trp或其代谢物可改善IBD[61-62]。这种作用的潜在机制是膳食Trp通过mTOR途径调节抗菌肽的表达，从而调节肠道菌群的组成[61]。饲粮中补充Gln促进ATF4基因表达缺失的C57BL/6鼠的回肠上皮细胞中抗菌肽表达，缓解DSS诱导的结肠炎症[8]。同样，DL-Met也被证明具有调节肠道抗菌肽表达的能力，增强先天免疫，减轻肠道炎症反应，其抗炎作用与抑制NF-κB途径、激活mTOR通路调节抗炎与促炎细胞因子密切相关[63]。Ren等[64]在体内、体外试验中发现，支链氨基酸包括Leu、缬氨酸(valine, Val)、异亮氨酸(isoleucine, Ile)，能显著诱导β-防御素表达，并增强肠道免疫功能，其中Ile的促进效果最显著。此外，Ren等[65]也证明，Ile调节断奶仔猪空肠、回肠内β-防御素的表达，能够同时抑制血浆内毒素和升高IL-6水平来减轻大肠杆菌感染。然而，高浓度支链氨基酸通过激活mTOR、NF-κB信号通路，促进ROS、促炎细胞因子产生，最终导致氧化应激、炎症反应的发生[66]。以上研究提示，饲粮中添加适当浓度的支链氨基酸能增强肠道免疫功能，维持肠道健康。目前，部分氨基酸已被证明通过调控内源抗菌肽的表达来缓解炎症反应。未来还需要进一步研究其它氨基酸是否具有调节抗菌肽表达的能力，及其与防治IBD相关的潜在途径和靶标。图 1概述了氨基酸在IBD中的作用及其信号通路。
3 氨基酸在畜禽生产中维持肠道健康的作用与应用
肠道健康对畜禽的整体健康状况和营养利用具有重要意义，其功能包括营养物质的消化和吸收、黏液和免疫球蛋白的分泌、对有害抗原和病原体的选择性屏障保护等[68]。但在集约化养殖中，若饲养管理不当如饲喂发霉变质的饲料[3]或营养不良[61]可能诱发IBD，导致动物腹痛、腹泻、体重损失等，严重影响畜牧业发展。氨基酸是畜禽的主要营养物质，更是维持肠黏膜质量和完整性的必需物质，在调控畜禽肠道健康中扮演重要角色[68]。近年来，在畜禽模型上发现，膳食氨基酸有益于肠道发育，具有防治IBD的潜力。表 1显示了近五年来一些重要氨基酸对改善畜禽IBD及维持肠道健康和功能的研究，提示饲粮中添加适当剂量的氨基酸可以改善肠道屏障功能，提高肠道免疫力，缓解应激引起的肠道损伤，从而维持肠道健康，提高畜禽生产性能。
|
表 1 膳食氨基酸在畜禽生产中的影响 Table 1 Effects of dietary amino acids on livestock and poultry production |
本文借鉴猪、鸡等动物模型及体外模型，阐述了膳食氨基酸在缓解IBD中的作用及其信号通路，然而，某些氨基酸的确切作用及潜在分子机制尚不完全清楚，如苯丙氨酸、赖氨酸、缬氨酸等，因此，为了充分发挥氨基酸在改善人类和动物健康和防治肠道疾病方面的潜力，今后还需进一步加强相关领域的研究。
| [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. DOI: 10.1016/j.jnutbio.2009.01.019 |
| [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. DOI: 10.1016/j.bbrc.2019.11.158 |
| [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. DOI: 10.3390/toxins11110663 |
| [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. DOI: 10.1177/1753425916632303 |
| [6] | KASER A, ZEISSIG S, BLUMBERG R S. Inflammatory bowel disease[J]. Annu Rev Immunol, 2010, 28: 573–621. DOI: 10.1146/annurev-immunol-030409-101225 |
| [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. DOI: 10.1038/nature17186 |
| [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. DOI: 10.1053/j.gastro.2018.11.033 |
| [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. DOI: 10.3390/nu9090920 |
| [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. DOI: 10.1021/acs.jafc.9b07611 |
| [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. DOI: 10.1007/s00726-017-2389-2 |
| [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. DOI: 10.1017/S0007114518002891 |
| [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. DOI: 10.1021/acs.jafc.8b06739 |
| [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. DOI: 10.1007/s11033-019-05090-1 |
| [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. DOI: 10.2527/jas.2015-9432 |
| [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. DOI: 10.1016/j.jnutbio.2013.12.006 |
| [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. DOI: 10.1016/j.aninu.2017.12.002 |
| [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. DOI: 10.1016/j.aninu.2018.03.006 |
| [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. DOI: 10.3390/ijms20071800 |
| [25] | LEE S I, KANG K S. N-acetylcysteine modulates lipopolysaccharide-induced intestinal dysfunction[J]. Sci Rep, 2019, 9(1): 1004. DOI: 10.1038/s41598-018-37296-x |
| [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. DOI: 10.1016/j.fsi.2017.09.035 |
| [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. DOI: 10.1177/1753425916664124 |
| [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. DOI: 10.3945/jn.114.194001 |
| [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. DOI: 10.14814/phy2.12327 |
| [30] | CITI S. Intestinal barriers protect against disease[J]. Science, 2018, 359(6380): 1097–1098. DOI: 10.1126/science.aat0835 |
| [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. DOI: 10.1017/S0007114518000740 |
| [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. DOI: 10.1039/C9FO00123A |
| [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. DOI: 10.1071/AN16249 |
| [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. DOI: 10.1111/jpn.13185 |
| [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. DOI: 10.1007/s00726-014-1675-5 |
| [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. DOI: 10.3945/jn.115.228312 |
| [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. DOI: 10.2527/jas.2014-8230 |
| [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. DOI: 10.1177/1753425917721631 |
| [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. DOI: 10.18632/oncotarget.17812 |
| [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. DOI: 10.1016/j.fsi.2015.05.001 |
| [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. DOI: 10.1093/jn/nxx062 |
| [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. DOI: 10.1016/j.jff.2017.10.026 |
| [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. DOI: 10.1007/s00726-017-2494-2 |
| [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. DOI: 10.1159/000500721 |
| [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. DOI: 10.1038/nri3112 |
| [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. DOI: 10.1371/journal.pone.0033546 |
| [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. DOI: 10.1017/S1751731117003342 |
| [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. DOI: 10.1016/j.livsci.2018.12.013 |
| [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. DOI: 10.1053/j.gastro.2008.09.062 |
| [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. DOI: 10.1021/acs.jafc.5b03749 |
| [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. DOI: 10.1371/journal.pone.0174441 |
| [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. DOI: 10.1016/j.jff.2018.11.019 |
| [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. DOI: 10.1016/j.nutres.2018.05.007 |
| [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. DOI: 10.1038/srep12018 |
| [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. DOI: 10.1016/j.febslet.2014.05.007 |
| [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. DOI: 10.1016/j.bbadis.2014.12.023 |
| [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. DOI: 10.4049/jimmunol.1402300 |
| [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. DOI: 10.1038/nature11228 |
| [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. DOI: 10.3389/fimmu.2019.02565 |
| [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. DOI: 10.1016/j.fsi.2017.12.051 |
| [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. DOI: 10.1021/acs.jafc.6b00968 |
| [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. DOI: 10.1039/C9FO00218A |
| [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. DOI: 10.1016/j.freeradbiomed.2017.01.009 |
| [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. DOI: 10.1017/S0007114515001877 |
| [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. DOI: 10.3390/ijms19071980 |
| [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. DOI: 10.1016/j.aninu.2015.11.005 |
| [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. DOI: 10.3389/fmicb.2018.01716 |
| [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. DOI: 10.1007/s00726-017-2424-3 |