生命科学   2017, Vol. 29 Issue (7): 669-681.  DOI: 10.13376/j.cbls/2017091.
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专刊:人体微生物组研究

引用本文 [复制中英文]

潘俊希, 谢鹏. 神经精神疾病微生物组研究现状和展望. 生命科学, 2017, 29(7): 669-681. DOI: 10.13376/j.cbls/2017091.
[复制中文]
PAN Jun-Xi, XIE Peng. Status and prospects of neuropsychological microbiome. Chinese Bulletin of Life Sciences, 2017, 29(7): 669-681. DOI: 10.13376/j.cbls/2017091.
[复制英文]

基金项目

国家重大科学研究计划(“973”计划)(2009CB918300)

作者简介

谢鹏,教授,归国学者,重庆医科大学副校长。国家“973”项目首席科学家,国务院学位委员会第六、七届学科评议组成员,教育部第二届全国专业学位教育指导委员会委员,卫生部突贡专家。现任中国医师协会神经内科医师分会会长,中国医师协会神经内科医师分会神经心理与情感障碍专委会主任委员,中国人类蛋白质组组织(CNHUPO)常务理事,中国生理学会神经科学专委会委员,阿德莱德大学南澳大利亚健康与医学研究所(SAHMRI)研究员,国家重点学科(神经病学)学科带头人。谢鹏教授长期致力于脑的高级认知功能和临床神经心理学研究,以及临床神经病学、脑血管疾病、中枢神经系统病毒感染性疾病和神经生化与分子生物学研究。近年来,先后主持了“863”项目、“973”项目及国家自然科学基金项目7项、省部级等各类基金项目14项。近5年以通讯作者在The LancetWorld PsychiatryMolecular PsychiatryBrain等杂志上发表SCI论文160余篇。主编和参编学术专著10余部,获得发明专利5项 。

通信作者

谢鹏,E-mail: xiepeng@cqmu.edu.cn

文章历史

收稿日期:2017-03-03
神经精神疾病微生物组研究现状和展望
潘俊希 1, 谢鹏 1,2     
(1 重庆医科大学神经科学研究中心,重庆 400016)
(2 重庆医科大学附属第一医院神经内科,重庆 400016)
摘要:人类肠道微生物组是一个数量庞大的微生物群落,它们与宿主互为影响,被认为是维持机体健康和许多疾病致病机制的重要环节。越来越多的研究认为,肠道正常菌群对于中枢神经系统的发育和情感的调控至关重要。随着微生物与大脑相互作用研究的深入,“肠-脑轴”的概念也被进一步扩展为“微生物-肠-脑轴”。目前,主要的研究集中于探究肠道微生物在健康和致病中的具体机制,如应激相关的疾病抑郁症、焦虑症等,神经退行性疾病帕金森病、阿尔兹海默症等。肠道微生物组与中枢神经系统的双向调节主要通过调节单胺类神经递质、下丘脑垂体肾上腺激活、调节神经营养因子分泌、神经免疫激活等途径来实现。微生物-肠-脑轴失衡可影响行为表型,导致神经精神疾病,因此,通过调节肠道微生物组成来治疗神经精神疾病是今后的研究热点。对神经精神疾病肠道微生物组的研究现状进行了总结,为肠道微生物组对神经心理的调控寻找更多的证据,以便能更好地理解微生物-肠-脑轴的潜在机制。
关键词肠道微生物组    微生物-肠-脑轴    神经精神疾病    
Status and prospects of neuropsychological microbiome
PAN Jun-Xi 1, XIE Peng 1,2     
(1 Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China)
(2 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China)
Abstract: The human gut microbiome is composed of an enormous number of microorganisms, which is an integral part for health and disease generally regarded as commensal bacteria. It is becoming increasingly recognized that the presence of a healthy and diverse gut microbiota is important to the development of central nervous system and emotional processing. The interconnectedness of gut microbiome and brain function has significantly contributed to establishing the microbiota-gut-brain axis as an extension of the well-accepted gut-brain axis concept. Many efforts have been focused on delineating the role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety to neurodegenerative disease such as Parkinson' s disease, Alzheimer' s disease. The bidirectional interaction between the gut microbiota and the brain occurs through various pathways including the serotonin, hypothalamus-pituitary-adrenal axis,  neurotrophin, the immune system. This axis has been shown to influence the behaviors that are often associated with neuropsychiatric conditions. Modulation of this gut microbiota as a novel therapy for neuropsychiatric conditions is gaining interest. In this review, we summarize the status of neuropsychological microbiome, which provided evidence supporting the role of gut microbiota in modulating neuropsychological functions of the central nervous system and exploring the potential underlying mechanisms.
Key words: gut microbiome    microbiota-gut-brain axis    neuropsychiatric disorder    

人体肠道栖居着一千多种微生物,其总数高达1013~1014个,细胞总数量大约是人体细胞总数量的10倍,其编码的细菌基因总数量是人体基因总数100倍,人体肠道微生物是一个庞大复杂的生态系统,它们与宿主存在着共生关系,共同维护着宿主的生理平衡[1]。近几年来,肠道微生物在机体健康和疾病中的作用越来越受到重视。研究表明,肠道微生物在机体能量摄取、物质转化、黏膜屏障、免疫成熟发育等多种重要生理功能中起重要作用,被形象地比喻为人体的一个被遗忘的“器官”[2]。从2007年美国国立卫生研究院(NIH)牵头提出人体微生物组计划,到2016年美国白宫正式启动“国家微生物组计划”,这期间产生了众多研究和成果,尤其是新一代测序技术和宏基因组研究以及生物信息学的发展,极大地推动了肠道微生物组学的研究。肠道微生物组研究发展非常快,肠道微生物组与人体的多种疾病相关联,深刻影响了疾病的治疗和临床研究,包括肥胖[3]、糖尿病[4]、肿瘤[5]、肠道疾病[6]、代谢疾病[7]、心血管疾病[8]、中枢神经系统[9]等,肠道微生物组基因被认为是人体的“第二基因库”[10]

近年来关于胃肠道和中枢神经系统的相关性的研究也越来越多,胃肠道与中枢神经系统这种复杂的双向调节被形象地称之为“肠-脑轴”,这是一个综合性的生理概念,整合了中枢神经系统和胃肠道间所有神经传导、内分泌、营养和免疫学信号传输[11-13]。这个概念的核心是肠道菌群和中枢神经系统间的相互作用,因此也有研究将其命名为“微生物-肠-脑轴”[14-15],神经精神疾病肠道微生物组的研究也是围绕这一核心进行,本文将对其进行综述,以期能对该领域有更深入理解。

1 微生物-肠-脑轴的概念

微生物-肠-脑轴是一个综合性生理概念,整合了肠道微生物组、胃肠道和中枢神经系统的神经发生、神经传导、内分泌、营养、炎症与免疫等生理过程的相互联系。肠道微生物组主要可能通过调节神经递质(如GABA或5-TH等)分泌、肠道微生物组直接合成某些神经活性代谢产物、影响下丘脑-垂体-肾上腺轴(hypothalamic-pituitary-adrenal axis, HPA轴)、局部或全身免疫系统的激活和浸润等方式影响中枢神经系统。反之,中枢神经系统可以调节肠道菌群的组成,例如HPA轴通过释放皮质醇调控肠道蠕动和肠道黏膜屏障的完整性,内分泌和神经通路也可以调节特定的肠道上皮细胞的分泌,包括潘氏细胞、肠内分泌细胞和杯状细胞。它们分泌的产物影响肠道微生物的生存和聚集环境,从而影响肠道微生物的组成。

2 微生物-肠-脑轴相关的行为表型

肠道微生物能通过肠-脑轴影响动物的行为,目前已有大量的动物实验通过无菌动物(germ-free, GF)移植微生物、大剂量广谱抗菌药物干预无特定病原体(specific pathogen free, SPF)动物、向动物定植特定病原菌、饲喂益生菌等,证实肠道微生物确实与动物的某些行为学表型相关(表 1)。焦虑样行为是报道最多的,重庆医科大学谢鹏实验室联合运用多种抗生素(头孢西丁、庆大霉素、甲硝唑、万古霉素)廓清小鼠肠道菌群以模拟GF小鼠,小鼠出现焦虑和抑郁样行为改变,并且在重新定植正常菌群后,部分行为表型可被逆转(焦虑样行为可逆转,抑郁样行为不能逆转),证实肠道菌群在早期脑的发育中至关重要,再重定植或清除肠道菌群并不能完全逆转菌群缺失或失衡导致的行为改变[16]。Neufeld等[17]对比GF小鼠和SPF小鼠在高架十字的行为学表现,发现GF小鼠焦虑样行为表型减少,并伴随中央杏仁核、海马齿状颗粒层脑区神经可塑性相关的基因表达水平改变,而对GF鼠定植SPF鼠肠道菌群后,这种焦虑样行为得到逆转[18]。在另一报道中,对成年GF鼠定植SPF鼠肠道菌群后,焦虑样行为未得到逆转,提示正常菌群对神经系统发育有重要作用,在成年后中枢神经系统异常较难改善[19]。在早期也有过类似的报道,Sudo等[20]将SPF小鼠正常菌群分别移植给6周、14周龄GF小鼠,可逆转6周龄GF鼠HPA轴对束缚的应答,在14周龄GF无改变。不同品系的小鼠,其出现焦虑样行为的倾向也不尽相同,研究认为可能与不同品系小鼠肠道菌群不同有关[21]。研究者发现,BALB/c小鼠比NIH Swiss小鼠更容易出现焦虑样行为,在新环境中表现出较少的探索运动,将这两种品系小鼠肠道菌群分别移植给对方,两者焦虑样行为表型也得到调换,再次证实焦虑样行为表型和肠道菌群密切相关。

表 1 与肠道微生物组相关的动物行为表型

抑郁样表型也被认为和微生物-肠-脑轴密切相关,在一些抑郁样行为小鼠模型中也同样存在肠道菌群的改变[22-23]。Zheng等[24]首次将抑郁患者肠粪便移植给GF小鼠后,小鼠自发出现抑郁样行为,说明小鼠抑郁样行为和肠道菌群的改变密切相关。在母婴分离大鼠模型中,给予双歧杆菌治疗后,可减轻其抑郁样行为表型,并纠正机体免疫应答和脑干部位去甲肾上腺素的浓度[25]。Gilbert等[26]对心肌梗死后合并抑郁样行为的大鼠给予Bifidobac-terium longumLactobacillus helveticus治疗,发现益生菌可减轻模型组的抑郁样行为表型,并可降低某些炎症因子的表达,改善肠黏膜的通透性。而某些抗菌药物,在一定程度上也可减轻动物的抑郁样表型。Wong等[27]最近的研究发现,米诺环素可调节肠道菌群的组成,降低束缚模型小鼠炎症通路相关分子的表达,减轻小鼠焦虑、抑郁样表型。

此外,微生物-肠-脑轴还被证实与动物的多种行为表型相关,例如社会交互[28]、认知与记忆[29-30]。清除肠道菌群可能影响小鼠空间记忆的能力[31]。因感染或饮食变化导致肠道菌群改变也可能会影响动物空间记忆的能力,小鼠肠道感染Citrobacter rodentium后其认知能力受损,在给予益生菌治疗后,认知损害可得以逆转[32]。有研究发现,饮食的改变也可导致肠道菌群改变,进而引起认知记忆能力的改变,在小鼠饲料中添加牛肉可改变小鼠肠道菌群,提高小鼠学习记忆能力[33]

3 微生物-肠-脑轴主要分子表型

目前很多神经精神疾病的病因和发病机制尚不清楚,研究者们从各自领域提出了相关的假说,如单胺类假说神经递质耗竭、HPA轴失调、神经免疫激活、神经营养因子表达失调等假说。然而,任何一种单一的假说,都不能解释神经精神研究领域的复杂机制,这些疾病往往涉及遗传、生化、神经内分泌、免疫和心理社会环境等因素,多年来众多的研究者试图以某一机制来阐述这些病因,但往往都显得“管中窥豹”。近年来肠道微生物与神经精神疾病的关联性引起了国内外研究者的重视,它们与宿主存在着共生关系,共同维护着宿主的生理平衡,并且微生物-肠-脑轴参与了以上假说的调控(表 2),通过微生物-肠-脑轴可将各独立的假说联系起来,对某些复杂的神经精神疾病做出更好的解释,也为这些疾病的治疗提供了新的思路。

表 2 与微生物-肠-脑轴相关的分子表型
3.1 单胺类神经递质

脑内单胺类神经递质释放水平与某些心理障碍类疾病,如抑郁症和焦虑症有密切关系,临床上不少常用的抗抑郁药物也是针对这一治疗靶点[34]。目前已有研究证实,肠道微生物可能参与调控宿主中枢神经系统5-TH的合成[35-36]。通过改变肠道菌群的组成,是否也会影响单胺类神经递质的转运呢,有研究对比GF鼠与SPF鼠发现,GF小鼠外周循环5-TH水平显著低于SPF鼠[37],肠道菌群的缺如可能导致GF小鼠外周某些组织,如结肠的色氨酸羟化酶表达下调[36]。Clarke等[38]的研究进一步证实,5-TH的前体色氨酸在雄性无菌小鼠外周循环中的浓度高于SPF鼠。Neufeld等[17]比较GF鼠与SPF鼠发现,5-TH1A受体在海马齿状回颗粒层表达下调。在束缚模型小鼠前额叶,5-TH水平升高,给予植物乳杆菌干预后,可逆转5-TH的水平,并可改善抑郁样行为表型[39]。也有研究发现,乳杆菌作为益生菌通过调节肠道菌群降低海马5-TH水平,改善抑郁样行为表型和认知减退[40]。Savignac等[41]发现,益生菌可通过调节大脑皮质区5-TH2A受体表达来发挥抗焦虑作用。微生物-肠-脑轴与单胺类神经递质转运的密切联系,为相关神经精神疾病的研究提供了新的思路,也为抑郁症等复杂疾病的治疗提供了新的可能。

3.2 HPA轴相关分子

神经内分泌系统的功能改变,特别是HPA功能的改变可能与某些精神疾病严重程度存在一定相关性[42]。Lyte[43]的研究发现,HPA轴的激活可引起肠道微菌群的改变。社会挫败可以显著减少大鼠肠道内拟杆菌属丰度,并伴随梭菌属丰度增加[44]。母婴分离所产生的应激在引起HPA轴改变的同时,也影响肠道菌群的成分。通过16S rRNA测序发现,母婴分离所产生的应激可显著改变母鼠肠道菌群成分,乳杆菌治疗可以逆转皮质酮水平的升高[45]。反之也有研究表明,肠道微生物可能参与HPA的调控,一项随机双盲实验表明L. helveticusB. longum的混合益生菌制剂可以降低健康人群24 h尿液中游离皮质醇水平[46]。通过对GF动物与SPF级动物的比较发现,应激后GF动物外周循环具有更高浓度的促肾上腺皮质激素和皮质酮[38, 47]。Sudo等[20]的研究也发现,束缚造模后,GF小鼠外周循环促肾上腺皮质激素(ACTH)和皮质酮的浓度比SPF鼠浓度高,并且将SPF鼠肠道菌群移植给GF鼠后,HPA轴的应答可部分被逆转; 在给予双歧杆菌治疗后,GF小鼠也可得到类似逆转。这表明肠道菌群不仅对防止应激所造成的HPA轴过激必不可少,而且对HPA轴的平衡存在调控作用[48]。益生菌治疗可改善动物应激后肠道菌群紊乱,唾液乳杆菌(L. salivarius)和香肠乳杆菌(L. farciminis)也可逆转应激诱导的皮质酮分泌、神经可塑性、神经发生异常[49]

3.3 脑源性神经营养因子

脑源性神经营养因子(brain derived neurotrophic factor, BDNF)参与调节突触可塑性、神经发生等生理功能,在抑郁症等精神疾病中被认为表达下调,并且有多种针对该靶点的抗抑郁药物。目前也有大量证据表明,肠道微生物可能参与调控中枢神经系统BDNF表达,在束缚刺激后,GF小鼠皮质区和海马BDNF浓度较SPF小鼠表达下调[20]。SPF级动物饲喂抗生素后,在肠道菌群改变的同时,BDNF在海马的表达水平也有所变化[21]。类似的结果在Desbonnet等[50]的报道中也有所呈现,抗生素可导致小鼠肠道菌群失衡,影响色氨酸代谢通路和BDNF表达水平,并引起认知能力减弱。给予益生菌或益生元治疗,可以调节肠道菌群失衡,在持续5周给予低聚半乳糖或低聚果糖治疗后,海马齿状回区BDNF mRNA水平上调,低聚半乳糖或低聚果糖调控海马BDNF表达的具体机制尚不清楚,可能是通过调控肠道菌群的组成来间接调控[51]。类似研究表明,乳杆菌可逆转慢性束缚诱导的海马BDNF mRNA水平低表达,发挥抗抑郁、抗焦虑的作用[52]

3.4 神经免疫反应相关分子

神经免疫调节异常也是微生物-肠-脑轴失衡的原因之一,肠道微生物有利于肠道免疫系统的建立,肠道菌群对促进宿主免疫系统的发育并维护宿主免疫系统的功能是必不可少的。通过比较普通小鼠和无菌小鼠的免疫特性发现,无菌小鼠存在免疫功能的缺陷,但在接受正常菌群移植后可以恢复免疫功能,特别是节丝状菌的移植可以完全重建肠道内B和T淋巴细胞的功能[53]。饲喂高脂饲料的小鼠,肠道黏膜通透性增加,并且内侧前额叶皮层炎症分子表达上调,提示膳食的调整可能导致肠道菌群的改变[54]。高脂饲料喂养可诱导小鼠出现焦虑样行为表型,给予瑞氏乳杆菌治疗21 d后可逆转焦虑样表型,但是在IL-10基因敲除的小鼠,焦虑样表型不能被逆转,神经免疫可能是微生物调节与中枢神经系统相互作用的途径之一[55]。抑郁症患者血清中的炎症标志物,如IL-6、TNF-α和C反应蛋白(CRP)明显升高[56]。同样的现象也在焦虑症中发现,并被认为是由于应激引起的,但是,现在对于这些炎性因子的来源缺乏定论,并且这些变化在抑郁症发病中究竟起到什么作用仍需要进一步研究。动物实验表明,应激可以使肠道黏膜通透性增加,导致肠道内细菌膜表面脂多糖进入血液和淋巴结,刺激Toll样受体(TLRs),最终导致炎性细胞因子的产生[57]。如果这种现象也发生在抑郁症患者中,也许可以解释炎症因子的来源。尽管仍然不清楚外周的炎症因子是否可以直接影响到大脑,但是已证明炎症因子可以增加血脑屏障的通透性[58]。注射致炎性细胞因子可以导致抑郁症状的产生,但抗抑郁药可以预防这种现象的产生[59]。曾有假说认为,抗抑郁药不仅对中枢神经系统内单胺类神经递质起作用,还可以产生免疫调节细胞因子IL-10来降低神经系统的炎症,从而达到抗抑郁效果[60]。而益生菌也可以通过诱导调节性T淋巴细胞群合成和分泌IL-10,从而起到抗炎作用[61]。因此,肠道菌群失衡可能与免疫系统对情绪和行为互为影响。

4 微生物-肠-脑轴与神经精神疾病

微生物-肠-脑轴参与动物行为表型的调控,并可与神经生化相关分子互为影响,在临床研究中,也证实肠道菌群与某些复杂的神经精神疾病密切相关,高脂膳食可影响肠道菌群的组成,继而导致认知能力受损[62]。也有临床证据表明,微生物-肠-脑轴调节失衡可能在其他神经精神类疾病的致病机制中起重要作用,如孤独症、抑郁症、焦虑症和帕金森病等。以下对微生物-肠-脑轴在神经精神领域的临床研究进行综述。

4.1 抑郁症

已有临床研究证实,抑郁症患者存在肠道菌群失调,重庆医科大学谢鹏实验室通过尿液代谢组学分析发现了肠道微生物紊乱相关的11个差异代谢物质,首次找到了抑郁症患者微生物-肠-脑轴调节失衡的临床证据[63]。通过对比抑郁患者肠道菌群16S rRNA,发现抑郁患者肠道厚壁菌门(Firmicutes)、放线菌门(Actinobacteria)丰度降低,拟杆菌门(Bactero-idetes)显著升高,将抑郁患者粪便给GF小鼠灌胃,可使小鼠自发出现抑郁样行为表型,从而首次构建了人源化抑郁症动物模型,并且16S rRNA检测发现,小鼠肠道菌群改变与抑郁症患者高度相似,进一步证实抑郁症与肠道微生物的关联性,表明抑郁样行为可通过肠道菌群在人和小鼠间得到传递[24]。谢鹏实验室进一步通过对比GF和SPF小鼠海马组织中部分microRNA和mRNAs的表达水平,发现肠道微生物能够影响小鼠海马组织中部分microRNA和mRNAs的表达水平,这些差异microRNA及其靶基因主要在脂质代谢和碳水化合物代谢中被显著影响,某些靶基因也与抑郁症密切关联,如调控多巴胺再摄取和多巴胺能神经元形态,在重定植正常菌群后,GF鼠焦虑样行为未得到逆转,但microRNA和mRNAs的表达水平被逆转[64]。Jiang等[65]的研究中发现,与对照组相比抑郁症患者肠道菌群α多样性指数(Shannon Index)显著增加,Bacteroidetes、变形菌门(Proteobacteria)和Actinobacteria丰度显著升高,Firmicutes显著降低,并且类杆菌属(Faecalibacterium)表达丰度和患者的抑郁程度呈负相关,推测抑郁症的发生发展可能与肠道益生菌减少和有害菌增加相关。另一研究也进一步证实,抑郁症患者肠道内双歧杆菌、乳杆菌丰度降低[66]。Kelly等[67]的类似研究也发现,抑郁患者肠道菌群埃格特菌属(Eggerthella)、HoldemaniaGelriaTuricibacterParaprevotellaAnaerofilm显著增加,普氏菌属(Prevotella)和小杆菌属(Dialister)丰度降低,将抑郁患者肠道菌群移植给小鼠后,可诱导小鼠出现抑郁样行为表型以及和抑制患者相类似的色氨酸代谢通路异常。犬尿氨酸是色氨酸的代谢产物,研究认为伴自杀倾向的青少年抑郁症患者存在犬尿酸代谢通路异常[68],而犬尿氨酸的代谢受微生物-肠-脑轴调控[69]

4.2 孤独症

孤独症被认为是一种遗传和环境共同作用的复杂性疾病,最近有研究认为,孤独症可能伴随胃肠道症状异常,并伴随皮质酮表达升高[70]。孤独症可能与肠道菌群组成和代谢改变有关[71-73]。Finegold等[74]的研究发现,孤独症儿童肠道菌群多样性显著增加,主要表现为拟杆菌属细减少和梭菌属细菌增加[75-76]。脱硫弧菌属(Desulfovibrio)也被发现在孤独症儿童肠道显著增加,并且在有自闭症家族史的家庭中,患儿与其兄弟姐妹间也可能共同携带该菌属,提示该菌在家庭内的传播可能与家族性自闭症有一定关联性[77]。孤独症模型动物肠道菌群显著改变,采用脆弱拟杆菌治疗后,可逆转肠道菌群改变和孤独症样行为表型[78]。对孤独症儿童采用抗菌药物治疗后,在一定程度上可改善其临床症状,其原因可能是与纠正菌群失衡后,控制脂多糖(LPS)浓度,降低中枢神经系统炎症因子表达有关[79]

4.3 精神分裂症

Severance等[80-81]研究发现,精神分裂症的患者肠道黏膜通透性增加,肠道菌群的改变可能导致对膳食中某些成分(如面筋)的代谢改变,生成某些具有神经活性的多肽,这些产物的吸收可增强肠黏膜局部炎症反应,导致多巴胺、5-TH通路改变,增加精神分裂的风险。Desbonnet等[28]通过三箱社交实验(three-chamber sociability test)证实,GF小鼠可表现出精神分裂样行为表型,与正常定植小鼠相比交互时间减少。这种趋势被认为是精神分裂或孤独症模型的表型之一,并且脆弱拟杆菌可以逆转这一行为表型[82]。在一项双盲随机对照实验中,给予乳杆菌、双歧杆菌治疗的患者的精神分裂相关症状并未优于安慰剂组[83]

4.4 帕金森病

帕金森病(Parkinson's disease, PD)是一种常见的神经退行性疾病,伴随多种非运动症状,如便秘、疼痛、抑郁、焦虑、淡漠、痴呆等[84]。近年来, 微生物-肠-脑轴在神经精神领域越来越受重视。Scheperjans等[85]发现PD患者肠道菌群失调,具体表现为肠杆菌科丰度增加并和PD患者运动障碍程度呈正相关,且普雷沃氏菌科丰度降低。PD的某些非运动症状被认为与微生物-肠-脑轴失衡存在密切关联,帕金森病患者胃肠道症状伴有肠道菌群的改变,这些患者肠道内某些产丁酸细菌,如布劳特氏菌属(Blautia)、粪球菌属(Coprococcus)和罗氏菌属(Roseburia)缺失,导致抗炎能力减弱[86-87]。也有研究发现,帕金森病患者肠黏膜定植罗尔斯通菌属(Ralstonia)显著高于对照组,导致肠道菌群失衡和更多的炎症表型,也可导致患者肠道菌群过载或感染幽门螺旋杆菌[88]。感染了幽门螺旋杆菌的PD患者,对左旋多巴的吸收减少,在给予抗幽门螺旋杆菌治疗后,左旋多巴吸收显著增加,相应临床症状得到改善[89]。PD患者肠黏膜通透性增加被认为是PD肠-脑调节失衡的重要环节[90]。肠道菌群过载、幽门螺旋杆菌感染、肠黏膜通透性增加可导致PD患者内脏性疼痛,乳杆菌治疗可以显著改善PD患者便秘、内脏性疼痛等非运动症状[87]。在给予PD患者抗菌药物(万古霉素、秋水仙碱、甲硝唑)治疗后,不仅使患者便秘得到缓解,其神经症状也得到一定的改善,提示改善患者肠道菌群分布可在一定程度上逆转PD患者的神经症状[91]。PD患者非运动症状包括抑郁、焦虑、淡漠等精神异常症状,已有大量临床或动物研究证明抑郁、焦虑等精神疾病存在微生物-肠-脑轴调节异常,并且益生菌治疗可得到一定改善; 遗憾的是,PD患者精神症状异常与微生物-肠-脑轴的报道尚不多见。

4.5 脑血管病

卒中的患者大多合并感染等并发症,抗生素被广泛运用于卒中后感染的治疗,特别是重症患者,可能持续5~10天应用广谱抗菌药物[92]。然而,抗生素不仅仅作用于致病菌,也可能会造成正常菌群失衡[93]。而脑卒中的患者自身也存在肠道菌群失衡,高龄除了作为卒中的危险因素,也可影响肠道微生物的组成[94]。有大量动物实验证明,脑血管模型组肠道菌群α多样性指数显著增加,大剂量抗菌药物廓清肠道菌群,可增加动物的死亡率[95-98]。脑卒中患者也被发现存在肠道菌群失调,Yin等[99]比较了无症状动脉粥样硬化患者和健康对照,发现动脉粥样硬化患者肠道菌群和血浆氧化三甲胺(trimetlylamine oxide, TMAO)浓度无显著差异,而卒中和短暂性脑缺血的患者肠杆菌属(Enterobacter)、MegasphaeraOscillibacter丰度升高,而BacteroidesPrevotellaFaecalibacterium丰度降低,并且这种趋势与疾病的程度呈一定的相关性,卒中和短暂性脑缺血患者TMAO浓度显著低于无症状的动脉粥样硬化患者。另一研究中,RoseburiaBacteroidesFaecalibacterium prausnitzii在急性卒中患者肠道菌群中的比例较健康对照降低,并伴随EnterobacteriaceaeBifidobacteriaceae和艰难梭菌(Clostridium difficile)比例的升高[100]。症状性粥样硬化(微梗死和短暂性脑缺血)的患者也存在肠道菌群失调,表现为柯林斯菌属(Collinsella)丰度升高和Roseburia、优杆菌属(Eubacterium)、Bacteroides丰度降低。血浆TMAO表达水平升高可能会增加心脑血管事件的危险性,通过抗生素治疗可调节肠道菌群,降低TMAO浓度[101]

4.6 多发性硬化症

多发性硬化症(multiple sclerosis, MS)是一种慢性的中枢神经系脱髓鞘病变,可能与中枢神经系统的自身免疫相关。自身免疫性脑脊髓膜炎(experimental autoimmune encephalomyelitis, EAE)模型是多发性硬化症的常用模型之一[102]。虽然EAE模型不能完全替代人类MS的所有特征,但是却能较好地复制神经炎症的病理过程[103]。通过对EAE模型肠道微生物组的研究发现,肠道微生物可能与MS的致病相关[104]。在给予脆弱拟杆菌治疗后,可显著改善模型的症状[105]。也有临床研究证实,MS患者肠道菌群失衡,与健康对照相比,MS患者肠道内假单胞菌属(Pseudomonas)、枝动杆菌属(Mycoplana)、嗜血杆菌属(Haemophilus)、BlautiDorea丰度升高,而ParabacteroidesAdlercreutziaPrevotella丰度降低[106]。在另一研究中,也发现MS患者存在肠道菌群异常[107]

4.7 其他

除了以上疾病,肠道微生物组也和其他神经精神疾病相关,如厌食症[108-109]、强迫症[110]、格林巴利综合征(Guillain-Barré syndrome, GBS)[111]、阿尔兹海默症[112]等。GF动物与正常菌群定植动物相比,存在认知和记忆能力减退的现象[113]。在阿尔兹海默症动物模型的研究中,肠道菌群能够调控宿主β-样淀粉的形成[112]。GBS是一种周围神经系统的自身免疫性疾病,与MS类似,是机体对周围神经系统的髓磷脂的自身免疫反应。空肠弯曲杆菌作为肠道常见菌群,被认为是引起结肠炎的一个重要诱因,而空肠弯曲杆菌性结肠炎患者GBS的风险性更高[114],并且弯曲菌属不同菌株GBS的风险性也不一样[115]

5 展望 5.1 目前研究微生物-肠-脑轴的主要载体

随着16S和宏基因组技术的发展,描绘不同疾病状态的菌群变化已不再难以实现。但很多研究并不能直接在人体开展,并且人肠道微生物组受饮食、生活习惯、抗菌药物的影响较大,而一般的SPF动物也满足不了当下研究需求,在此背景下对实验动物提出了更高的要求。GF动物的微生物背景清晰,且在解剖与形态学、代谢生理及免疫系统方面与常规实验动物相比有明显的特点,现已成为研究肠道菌群的生理病理功能的最佳动物模型。通过对比GF动物和正常菌群定植动物,可以研究正常菌群对微生物-肠-脑轴的调控; 通过对GF动物接种特定的一种或多种微生物,可以充分地研究微生物与宿主之间以及微生物之间的相互作用; 通过移植患者特定的微生物菌群,可以研究疾病相关的特异性的微生物菌群改变,并进一步探究微生物在各种神经精神疾病的致病机理,但目前GF动物存在培养规模尚比较小、对无菌培养环境要求高、培养成本高等局限性,并且GF动物在神经、免疫等多个系统发育过程与普通动物存在明显差异,不一定适用于所有的研究。通过广谱抗菌药物廓清普通动物肠道菌群,可作为GF动物的一种替代方案,并且区别于GF动物的绝对无菌,可能也更贴近于人肠道微生态失衡的状态,可能比GF动物更适合用于开展微生物-肠-脑轴的研究。

5.2 肠道微生物组对脑的调节作用将越来越受关注

大脑作为人体的中枢,调控着各个系统的功能,微生物-肠-脑轴的双向调节作用中,被广泛认可的是中枢神经系统可调节肠道菌群组成,肠道微生物组对大脑的调节正在逐步被探索。随着研究的深入,肠道微生物在中枢神经系统发育、神经免疫等中的生理病理机制逐渐被揭示,肠道微生物组对肠-脑-轴的调节将可能成为神经精神疾病研究的焦点之一。肠道微生物组对中枢神经系统的调节机制也还待于进一步明确,微生物某些特定的代谢产物、神经内分泌、神经免疫途径可能是沟通外周到中枢的潜在途径,示踪技术的运用也有助于进一步明确微生物-肠-脑轴的因果关系。

5.3 调节肠道微生物组成可能成为治疗神经精神疾病的一种新的科学方法

古人所推崇的“修身养性”,通过调节饮食和生活作息以及心境,其实也是在调节肠道菌群的组成,来颐养生命、增强体质、预防疾病,从而达到延年益寿的作用。随着肠道微生物在神经精神疾病中的研究的深入,疾病相关的特定菌群也是今后研究的重要方向,通过靶向调节肠道微生物组的组成,通过调控微生物-肠-脑轴来实现对某些神经精神疾病的治疗。

5.4 目前研究的局限性

目前已有的研究往往只面向单一疾病,比较孤立,尚不构成体系,并且大多数为随机化样本采集,容易受到饮食、生活习惯,基础疾病、药物等因素的影响,还需要进行随机对照实验等进一步验证。对于宏基因组数据的挖掘和利用还局限于较浅表的层次,要实现将来自于海量样本的基因型和表观型数据进行整理和分析,进而提供个性化预测任重而道远。

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