炎症性肠病(IBD)是一种慢性胃肠道自身免疫性疾病，溃疡性结肠炎(UC)和克罗恩氏病(CD)是IBD的2种主要形式[1-4]。UC的发病部位局限于黏膜并持续影响直肠和结肠[5]；CD的典型特征是肠道的透壁炎症，并可能影响从口腔到肛周区域的胃肠道的任何部分[6]。近年来的研究表明，辅助性T细胞17(Th17)/调节性T细胞(Treg)平衡作为机体免疫调节网络的重要部分，可以对IBD进行免疫调节。并且由于Th17/Treg平衡与众多细胞因子和转录因子相互影响，这些细胞因子与转录因子组成的信号通路也可以间接对IBD产生调控作用。参考前人研究，本文综合阐述了Th17/Treg平衡轴的分化形成、IBD的发病机制及其对动物生产的危害性、Th17/Treg平衡的信号通路以及基于Th17/Treg平衡开发饲料添加剂治疗IBD等方面的内容，以期为Th17/Treg平衡应用于畜禽生产中IBD的预防和治疗等方面提供科学依据，同时为“替抗”添加剂的使用与开发奠定理论基础。
1 IBD概述 1.1 IBD的发病机理IBD通常由易感基因、环境和免疫系统之间复杂的一系列相互作用引起[7]。IBD的发病原因包括肠黏膜缺血及再灌注损伤、肠道菌群失衡、肠黏膜的失用性损伤和细胞因子致肠屏障损伤等[8]。遗传和环境因素都参与了疾病过程[9]。IBD的发病过程涉及先天性和适应性免疫系统功能障碍[10]，多种炎性细胞因子的过度表达，效应器T细胞反应过度和调节性T细胞功能受损[11]等，许多细胞信号通路被认为参与了IBD的过程[12]。Th17细胞有助于炎症的诱导和传播，Treg则负责维持自身耐受性，从而抑制自身免疫[13]。因此，Th17细胞和Treg细胞之间的平衡被认为是治疗自身免疫性疾病的重要靶点。在多种自身免疫性疾病的报道[14-18]中显示，Th17/Treg平衡朝着促炎的Th17一侧转移，导致自身免疫性疾病的恶化[19]，这印证了Th17/Treg平衡失衡的致病性。
1.2 IBD对动物生产的危害畜禽腹泻是养殖场最常见的疾病之一，细菌、寄生虫和营养不良等造成的长期腹泻常并发或继发IBD[20]。研究报道，10~30日龄仔猪极易罹患迟发性腹泻病，俗称仔猪白痢[21]。该病流行面广，发病率与死淘率居高不下，给养猪业带来巨大的经济损失[22]。在腹泻过程中，猪的肠道上皮生理功能发生变化，白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、白细胞介素-10(IL-10)等炎症因子水平随之发生改变，影响肠道消化吸收功能[23]。牛的IBD多发于1~2周龄犊牛，常见体温升高、下痢、粪便异常和腹痛等病征，且病犊恢复缓慢、发育迟缓，可能并发其他炎症[24]。IBD可以发生于2~24周龄的鸡，发病率高达50%，表现出各种不同程度的肠道组织病变及下痢、消瘦、体虚等症状[25]。发生坏死性肠炎(NE)时，鸡肠道黏膜发生慢性损伤，影响鸡的采食量和体重[26]。这是导致料重比升高、饲料转化率降低和粪便富营养化等问题的原因。据报道，发生严重NE的鸡群收益仅占无NE鸡群收益的67%[27]。由此可见，IBD易导致发病动物肠道损伤、腹泻和发育迟缓，病情严重还可能致死，对动物福利、经济效益及环境保护都产生不利影响，严重危害动物生产行业。
2 Th17/Treg平衡白细胞分化抗原4阳性辅助T细胞(CD4+T)在启动和维持由多种微生物病原体引发的保护机体免疫反应中起着核心作用。在微环境中不同细胞因子的影响下，幼稚CD4+T可被活化并分化为几个高度专业化的辅助细胞(Th)子集。到目前为止，一共有7种Th的亚群已被发现，分别是辅助性T细胞1(Th1)、辅助性T细胞2(Th2)、辅助性T细胞9(Th9)、辅助性T细胞22(Th22)、滤泡性辅助T细胞(Tfh)、Th17和Treg[28]。其中，Th17的谱系定义因子为维甲酸相关孤核受体γt/α(RORγt/α)，RORγt及其同种型RORγ由称为Rorg(也被称为Rorc)的单个基因编码[29]；Treg的谱系定义因子为叉头框蛋白3(Foxp3)，二者分别与信号传导与转录激活因子(STAT)3和STAT5组成“两因子”模型，分别驱动Th17和Treg的分化[30]。参与Th17发育的因子主要包括：分化因子如转化生长因子-β(TGF-β)、IL-6、白细胞介素-21(IL-21)[31]，生长和稳定因子如白细胞介素-23(IL-23)，转录因子如STAT3以及RORγt/α[32]。Th17可以通过衍生细胞因子白细胞介素-17A(IL-17A)、白细胞介素-17F(IL-17F)、IL-21和白细胞介素-22(IL-22)等刺激广泛的组织反应，从而保护机体免受细胞外细菌和真菌感染[13]。Treg根据其来源分为2个不同的子集，天然发生的调节性T细胞(nTreg)源自胸腺细胞，而外周诱导型调节性T细胞(pTreg)则来自于受TGF-β刺激的CD4+T[33]，也有学者表示pTreg的产生似乎并不需要TGF-β刺激[33]。nTreg可以对白细胞介素-2(IL-2)产生应答，并通过STAT5发出信号，促进Foxp3表达并分化为Treg，产生抗炎因子，抑制炎性反应[34-35]。nTreg可确保自我耐受的控制，目前用于临床试验中以减轻造血干细胞移植后的自身免疫性疾病和移植物抗宿主病[36]。CD4+T在体内受各种信号刺激产生外周诱导性调节性T细胞(iTreg)，该细胞由外周成熟的T淋巴细胞亚群CD4+CD25-T在特异性抗原刺激下分化而成，可分泌大量IL-10[37]，但其具体转化过程、稳定性及抑制功能目前均没有明确定义[38]。
3 介于Th17/Treg平衡调控IBD的相关信号通路目前已有大量研究表明，通过调节Th17/Treg平衡可以调控IBD，该平衡又通过其上、下游各种细胞因子和转录因子组成的信号通路形成免疫调节网络。以下介绍几种常见的信号通路，其相关性如图 1所示。
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IBD：炎症性肠病inflammatory bowel disease；IFN-γ：干扰素-γ interferon-γ；IL-1β：白细胞介素-1β interleukin-1β；IL-6R：白细胞介素-6受体interleukin-6 receptor；IRAK1/2：IL-1受体相关激酶1/2 interleukin-1 receptor-associated kinase；MyD88：髓样分化因子88 myeloid differentiation factor 88；TLR：Toll样受体Toll-like receptor；TRAF6：肿瘤坏死因子受体相关因子6 tumor necrosis factor receptor-associated factor 6；NF-κB：核因子-κB nuclear factor-κB；p50/p65：NF-κB的亚单位NF-κB subunit；TNF-α：肿瘤坏死因子-α tumor necrosis factor-α；PIP2：磷脂酰肌醇二磷酸酯phosphatidylinositol diphosphate；PIP3：磷脂酰肌醇三磷酸酯phosphatidylinositol triphosphate；PI3K：磷酸肌醇3激酶phosphoinositide 3-kinase；STAT3：信号传导及转录激活因子3 signal transducers and activators of transcription 3；RORγt：维甲酸相关核孤儿受体γt retinoic acid related nuclear orphan receptor γt；gp130：糖蛋白130 glycoprotein 130；AKT：蛋白激酶B protein kinase B；mTOR：哺乳动物雷帕霉素靶蛋白mammalian rapamycin target protein；TYK-2：酪氨酸激酶-2 tyrosine kinase-2；Th17：辅助性T细胞17 helper T cells 17。 图 1 Th17/Treg平衡相关信号通路 Fig. 1 Th17/Treg balance related signaling pathway |
IL-6是一种分子质量为21~28 ku的糖基化蛋白，包含184个氨基酸，细胞对IL-6的反应是通过由白细胞介素-6受体α(IL-6Rα)和糖蛋白130(gp130)组成的受体复合物介导的[39]。IL-6的信号传导有3种模式：1)经典信号传导。IL-6与同一细胞的膜结合受体白细胞介素-6受体(IL-6R)结合[40]。2)反式信号传导。IL-6与可溶性白细胞介素-6受体(sIL-6R)结合[41]。3)反式表达。IL-6R与相邻细胞的gp130结合[42-43]。JAK是一类重要的蛋白酪氨酸激酶，激活JAK-STAT信号通路需要2个JAK亚型作为自身磷酸化的同二聚体或异二聚体，从而允许募集和磷酸化各种信号分子，包括DNA结合蛋白的STAT家族的成员[44]。JAK家族包含4个细胞内蛋白，均为酪氨酸蛋白质激酶：JAK1[45]、JAK2、JAK3[46]和酪氨酸激酶2(TYK2)[47]，它们可以激活常见或不同类型的STAT成员(STAT1~4，STAT5a和5b，STAT6)[39]并由此启动不同的下游细胞反应[48]。STAT可以被许多肽类蛋白如生长因子和细胞因子激活，是后生细胞磷酸酪氨酸调节信号传导的重要介体之一[49]，既具有信号传导作用又具有转录作用[50]。STAT在JAK的下游传递Ⅰ/Ⅱ型细胞因子信号：Ⅰ型细胞因子受体在其细胞外氨基酸结构域中具有某些保守的基序，包括常见的γ链(γc，也称为IL-2受体γ亚基)细胞因子[如IL-2、白细胞介素-4(IL-4)和IL-21等]、gp130家族(如IL-6)、p40亚基[如白细胞介素-12(IL-12)和白细胞介素-23(IL-23)]和常见的β链细胞因子受体[如白细胞介素-3(IL-3)、白细胞介素-5(IL-5)和粒细胞-巨噬细胞集落刺激因子(GM-CSF)等)[51]；Ⅱ型细胞因子受体是IL-10和干扰素(IFN)家族的成员[52]。IL-6-JAK-STAT3信号通路即IL-6与糖蛋白130受体(gp130R)的连接导致酪氨酸磷酸化，以及gp130R相关的JAK和胞质STAT3转录因子的活化[53]，然后磷酸化的STAT3二聚体转运到细胞核，进而调节基因转录，最终参与炎症反应的过程[54]。STAT3被IL-6R/gp130激活时发挥促炎作用，被白细胞介素-10受体(IL-10R)激活时发挥抗炎作用[55]。
3.2 Toll样受体(TLR)4-髓样分化因子88(MyD88)-核因子-κB(NF-κB)信号通路TLR是一个Ⅰ型跨膜受体超家族[56]，在针对病原微生物或组织损伤的先天免疫应答中起重要作用。目前，在人体中发现约有10个功能性TLR(TLR1~10)，在小鼠中约有12个(TLR1~9，TLR11~13)[57]。除炎性细胞因子[如TNF-α和白细胞介素-1(IL-1)]之外，革兰氏阴性细菌的外膜中的脂多糖(LPS)，革兰氏阳性细菌细胞壁中的脂蛋白酸和肽聚糖，细菌鞭毛蛋白以及病毒等的单链或双链RNA均可激活TLR[57]。TLR被刺激后，激活细胞内级联反应，然后将刺激信号传递到与MyD88偶联的下级信号蛋白NF-κB[58]。NF-κB是一种可诱导的转录因子，在免疫反应、炎症反应、细胞分化以及正常和恶性细胞的存活中起着核心作用[59]。被激活的NF-κB可参与多种靶基因的转录调控，导致各种炎性因子及抗菌肽的释放[60]，如使效应细胞分泌TNF-α、干扰素-γ(IFN-γ)、IL-1β、IL-6等促炎因子[61]，造成肠道组织损伤和IBD[56, 62]。此外，Th17、Treg的分化也受NF-κB的调控。NF-κB包含Rel转录因子家族的5种蛋白质的二聚体：p105/p50、p100/p52、RelA(p65)、RelB和与v-Rel癌基因共享N端同源性的c-Rel[63]。在没有刺激的情况下，这些亚基的异二聚体被核因子-κB抑制蛋白(IκB)保留在细胞质中[64]。受到细胞外刺激时，p65/c-Rel与p50组成的异二聚体或者RelB与p52组成的异二聚体的激活可以激活NF-κB信号通路[65]，p50和p52的二聚体为转录抑制剂[66]。c-Rel缺陷型CD4+T内iTreg生成受到严重阻碍，并且与体内Foxp3+T细胞数量减少相关[67]。c-Rel在高表达CC类趋化因子受体7(CCR7)的胸腺调节性T前体细胞(pre-tTreg)中高度激活，启动Treg相关编码基因的转录，促进pre-tTreg分化为胸腺调节性T细胞(tTreg)[68]。NF-κB c-Rel的消融能够特异性地损害活化的调节性T细胞(aTreg)的生成和维持[69]。此外，c-Rel和p65可以通过促进Foxp3特异性增强体的形成来驱动Treg的发育[70]。由于Rorg/Rorc是Th17细胞中转录因子p65的直接靶标，因此当c-Rel或p65缺乏时，RORγt mRNA表达量降低，CD4+T向Th17分化减弱，且Th17的IL-17A/IL-17F表达量降低[29]。
3.3 哺乳动物雷帕霉素靶蛋白(mTOR)信号通路跨膜的受体酪氨酸激酶在几种生长因子或细胞因子的刺激下被激活，而后与磷酸肌醇3激酶(PI3K)结合，激活PI3K-蛋白激酶B(AKT)-mTOR信号通路。PI3K是一种脂质激酶，可将磷脂酰肌醇二磷酸酯(PIP2)磷酸化为磷脂酰肌醇三磷酸酯(PIP3)，抑癌基因PTEN为其抑制基因[71]。产生的PIP3通过PIP3和普列克同源(PH)结构域之间的特异性相互作用，将包含PH结构域的信号蛋白(如AKT)募集到质膜上[72]，活化的AKT通过直接磷酸化mTOR或磷酸化mTOR的负调控因子来刺激mTOR复合物，进而控制蛋白质翻译和细胞生长[73]。mTOR的哺乳动物靶标是丝氨酸-苏氨酸激酶，其活性受各种细胞外和细胞内因素(例如氨基酸、能量和激素)的调节，可以改变翻译、转录、蛋白质合成和降解[74]，细胞信号传导，新陈代谢[75]以及细胞骨架动力学的速度[76]。PI3K-AKT-mTOR信号通路可以调控细胞的新陈代谢、增殖、分化和生存等生命过程[77]。越来越多证据表明，PI3K-AKT-mTOR信号通路在炎症反应发生的发展过程中起重要作用，是促炎关键因素，且对TNF-α、血管内皮生长因子(VEGF)、IL-1β、IL-6以及IL-12p40等细胞因子的释放具有调节和保持其稳定性的作用[78]，既可修复肠黏膜损伤，还可以维持肠上皮细胞正常代谢。此通路在肿瘤[71]、白血病[79]、血管及皮肤过度生长综合征[77]等多种情况下都存在异常表达，与IBD在机体中的长期存在导致的胃肠道恶性肿瘤密切相关。
在效应CD4+T中，mTOR促进Th1、Th2和Th17分化，尤其对于Th17的体外和体内分化至关重要，缺乏mTOR的T细胞无法分化为Th17[80]。在细胞培养试验中，微小核糖核酸(miRNA)可调节mTOR信号传导，通过分别释放抗炎或促炎因子以诱导或抑制肠道细胞自噬[81]。雷帕霉素(RAPA)可能通过限制必需氨基酸(EAA)抑制mTOR诱导Foxp3表达并促进从幼稚CD4+T生成Treg[82]。由此可见，PI3K-AKT-mTOR与Th17/Treg平衡密切相关，并且该信号通路可以经由Th17/Treg平衡调控IBD。
4 基于Th17/Treg平衡开发饲料添加剂或药物调控IBD寻找绿色环保型饲料添加剂替代抗生素一直是动物营养领域的研究热点和畜牧行业的迫切需求。尤其是2020年全面“禁抗”政策出台以来，这种需求变得尤为关切。研究表明，幽门螺杆菌定植可通过调节Th17/Treg平衡来预防慢性试验性结肠炎[83]；芦荟多糖按体重15 mg/kg结肠灌注可以显著抑制大鼠结肠中RORγt的表达及STAT3的磷酸化，从而抑制Th17生成，促进Treg分化[84]；IL-33治疗既可以增加葡聚糖硫酸钠(DSS)诱发的慢性结肠炎小鼠中的Treg的反应，又可以降低Th17的反应[85]，缓解肠道损伤。大豆衍生的二肽和三肽可以抑制DSS诱导的猪结肠IL-1β、TNF、RORc和IL-17A以及Foxp3+T调节转录因子表达的上调，提示大豆衍生肽可以通过Th17/Treg平衡在体内发挥抗炎活性[86]。由此可见，Th17/Treg平衡的失衡可以加重或缓解动物IBD的症状。进一步研究发现，Th17/Treg平衡对IBD的这种调控作用与许多信号通路密切相关。研究表明，姜黄素可以通过IL-6-STAT3信号通路调控Th17/Treg平衡治疗小鼠的UC[87]。饲粮添加0.2%和0.4%的色氨酸可以抑制乙酸诱导的断奶仔猪结肠组织STAT3的磷酸化、p65蛋白表达的上调和白细胞介素-1α(IL-1α)、IL-1β、TNF-α、IL-6、TLR4 mRNA表达的上调[88]，降低仔猪结肠IFN-γ、IL-12 p40、IL-17A的mRNA表达[89]，提示色氨酸可能通过IL-6-JAK-STAT3和TLR4-NF-κB 2种信号通路的联合作用参与Th17/Treg平衡对IBD的调控。腹腔注射抗菌肽CWA可以降低断奶仔猪空肠组织TNF-α、IL-6、TLR4、NF-κB的mRNA表达和NF-κB、IκB-α的磷酸化水平，并促进IL-10的mRNA表达，提示抗菌肽CWA可能通过下调TLR4-MyD88-NF-κB信号通路缓解仔猪IBD[90]。巩栋梁[91]通过建立热应激猪的IBD模型证明，热应激通过激活肠道组织中TLR4-NF-κB信号通路，上调炎性因子IL-6、IL-8和IL-17的表达，证明TLR4-NF-κB信号通路的激活可以促进Th17/Treg平衡向Th17一侧偏移，添加TLR4特异性抑制剂可以缓解猪的IBD。雷公藤根提取物可以通过抑制IL-10缺乏小鼠结肠组织中的PI3K-AKT-mTOR信号通路来增强自噬，从而限制结肠炎症[92]。孟宪邑[78]的研究表明，娃儿藤碱类化合物W-8对AKT/mTOR信号通路中AKT的磷酸化及其下游底物mTOR的活性有明显的抑制作用，提示W-8可能通过对AKT/mTOR信号的阻断间接上调了Foxp3基因表达的关键蛋白Smad3的磷酸化水平，并最终增强了Treg的分化。Xu等[93]的试验证明，饲粮补充甘氨酸能够降低LPS诱导的空肠TLR4、MyD88和NF-κB mRNA的表达和TNF-α、IL-1β和IL-6的过量产生，这说明甘氨酸可以通过抑制炎症信号通路TLR4-NF-κB的活化来缓解IBD，并且可能通过抑制促炎因子的产生而抑制了Th17的分化和表达。Yi等[94]的试验证明，饲粮补充N-乙酰半胱氨酸(NAC)能够提高仔猪空肠mTOR mRNA的表达，并减弱LPS诱导的PI3K和AKT磷酸化水平的相对降低，提示NAC可以通过PI3K-AKT-mTOR信号通路改善肠道细胞蛋白的合成[95]，改善肠道的完整性。综上所述，目前已知大量的饲料添加剂或药物可以有效缓解动物IBD，其作用机制可能是：Th17/Treg平衡相关的IL-6-JAK-STAT3、TLR4-MyD88-NF-κB、PI3K-AKT-mTOR等信号通路受外界刺激发生活化，进一步影响Th17或Treg的分化及其相关炎性细胞因子的表达，最终加重或缓解IBD。因此，我们可以开发各类绿色、无公害的饲料添加剂或药物，借助这种免疫调节手段治疗畜禽IBD，最终达到替代抗生素的效果。
5 小结与展望IBD作为畜禽生产中最为常见的疾病之一，不仅危害动物健康、降低动物福利、损害养殖业者的经济利益，还对环境保护工作造成巨大的压力。Th17/Treg平衡作为重要的免疫调控途径，受IL-6-JAK-STAT3、TLR4-MyD88-NF-κB、PI3K-AKT-mTOR等信号通路影响和调节，与众多免疫细胞因子相关联，可以对动物IBD产生二重性的调控作用。2020年7月起，我国饲料全面“禁抗”令开始正式实施，寻找和开发有效的“替抗”饲料添加剂和药物已成迫在眉睫。因此，基于Th17/Treg平衡及其相关信号通路开发饲料添加剂或药物对于治疗IBD在抗生素替代方面具有重要意义。然而，目前用Th17/Treg平衡调控反刍动物、水产动物、禽类及除猪以外其他单胃动物IBD的研究仍然较为少见，并且已知可以产生调控作用的添加剂和药品在其具体作用机制、动物应用安全性等方面仍有待进一步研究。因此，从这些方面出发而展开的研究将为今后Th17/Treg平衡更好地应用于动物生产提供科学依据。
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