2023, Vol. 50扩展功能
文章信息
- 高慧, 贾宁, 梁家兴, 刘佳, 邓智中, 杨彦玲
- GAO Hui, JIA Ning, LIANG Jiaxing, LIU Jia, DENG Zhizhong, YANG Yanling
- 肠道菌群在脊髓损伤后胃肠道炎症反应中的研究进展
- Gut microbiota in gastrointestinal inflammatory response after spinal cord injury: a review
- 微生物学通报, 2023, 50(2): 709-718
- Microbiology China, 2023, 50(2): 709-718
- DOI: 10.13344/j.microbiol.china.220493
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文章历史
- 收稿日期: 2022-05-18
- 接受日期: 2022-08-11
- 网络首发日期: 2022-09-28
脊髓损伤(spinal cord injury, SCI)是一种毁灭性的神经创伤性疾病，造成损伤平面以下运动、感觉和自主神经功能障碍，严重影响患者的身体健康及正常生活，给患者家庭和社会带来严重的危害，目前尚无有效的治疗方法[1-3]。脊髓损伤后，27%−62%的患者会出现结肠转运减少、便秘和排空协同失调等胃肠道功能障碍，可能会加重神经功能障碍[4-6]。然而，目前大量的研究集中在脊髓损伤的病理生理机制上[7]，关于脊髓损伤影响胃肠道的机制尚未完全清楚[8-9]。有研究显示，脊髓损伤后产生的炎症可以刺激机体产生免疫反应，从而影响器官的生理功能[8]。近年来，肠道菌群是研究中枢神经系统疾病的一大热点，研究发现脊髓损伤后肠道菌群的紊乱和胃肠道炎症反应密切相关[10]。因此，本文综述了肠道菌群对脊髓损伤后胃肠道炎症反应的作用机制及其对脊髓损伤的调控作用，以期为今后治疗脊髓损伤的深入研究和药物开发提供理论依据。
1 肠道菌群和微生物-肠道-大脑轴肠道菌群是一类定殖于肠道与宿主共生的微生物[11-12]，其数量与哺乳动物细胞之比约为10:1，其基因组大约是人类基因组的100倍[13-14]。肠道微生物在门水平上主要有厚壁菌门(Firmicutes)和拟杆菌门(Bacteroidetes)[15]，经过发酵产生不可消化的多糖并产生如短链脂肪酸(short chain fatty acids, SCFA)的代谢产物，其中丁酸盐是最主要的SCFA[16]。此外，肠道微生物还影响宿主生理的许多方面，包括营养代谢、抗感染及免疫系统的发育和成熟[14, 17-18]，同时还调节中枢神经系统的正常发育和疾病发病机制[19-21]。
肠-脑轴(gut-brain axis, GBA)通常是指中枢神经系统(central nervous system, CNS)和肠神经系统(enteric nervous system, ENS)之间的双向通讯，而肠道菌群在大脑和肠道之间的相互作用中发挥了重要作用，因此又提出了微生物-肠-脑(microbiota-gut-brain, MGB)轴的概念[22]，即CNS通过自主神经系统(autonomic nervous system, ANS)、下丘脑-垂体-肾上腺(hypothalamus-pituitary- adrenal, HPA)和免疫系统调节胃肠道的功能和完整性，包括肠道屏障通透性、胃肠道运动、肠道分泌活性物质和肠道菌群组成等，同时，胃肠道系统也可以通过应激反应激活、神经递质合成和血脑屏障完整性来影响大脑功能和行为[22-23]。
MGB轴使大脑能够影响肠道功能效应细胞的活动，反映了中枢神经系统和胃肠道之间的持续连接[23]。脊髓损伤后，外在神经纤维的破坏导致ENS活性改变，使得脊髓损伤患者大脑与肠道之间的神经传导通路受损，导致胃肠功能紊乱[24]。当胃肠功能发生紊乱时肠道屏障功能受损，菌群分解产生的脂质可透过肠上皮细胞进入血液循环，氧化修饰的脂质和脂蛋白充当“危险信号”，并激活巨噬细胞Toll样受体4 (Toll-like receptors 4, TLR4)和Toll样受体2 (Toll-like receptors 2, TLR2)，使小胶质细胞和星形胶质细胞活化，刺激小胶质细胞向有促炎作用的M1型巨噬细胞极化[25-26]，从而上调肿瘤坏死因子-α (tumor necrosis factor-alpha, TNF-α)、白介素1β (interleukin-1β, IL-1β)和一氧化氮合酶(inducible nitric oxide synthase, iNOS)等促炎因子的表达，从而加重全身炎症反应[3, 27]。例如，γ-氨基丁酸、血清素、多巴胺及短链脂肪酸等多种神经递质和神经调节剂的合成使微生物群与受体宿主之间的细胞内交流成为可能[28]。同时，体内大多数免疫细胞位于肠道相关淋巴组织(gut associated lymphoid tissue, GALT)内，脊髓损伤诱导的肠道菌群失调可激活肠相关淋巴组织中的黏膜免疫细胞，进而影响全身和脊髓内炎症[29]；还有研究表明，肠道微生物群或潜在的益生菌对大脑功能的许多影响依赖于迷走神经的激活[30-32]。此外，微生物-肠-脑轴的功能障碍已牵涉应激相关障碍，如抑郁、焦虑、肠易激综合征、炎性肠病及神经发育障碍等[28]。
脊髓损伤作为最常见的创伤性神经系统疾病之一，目前尚无有效的治疗方法。研究显示，在脊髓损伤人群中，胃肠道并发症通常占住院治疗的11%，是影响脊髓损伤患者生活质量的严重问题[33]。同时，在脊髓损伤人群的调查中发现，肠功能的恢复优先于运动功能的恢复[34]，因此，建立微生物-肠-脑轴和脊髓损伤之间的有效联系，对病情后续的发展具有重要意义。
2 脊髓损伤后肠道菌群的变化肠道微生物群的生长和组成取决于各种参数，包括免疫机制、饮食因素和胃肠动力等。临床资料显示[35]，脊髓损伤后会导致急慢性全身免疫紊乱、肠道运动障碍等并发症，也可引起肠道微生物群的丰度和组成发生改变及肠道细菌易位，这些变化在不同的物种之间均有体现。
例如，Kigerl等[36]研究发现，脊髓损伤小鼠与受伤前相比拟杆菌门和厌氧菌门(Anaerobic bacteria)增多，而厚壁菌门和丁酸单胞菌(Butyricimonas)减少。Doelman等[37]在尤卡坦小型猪脊髓损伤模型中描述了肠道微生物组成，发现脊髓损伤急性期变形菌门和蓝藻的丰度与对照相比减少，而拟杆菌门、厚壁菌门和螺旋体(Spirochete)种类增加。Bazzocchi等[38]对100名脊髓损伤患者中的肠道微生物群进行分析发现，脊髓损伤患者肠道微生物群中与炎症性疾病有关的肠道菌群增多，如铜绿假单胞菌(Pseudomonas aeruginosa)数量从0.5%增至3.8%；肠球菌(Enterococcus)数量从0.03%增至6.30%；乳杆菌(Lactobacillus)数量从0.2%增至2.5%；链球菌(Streptococcus)数量从0.6%增至5.4%；甲烷杆菌(Methanobacteriaceae)数量从0.002%增至0.300%；肠杆菌(Enterobacteriaceae)数量和韦氏芽孢杆菌(Verrucomicrobiaceae)数量分别从0.5%和0.4%增至8.3%和7.2%；而普雷沃氏菌(Prevotellaceae)、梭菌科(Clostridiaceae)和产生短链脂肪酸的疣微菌门(Ruminococcaceae)数量分别从12.6%、1.0%和23.6%下降至0.7%、0.6%和23.6%，这些变化可能与脊髓损伤后病变的严重程度密切相关，从而对脊髓损伤后的长期恢复产生影响。
O’Connor等[10]使用胸段脊髓损伤大鼠模型和微生物组测序研究了损伤7 d大鼠的肠道微生物区系的变化，结果发现，与对照组相比，脊髓损伤大鼠肠道内的肠乳杆菌(Lactobacillus intestinalis)、弥散性梭状芽胞杆菌(Clostridium disporicum)和乔氏双歧杆菌(Bifidobacterium choerinum)的数量显著增加，分别从41.7%、1.2%和0.961%增至43.8%、19.3%和12.5%；而糖链球菌(Clostridium saccharogumia)的数量则显著减少，从10.7%减少至1.2%。研究表明，双歧杆菌可以有效抑制肠道致病菌的生长，脊髓损伤后双歧杆菌数量的显著增加可能会促进后续的恢复[39-41]。此外，由于梭状芽孢杆菌在健康人的肠道菌群中不占主导地位，对于梭状芽孢杆菌的研究并不多，但是有研究发现，在克罗恩病等胃肠道功能障碍患者的微生物区系中，出现了梭状芽孢杆菌的增加，这与O’Connor等[10]研究结果相对应，但是目前仍不清楚梭状芽孢杆菌在此类疾病中发挥的具体作用[42]。与上述讨论的肠道菌群相反，糖链球菌在脊髓损伤后是显著减少的，而在动物体内，糖凝胶梭菌可以将植物木脂素转化为有利于人体抗癌和心血管健康的生物活性分子——肠内酯，因此，脊髓损伤后肠道糖链球菌的减少很可能对机体产生有害影响[10]。
Yu等[43]评估45名脊髓损伤患者与24名健康人肠道菌群改变，与健康个体相比，脊髓损伤患者的放线菌(Actinomycetes)、互养菌门(Synergistetes)、乳杆菌、梭状芽胞杆菌科和苏特氏菌科(Sutterella)显著富集，而拟杆菌门、蓝藻(Cyanobacteria)和变形杆菌(Proteobacteria)丰度显著降低，这可能是因为放线菌、互养菌门、乳杆菌、真细菌(Eubacterium)、梭状芽胞杆菌和苏特氏菌在维持肠道内环境稳定方面起着关键作用；同时，脊髓损伤患者肠道内变形杆菌的减少也应该被注意，变形杆菌是一含有内毒素且与炎症标志物相关的革兰氏阴性细菌，可能与脊髓损伤后的炎症反应相关[44]。另外，Jing等[45]将健康未受伤的小鼠粪便移植到脊髓损伤小鼠，发现粪菌移植治疗可以改善肠道微生物失调并调节菌群代谢物，减轻神经炎症，从而减轻神经功能障碍并改善神经再生。
综上所述，由于脊髓损伤是一种不同于原发神经损伤疾病的神经损害性疾病，肠道微生物区系与脊髓损伤之间无因果关系，但是肠道微生物区系与损伤后继发性损伤及并发症之间存在一定的相关性。研究表明[46]，肠道微生物群对宿主神经功能和发育具有相当大的调节作用，肠道微生物区系可以影响和调节免疫及中枢神经系统，从而改变宿主的情绪和行为，因此，肠道微生物群对于脊髓损伤患者免疫功能障碍的调节至关重要。
3 肠道菌群通过不同方式调控脊髓损伤后胃肠道炎症的发生发展脊髓损伤不仅能引发肠道菌群微生态失调，还能导致肠道菌群异位及胃肠道的自主神经失衡[47]，这种失衡打破了对支配胃肠道的节后神经元的稳态和控制，导致脊髓损伤后胃肠道炎症的发生，进而加重脊髓损伤后的神经炎症[36]。造成菌群失调的可能原因包括：脊髓损伤后严重的自主神经功能障碍导致的神经源性肠功能障碍[38, 48]，肠屏障功能减弱造成的肠道菌群易位[49]，以及创伤导致的营养摄入和吸收发生改变等，这些改变会减弱血脑屏障的作用，从而影响脊髓损伤后神经功能的修复(图 1)。肠道菌群主要通过以下几种方式影响脊髓损伤后胃肠道炎症的发生发展(图 2)。
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| 图 1 脊髓损伤后肠道菌群失调 Figure 1 Gut microbiota imbalance after SCI. 脊髓损伤后胃肠道的自主神经失衡(腹腔神经节)，这种失衡打破了对支配胃肠道的肠系膜神经节的稳态和控制，从而导致肠道菌群异位，同时血脑屏障的功能减弱 After SCI, there is an autonomic nervous imbalance (celiac ganglion) in the gastrointestinal tract. This imbalance disrupts homeostasis and control of the mesenteric ganglion that innervates the gastrointestinal tract, resulting in ectopia of the intestinal flora and reduced function of the blood-brain barrier. |
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| 图 2 肠道菌群调控脊髓损伤后胃肠道炎症的发生发展 Figure 2 Regulation of gut microbiota on the occurrence and development of gastrointestinal inflammation after SCI. 肠道菌群通过3种途径调控脊髓损伤后胃肠道炎症的发生发展 Gut microbiota regulates the development of gastrointestinal inflammation after spinal cord injury in three ways. |
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迷走神经可调节多种重要的机体功能，胃肠动力由副交感神经迷走神经支配，以调节与消化相关的推进、储存、碾磨和排空反射[50-51]。脊髓损伤后，微生物群可以通过迷走神经向大脑发出信号[52]。当迷走神经受抑制时，胃肠蠕动减弱，肠神经元对肠内血清素和营养素的敏感性降低，并导致肠道微生态发生改变[53]。此外，脊髓损伤后肠道微生物群产生的活性物质，如短链脂肪酸、γ-氨基丁酸、乙酰胆碱等可以在肠道通透性受损的条件下直接激活迷走神经，从而对CNS功能产生有益作用[54-55]。同时，来自肠道的迷走神经信号能以烟碱型乙酰胆碱受体α7亚基依赖性方式引发抗炎反应，而且胆囊收缩素(cholecystokinin, CCK)、胰高血糖素样肽1 (glucagon-like peptide 1, GLP-1)和5-羟色胺(5-hydroxytryptamine, 5-HT)等活性物质[51, 56]也可以通过中枢调节迷走神经元的活动。相关研究发现，口服鼠李糖乳杆菌会导致迷走神经节双侧神经元中c-Fos表达显著增加[57]，而在迷走神经切断的小鼠中却不存在这样的作用，这有力地验证了菌群紊乱导致的肠道局部感染可以激活迷走神经。
3.2 下丘脑-垂体-肾上腺HPA轴是一种有效的神经内分泌系统，可提供快速反应并保护急性应激[58]。该系统通过下丘脑分泌促肾上腺皮质激素释放因子(corticotropinreleasing factor, CRF)，刺激垂体分泌促肾上腺皮质激素(adrenocorticotropic hormone, ACTH)，从而导致皮质醇从肾上腺释放，进而影响肠道稳态以响应各种刺激[28, 59]。脊髓损伤后肠道菌群的改变可以激活HPA轴，使得皮质醇或皮质酮从肾上腺皮质释放到血液中，进而导致肠道通透性改变，使菌群分解产生的脂质等其他细胞因子进入肠壁，最终导致TLR-4等炎症因子的激活、血脑屏障(blood-brain barrier, BBB)的破坏和脑组织的损伤[58, 60]。此外，激活HPA轴后产生的活性物质与迷走神经相互作用，也会影响脊髓损伤后的神经修复[29]。更有相关研究表明，微生物的稳态也会影响HPA轴的活性[61]。与其相反的是，某些微生物释放的一些代谢物如SCFA却可以减弱HPA轴反应[62]。
3.3 肠道菌群代谢物SCFA是目前研究较为广泛的肠道菌群代谢物之一，其中丁酸、乙酸和丙酸是SCFA中的主要物质，它们是在近端结肠中由细菌发酵不可消化的碳水化合物产生[63-64]。丁酸的免疫调节特性通过抑制组蛋白去乙酰化酶(histone deacetylase, HDAC)或通过代谢物感应G蛋白偶联受体41 (G protein-coupled receptors 41, GPR41)、G蛋白偶联受体43 (G protein-coupled receptors 43, GPR43)和G蛋白偶联受体109A (G protein-coupled receptors 109A, GPR109A)的激活介导[65-66]。例如，SCFA通过抑制HDAC降低神经胶质细胞中核因子(nuclear factor, NF)-κB信号通路的活化，下调TNF-α表达[67]；而SCFA与GPR41或GPR4的结合则可以生成有抗炎作用的白介素10 (interleukin 10, IL-10)，还能使得辅助性T17 (helper T-17, Th17)细胞转化为调节性T (regulatory T, Treg)细胞，进而抑制中枢神经系统的炎症反应[57]。此外，M1型小胶质细胞能引起神经炎症，成熟的M2型小胶质细胞起抗炎作用[68]，而Erny等[69]的研究发现，无特定病原体小鼠的小胶质细胞表现出正常的发育和功能，但无菌小鼠在稳态条件下表现出发育不良的小胶质细胞，在无菌小鼠体内补充SCFA后，不成熟的小胶质细胞被SCFA补充逆转，即肠道微生物的改变会影响小胶质细胞的发育和功能。因此，SCFA发挥有益作用一是直接作用于肠细胞，维持肠道屏障的完整性；二是通过抑制组蛋白去乙酰化酶或感应G蛋白偶联受体激活间接作用，调节炎症和免疫反应从而发挥神经炎症保护作用。
4 结论与展望脊髓损伤患者的胃肠道功能障碍使炎症反应加重，因此，研究脊髓损伤后肠道微生物群的组成、变化及相关干预措施显得迫在眉睫。目前已有研究表明[35]，可以通过采用药物调整肠道菌群组成的方法而达到治疗疾病的目的。例如，Jing等[70]基于脊髓损伤小鼠模型的数据研究表明，褪黑素可以重塑肠道微生物区系，直接或间接促进脊髓损伤后运动功能的修复。此外，赵丽萍等[71]发现，鼠李糖杆菌可能通过降低肠道致病菌丰度来抑制斑马鱼脊髓损伤引起的肠道炎症，从而进一步促进斑马鱼脊髓损伤后运动功能的恢复。
还有一些研究将微生物及其代谢物作为治疗靶点，也取得了不错的效果。研究发现[36, 70]，益生菌如罗伊氏乳杆菌、乳酸杆菌和双歧杆菌可以通过产生丁酸和其他短链脂肪酸神经活性代谢物及神经递质来逆转部分脊髓损伤，并有助于运动功能的修复。然而，尽管大量研究论证了肠道菌群的稳态对于脊髓损伤的重要作用，但仍缺乏对于它们相互作用的深入理解。因此，未来的研究可能会借助新技术进一步解释脊髓损伤与肠道微生物区系相互作用的病理生理机制，梳理肠道微生物区系与宿主之间的相互作用模式，并帮助开发基于微生物区系或其代谢产物的个性化靶向细菌治疗和药物，更好地帮助脊髓损伤患者恢复。
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