炎症性肠病(IBD)的发病机制目前仍不完全清楚，然而，在宿主-微生物相互作用的背景下，发生IBD的首要因素可能是遗传和环境[1]。肠道菌群失衡会导致肠道微生物易位、肠屏障功能受损并促进黏膜免疫系统的超活化和促炎细胞因子的产生，共同促进动物IBD的发生[2-4]。肠道微生物组是一个复杂的微生物生态系统，其与宿主共同进化出互利关系。肠道微生物群通过膳食纤维发酵、病原体防御以及维生素和必需代谢物的生物合成来参与宿主的生命活动，并通过与宿主的相互作用，参与维持宿主免疫系统的成熟和功能，从而有助于宿主的内环境稳态[5]。肠道除了与营养物质的消化和吸收功能相关之外，还通过调节宿主免疫系统使肠道对共生微生物具有耐受性，并且对致病菌有持续的控制，防止微生物过度生长和侵入肠上皮屏障[6]。当这种微妙平衡受到破坏时，可能对宿主的健康状况产生病理后果，例如微生物组成的改变引发的生态失调可导致机体发生慢性炎症[7-8]。本文将讨论IBD动物的微生物群和免疫系统之间的关系和相互作用，并探讨IBD的发生机制，以及通过现有的微生物靶向疗法(包括抗生素、益生菌、益生元、后生素和粪便微生物群移植)调控肠道微生物群来治疗并恢复体内免疫平衡的研究进展。
1 IBD动物黏膜免疫功能紊乱与肠道菌群失调微生物稳态失衡导致致病菌在肠道内定植和侵袭，增加宿主免疫应答的风险，导致IBD的发生[9]。研究表明，IBD是一种多微生物疾病，多种肠道微生物因子、异常免疫应答和肠黏膜屏障减弱都会导致宿主对共生微生物出现异常免疫反应[10]。上皮屏障在维持肠内稳态中起着关键作用，因为它位于肠腔微生物和宿主免疫系统之间，同时也是暴露于许多环境因素的第一个位点，这些环境因素可以作为疾病活动的触发因素[11]。
有研究发现，肠上皮细胞(IEC)中的TNFα-TNFR2信号传导途径通过增加肌球蛋白轻链激酶(myosin light chain kinase，MLCK)的表达，从而破坏肠道紧密连接[12]，表明促炎细胞因子可以进一步增强上皮层的“渗漏”。此外，炎症可诱导“杯状细胞耗竭”，使细胞因子IL-7分泌失调，从而导致慢性炎症[13]。Th17细胞大量存在于小肠黏膜固有层中[14]，它们保护宿主免受感染，但是其过度活化也会引起肠道自身免疫性炎症[15]。肠道微生物群对Th17的影响非常强[16]。例如，分段丝状细菌(segmented filamentous bacterium，SFB)可以诱导产生黏膜CD4+Th17细胞，从而产生白介素IL-17和IL-22[17]。Nizzoli等[18]研究发现，从克罗恩病(CD)和结肠炎的宿主中分离的IL-17分泌细胞的致病性直接依赖于干扰素-γ(IFN-γ)分泌，从IFN-γ-/-小鼠中分离的Th17细胞的致病活性降低证明了这一点。相反的是，苏金单抗(一种用于治疗皮肤病和风湿病的单克隆抗体，其通过阻断IL-17途径发挥作用)与约1%的宿主中的IBD发病相关[19-20]。这种相互矛盾的作用可能是由于IL-17似乎发挥了抗炎的保护作用，有助于抑制Th1应答并维持肠上皮细胞的上皮屏障和肠内稳态的完整性[21]。
共生微生物群(例如双歧杆菌和乳杆菌)组成的改变也可以影响肠黏膜调节性T细胞(T regulatory cell，Treg)的生成，已知共生微生物群在IBD的发病机制中起关键作用[22]，缺乏Treg的小鼠发生了自发性结肠炎的结果证明了这一点[23]。革兰阳性共生细菌在维持Treg体内平衡中起主导作用[24]，有试验证实，用革兰阳性孢子对无菌(GF)小鼠进行微生物重建，发现小鼠恢复了Treg群体水平[25]。研究证明，来自梭状芽胞杆菌定殖的小鼠IEC的培养上清液可以显著增强叉头翼状螺旋转录因子3(winged helix transcription 3，Foxp3)表达细胞的分化，表明梭状芽胞杆菌激活IEC并在结肠内产生TGF-β和其他Treg诱导分子[24]。这些数据表明，肠道微生物群的组成可以通过作用于Treg诱导轴来影响结肠稳态[26]。有研究表明，雏鸡摄入肠炎沙门菌(S.Enteritidis)后能够在转录层面启动以炎症反应为主的先天免疫反应，并在攻毒后第3天加强对炎症反应的控制，促进机体向耐受阶段转变，部分肠道共生菌在沙门菌入侵过程中增殖，通过促进苯丙素类等次生代谢产物的产生形成与宿主的共生关系以及对致病菌的抗性，从而有助于维护肠道稳态[27]。
固有淋巴样细胞(innate lymphoid cells，ILC)，特别是ILC的亚型——3型固有淋巴样细胞(group 3 innate lymphoid cell，ILC3)，对肠黏膜免疫具有双向调节作用，其分泌的白介素IL-22、IL-17在维护机体肠道免疫系统中具有重要功能，而非正常激活ILC3致使IL-22过量分泌则会加重动物肠道炎症[28]。ILC3也被认为在IBD的发病机制中发挥重要作用[29]。在克罗恩病(CD)宿主的肠道中，产生IL-17的ILC3细胞增加[29]。在动物IBD模型的肠黏膜中发现的IL-22+ILC3s缺乏引起肠黏膜屏障损伤，导致肠组织暴露于大量抗原[30]。通过ILC3产生IL-22是针对病原体(例如啮齿柠檬酸杆菌)的保护性免疫，是机体所必需的，因为缺乏ILC3或IL-22的小鼠很快死于感染[31]。在IBD宿主的炎性发展期间，单核细胞移动到肠中分化成巨噬细胞和树突状细胞(dendritic cells，DC)，并且后者表达更高水平的TLR2和TLR4，这可能有助于改变对共生体和CD40的免疫应答[32]。此外，中性粒细胞显示出重要的抗菌功能，其依赖于中性粒细胞胞外陷阱(neutrophi L extracellular traps，NETs)的形成[33]。异常NET的产生和/或清除与几种免疫疾病相关，包括溃疡性结肠炎(UC)[34]。在UC中，TNFα刺激下过度NETs形成可放大肠道中的致病信号[35]。已经有研究表明，白色念珠菌可能通过巨噬细胞中的树突状细胞相关C型凝集素-1(dendritic cell-associated C-type lectin-1，Dectin-1)[36]和嗜中性粒细胞中的TLR4相关的途径与黏膜先天免疫细胞相互作用，并通过诱导B淋巴细胞的增殖和分化，同时增加免疫球蛋白IgA分泌浆细胞数量[37]。有研究表明，从健康鸡肠道成功筛选到1株益生特性优异的益生菌株L.reuteri S5，从乳酸菌调控肉鸡肠道菌群和宿主基因表达抗病原菌感染的角度，证明了其抗S.enteritidis ATCC13076肠道感染的调控作用[38]。
2 调控肠道微生物群治疗肠道炎症流行病学调查表明，随着经济的持续增长，IBD的发病率正在迅速上升，众多学者利用高通量测序的方法研究了IBD中相关遗传易感性因素与肠道菌群之间的关系[39]。IBD被认为是宿主与微生物相互作用的结果，肠道菌群失衡可能促进炎症过程的发生和/或恶化[40]。
IBD的常规治疗主要是通过使用类固醇、硫嘌呤、生物药物(即免疫抑制剂)来抑制增强的免疫应答。用于IBD治疗的多种化合物能够预测治疗结果的变量或生物标志物，以找到给定治疗的最佳候选药物。最近的研究表明，IL-6的水平可以预测生物治疗12个月时的临床反应，从而有助于设计个性化治疗策略[41]。这些生物药物也可以通过恢复肠道微生物群的组成起作用，例如阿达木单抗能够通过使C反应蛋白(C-reactive protein，CRP)水平和肠道微生物群落结构正常化来控制炎症[42]。这些免疫抑制疗法并不总是有效的，并且有可能带来严重的副作用。因此，需要开发个性化策略，来确定不同动物应当使用的特定药物，再用该药物进行治疗[43]。基于对IBD发病机制现有的了解，旨在恢复IBD宿主肠道生态失调和免疫稳态的微生物靶向治疗似乎是有希望的治疗选择。目前，已经探索了几种疗法，其中包括抗生素治疗、益生菌和益生元的使用，以期靶向调节肠道微生物群组成[44]。
2.1 抗生素由于目前已经认识到一些细菌种类可能在IBD宿主中起作用，因此，人们开始有选择性地应用抗生素来控制肠道炎症。如使用环丙沙星、甲硝唑或利福昔明来减少致病菌的丰度[45]。用米诺环素(一种半合成的第二代四环素)治疗小鼠结肠炎，可减少促炎细胞因子产生[46]。利福昔明是一种不可吸收的抗生素，能减少结肠炎症和肠系膜淋巴结(mesenteric lymph nodes，MLN)细菌移位，显示出极好的安全性[47]，然而，它的治疗功效还没有得到验证[48]。尽管广谱抗生素的使用有一些不错的临床效果，但其严重影响肠道微生物群的组成，阻碍肠道微生物群的重建[49]。有研究证明，广谱抗生素短期治疗会影响肠道恒定自然杀伤T细胞(invariant nature killer T cell，iNKT)的功能，但在肠道没有炎症的情况下，对CD4+T细胞的功能没有影响[50]。抗生素治疗后，肠道微生物群的重建足以将结肠iNKT和CD4+T细胞转向Th1-Th17促炎表型，导致肠道炎症发生时临床状况加重[50]。
2.2 益生菌益生菌是活的微生物，能够以非药理学方法促进肠道健康，并可能调节IBD中的生态失调[51]，其使用效果主要取决于它们的代谢和代谢副产物，这些产物能够促进肠道环境中细胞组分的释放，进而激活免疫应答，这种作用的机制在很大程度上是应变依赖性的[52]。口服益生菌治疗炎症性肠病，可以有效调节炎症和肠道微生物群[53]。益生菌和树突状细胞之间的相互作用，可能影响随后抗原特异性T细胞对Th1、Th2、Th17或Treg细胞的应答[54]。乳杆菌属和双歧杆菌属的不同菌株能够显著降低促炎因子IL-6和IL-17水平[55]，通过抑制巨噬细胞和上皮细胞中的NF-κB信号通路恢复Treg/Th17平衡[56]，并控制属于肠杆菌科的致病菌的过度生长[57-58]。大肠杆菌Nissle 1917(Escherichia coli Nissle 1917，EcN)鞭毛蛋白能够诱导TLR5的强烈活化，并因此增强IL-22的产生，IL-22是介导上皮重建的细胞因子[59]，其通过Treg扩增促进肠免疫稳态[60]。此外，益生菌可通过宿主的PPARγ信号通路间接影响致病菌定殖[61]。产丁酸菌与微生物失调引发的消化道炎症等现象也相关，产丁酸菌能够利用饲料中不易消化的碳水化合物合成丁酸，通过调控肠道菌群结构、为肠道上皮细胞供能、增强肠黏膜屏障功能等维护肠道健康，发挥对动物健康的有益作用[62]。
2.3 益生元与合生元益生元是刺激益生菌生长和提高活性的不可消化的膳食化合物，能够提升代谢这些底物的共生细菌竞争优势，或通过增加由其发酵产生的有益代谢产物[4]。由于益生元对消化道酶的水解具有抗性，因此它们可以被结肠厌氧菌发酵，产生对宿主生理重要的代谢物，如短链脂肪酸(SCFA)[63-64]。据报道，高纤维饮食可防止实验性肠道炎症的发展[65]，并直接与宿主细胞相互作用，调节免疫反应[66]。高剂量的果胶降低包括IL-1β和IL-6在内的结肠促炎介质的表达[67]。口服补充2-岩藻糖基乳糖显著降低IL-10-/-小鼠结肠炎的严重程度，并降低IL-1β和IL-6的表达，增加TGF-β的表达和盲肠丙酸的浓度，同时增加共生瘤胃球菌的数量[68]。竹荪多糖(DIP)被证明在BALB/c小鼠[69]和DSS诱导的结肠炎小鼠[70]中具有恢复抗生素诱导的肠道生态失调和炎症反应的治疗潜力。在实验性DSS结肠炎中，圆叶葡萄或葡萄酒植物化学物质能够降低结肠髓过氧化物酶(myeloperoxidase，MPO)活性以及IL-1β、IL-6和TNF-α的水平[71]。在结肠炎动物中补充全麝香葡萄(FMG)或脱醇麝香葡萄酒(DMW)可降低梭菌属和阿克曼氏菌属的相对丰度，增加罗斯拜瑞氏菌属、厌氧杆菌属和粪球菌属的丰度，导致粪便中丁酸、乙酸和IgA的水平升高，表明适应性免疫系统具有强大的激活能力[72]。益生元和益生菌的组合，称为“合生元”，可以为宿主提供有益效果并提高其各成分的活力[73]。饲粮中添加益生菌和合生元可以降低妊娠-哺乳期母猪血浆促炎细胞因子含量，增强妊娠至哺乳阶段母猪体液免疫功能，改善哺乳后期母猪抗氧化能力，有利于母猪的机体健康[74]。益生菌、益生元等物质可改善犬猫肠道菌群结构及相关代谢产物含量，满足宠物不同阶段的生理需求，优化伴侣动物的营养和健康状况，为伴侣动物的健康与福利提供保障[75]。合生元对机体的效果优势更明显，但有关其具体配伍及使用还需大量的基础研究支持[75]。
2.4 后生素后生素也有称为“益生素”，或代谢产物、生物源素(biogenics)，是指由活菌代谢活动分泌(代谢产物)或细菌死亡溶解后释放的可溶性因子，能够对宿主产生有益影响。可溶性因子包括：SCFA、酶类、肽、磷壁酸、肽聚糖衍生物—胞壁肽、内源性和外源性多糖、细菌外膜蛋白、维生素、胆汁酸、缩醛磷脂以及长链脂肪酸等[76]。在大多数情况下，其来源于乳杆菌属和双歧杆菌属菌株，但也有来源于链球菌属和粪杆菌属物种[77]。共轭亚麻酸(conjugated linolenic acid，CLNA)是从植物乳杆菌ZS2058发酵过程中产生的一种不饱和脂肪酸，也是一种潜在的后生素。CLNA的异构体CLNA-1和CLNA-2能显著降低MPO和促炎细胞因子(TNF-α、IL-1β和IL-6)的水平，同时上调IL-10和核受体PPARγ的表达[78]。木聚糖丁酸酯(XylB)是释放丁酸酯的多糖衍生物。XylB治疗可以逆转实验性结肠炎中促炎因子(IL-1β、TNF-α和IL-17A)和抗炎细胞因子(IL-10)之间的失衡。此外，XylB重新平衡了肠道微生物群，并显著降低了颤杆菌属、瘤胃球菌科、丹毒梭菌属和Defluviitaleaceae菌科的相对丰度[79]。
2.5 粪便微生物群移植通过粪便微生物群移植(FMT)的肠道微生物群操作，也就是将健康供体的微生物群转移到IBD宿主体内，以治疗微生物生态失调[80-81]。目前，FMT已被证明在治疗复发性和抗生素耐药的艰难梭状芽胞杆菌感染(CDI)方面效果不错，治愈率接近90%[82]。然而，尽管在CDI中FMT有效地消除了病原体及其毒力因子，但对FMT在IBD中的治疗作用背后的机制知之甚少[83]。在急性实验性结肠炎期间施用治疗性FMT，可以直接调节先天性和适应性黏膜免疫应答，以控制肠道炎症，治疗性FMT不仅能够减少结肠炎症，降低促炎细胞因子TNF、IL-1β和IFN-γ的水平，而且还能够通过同时激活不同的免疫介导的途径来启动肠道稳态的恢复；事实上，与DSS处理的小鼠相比，FMT处理的小鼠结肠IL-10含量更高，产生IL-10的抗原提呈细胞(antigen-presenting cells，APC)、CD4+T细胞和iNKT细胞的频率更高。FMT治疗降低了DC、单核细胞和巨噬细胞向结肠T细胞呈递主要组织相容性复合体(MHC-II)依赖性细菌抗原的能力[84]。此外，在慢性实验性结肠炎背景下，治疗性FMT给药通过调节促炎基因的表达稳定地降低了结肠炎症[84]。FMT的小鼠表现出表达细胞毒性相关分子CD107a的CD4+T和CD8+T细胞比例较低，以及表达结肠MHC-II的专职APC减少[84]。Tang等[85]研究表明，给仔猪服用FMT胶囊可使受体仔猪外周血中CD4+T细胞和CD4+/CD8+比值显著升高，且FMT胶囊可提高仔猪结肠组织中IL-4和IL-10的含量，并降低TNF-α和IFN-γ的含量。一项基于小鼠模型观察肠道菌群紊乱对牛病毒性腹泻病毒(bovine viral diarrhea virus，BVDV)易感性的影响研究证实，FMT回补给菌群紊乱小鼠后，BVDV载量显著降低，十二指肠病理变化也明显改善，说明FMT回补具有抑制BVDV感染的作用[86]。还有研究证实，采用FMT对腹泻羔羊进行治疗能够有效改善羔羊腹泻症状，抑制肠道炎性反应，显著降低羔羊腹泻率[87]。更好地了解宿主对这些微生物的反应可能会有助于挖掘基于微生物组治疗结果产生的潜在的预测标志物，并应在未来的FMT试验中进一步探索[88]。
3 小结与展望IBD是由遗传易感宿主对肠道微生物群的免疫应答失调引起的。尽管IBD动物的临床异质性以及其独特的肠道微生物群特征可能降低当前治疗的功效，但在未来根据个体的微生物群模式和免疫学特征选择治疗靶点及设计个性化的有效干预策略是可以尝试的。迄今为止，IBD动物的基础治疗采用抗生素和免疫调节剂，由益生菌、益生元、后生素或粪便微生物移植作为更进一步的治疗手段。基于个体宿主的临床和微生态状态的不同，应在当前临床实践中实施，以促进稳态免疫应答，从而以更有效、以宿主为导向的方式治疗IBD动物。
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(编辑 范子娟)