肠道微生物群对帕金森病的研究进展
Research Progress of Gut Microbiota on Parkinson’s Disease
DOI: 10.12677/ACM.2024.141154, PDF, HTML, XML, 下载: 168  浏览: 324 
作者: 袁 薇*, 魏小彤, 张佳慧:延安大学咸阳医院神经内科,陕西 咸阳;延安大学医学院,陕西 延安;王丙聚#:延安大学咸阳医院神经内科,陕西 咸阳;姜 珊, 刁德敦:延安大学医学院,陕西 延安
关键词: 帕金森病肠道微生物群脑肠轴微生物–脑–肠轴肠道屏障Parkinson’s Disease Gut Microbiota Gut-Brian Axis Microbe-Gut-Brian Axis Gut Barrier
摘要: 帕金森(PD)在我国老年人的发病率居高不下,对于其发病机制目前尚不完全清楚。肠道微生物是健康和疾病研究的新前沿,不仅许多疾病与微生物区系紊乱有关,而且越来越多的研究指出了因果关系。近年来的研究发现帕金森与肠道微生物群密切相关。本文通过对相关研究文献的整理,总结了PD与肠道菌群之间的相关机制,并在治疗方面总结了饮食干预、粪便移植、益生菌等改善帕金森患者的症状。以期能通过肠道微生物群为PD提供新的治疗策略。
Abstract: The incidence of Parkinson’s disease (PD) in the elderly is very high in our country, and the patho-genesis of PD is not completely clear at present. Gut microbes are a new frontier in health and dis-ease research, and not only many diseases are associated with microbiota disturbances, but more and more studies are pointing to cause-and-effect relationships. Recent studies have found that Parkinson’s disease is closely related to the gut microbiome. Based on the review of relevant re-search literature, this paper summarized the mechanism between PD and gut microbiota, and summarized the improvement of symptoms of Parkinson’s patients with dietary intervention, fecal transplantation and probiotics in terms of treatment, in order to provide a new treatment strategy for PD through gut microbiota.
文章引用:袁薇, 王丙聚, 姜珊, 刁德敦, 魏小彤, 张佳慧. 肠道微生物群对帕金森病的研究进展[J]. 临床医学进展, 2024, 14(1): 1069-1078. https://doi.org/10.12677/ACM.2024.141154

1. 引言

神经退行性疾病,包括阿尔兹海默症 [1] 、帕金森 [2] 、肌萎缩侧索硬化症等 [3] 。其中帕金森病是一种对全球范围内老年人产生显著影响的第二大常见神经退行性疾病 [4] [5] 。在60岁以上人群中发病率占1%,目前已知的病因有年龄、遗传和非遗传因素相结合等 [3] [5] 。

依据帕金森的主要运动系统症状(静止性震颤、四肢肌肉强直或僵硬、动作迟缓以及姿势平衡障碍),研究发现常与原发性震颤、血管性帕金森病以及阿尔茨海默病相误诊 [6] [7] 。基于PD致病性广及易误诊,因此需重视其临床前表现。而之前对于PD研究以及治疗大多集中于大脑,发现其发病机制主要包括:中枢神经系统中异常折叠的α-突触核蛋白的堆积、黑质纹状体多巴胺能神经元的丢失、神经递质水平降低、氧化应激以及线粒体功能障碍 [8] [9] 。Sangjune Kim等人通过对小鼠模型的研究中首次证实了肠道中病理性的α-突触核蛋白通过迷走神经进行脑肠传播来导致PD,且研究证实肠道微生物群的存在对于促进与PD中所见相似的病理学改变和运动功能障碍起着重要作用 [10] 。

2. 肠道屏障

众所周知肠道屏障可以限制毒素、病原体和抗原的进入,同时调节各种神经活性化合物的表达。脑肠轴的存在提出了肠道屏障改变可能参与中枢神经系统疾病的病理生理学 [11] 。之前的实验模型中证实了肠道中微生物群,肠道屏障以及免疫功能在肠道防御屏障中的重要作用 [12] 。

2.1. 物理屏障

肠道物理屏障的形成主要依靠肠上皮细胞(IECs)以及粘膜。肠上皮细胞在阻止肠腔内的有害物质如毒素、病原体和抗原进入机体内部及体循环发挥重要作用 [11] [13] 。ISCs位于隐窝的底部通过平衡增殖和分化来维持上皮稳态和再生细胞 [14] 。细胞旁间隙小分子亲水物质主要受顶端紧密连接(TJ)的高度调节,其中TJ蛋白包括连接粘附分子(JAM)等 [13] [15] 。JAM-A参与了物理屏障中的防止炎症进入循环的调节,可能也参与了渗透性调节 [16] [17] 。此外,肠粘膜中富含有丰富的肠神经胶质细胞(EGCs),其在控制肠上皮屏障中起关键作用 [18] 。在PD中,肠道微生物群的改变,导致肠道炎症环境的形成,以至于IECs被破坏,激活炎症反应过程,最终传递到CNS [19] 。

2.2. 免疫屏障

肠上皮包括六种不同的成熟细胞类型,其中肠上皮细胞和M细胞为吸收细胞;潘氏、杯状、肠内分泌(EECS)和簇状细胞为分泌细胞。这些不同的细胞类型提供了营养摄取、代谢控制和免疫调节 [20] 。其中免疫调节通过Toll结构域的识别触发信号转导途径,然后诱导树突状细胞(DC)成熟和细胞因子产生,导致适应性免疫应答的发展。存在与上皮下的DC,通过M细胞转运后摄取分泌型免疫球蛋白A (IgA);存在于粘膜固有层(LP)中的DC通过伪足摄取肠腔中的IgA来发挥保护肠上皮免受攻击 [21] 。临床流行病学证据支持关于PD在肠道中产生α-突触核蛋白并通过迷走神经扩散到大脑激活胶原细胞的概念 [22] 。在实验中我们发现:胃肠道中的α-突触核蛋白由EECS表达 [18] ,另一项研究发现肠道微生物可能通过影响EEC的变化来影响神经系统。因此,通过胃肠道活检来检测早期或临床前PD个体中EEC中的异常α-突触核蛋白 [23] ,对于PD临床前干预至关成为可能。

2.3. 肠上皮微生物群

人体肠道微生物菌群复杂,其中包括数万亿微生物,由超过3000种不同的细菌物种 [24] 。微生物菌群失调可能会导致机体功能失调和疾病 [25] 。Robin M Voigt在文章中提到65岁以上人群出现肠道微生物菌群失调,从而通过影响宿主免疫和代谢相关病理学的易感性,例如神经退行性疾病、感染等 [26] 。

3. 脑–肠轴

脑肠轴(GBA)是近年研究的热点,GBA是肠(ENS)和中枢系统(CNS)之间的复杂双向通信 [27] 。ENS其是独立于中枢神经系统控制胃肠功能的网络结构 [18] 。已经有16项病例对照研究公布了PD患者的肠道微生物组组成变化 [28] ;且肠道感染后不仅引起肠道症状同时也影响中枢神经系统功能 [29] 。肠道病原体和生物失调可导致外周炎症状态或触发下游代谢效应,从而加剧神经退行性疾病的变化过程 [30] 。这充分说明了脑肠轴之间为双向通路。

4. 帕金森中的微生物–脑–肠轴

4.1. 帕金森患者肠道症状

对于PD患者非运动系统症状同时甚至先于其运动症状的发作 [31] 。其中肠道症状主要表现为唾液过多、吞咽困难、恶心、排便频率降低和排便困难 [19] 。超过50%的PD患者存在便秘 [32] ,且在PD运动症状发作前发生便秘的PD患者平均便秘时间为18.7年 [33] 。

4.2. 帕金森中的微生物–脑–肠轴

微生物与大脑之间存在着密切的联系,现已证实肠道微生物群通过作用于脑肠轴之间的神经元来影响PD早期肠道症状 [34] 。其中肠道微生物主要通过免疫、神经内分泌和潜在的神经通路调节脑–肠轴 [35] ;同时微生物代谢物:如短链脂肪酸、支链氨基酸和肽聚糖来对帕金森患者脑肠轴产生影响 [36] 。

5. 肠道微生物群对帕金森的作用机制

5.1. 肠道中微生物群

人类肠道中的微生物受到来自宿主和微生物之间竞争选择压力,其在肠道分布存在差异 [37] 。在研究中发现,PD与粘胶球形菌纲、慢球菌属、草酸杆菌科、食物谷菌目、芽孢杆菌目、霍氏真杆菌、厌氧菌属和梭形芽孢杆菌等有关 [38] 。普雷沃氏菌科是PD高度特异性的前驱标志物,其与PD患者2年进展性运动症状相关及特发性快速眼动睡眠行为障碍相关(RBD) [39] [40] 。Filip Scheperjans等人通过使用广义线性模型分析报告了PD患者粪便中普雷沃氏菌科与对照组相比减少 [37] 。Anelise Miglioranza等人证实与正常人相比,同型半胱氨酸水平在PD患者中增加,同时这种增加与叶酸水平的降低密切相关 [41] 。另一项研究证实普雷沃氏菌科降低了PD患者的硫胺素和叶酸生物合成能力 [41] 。在先前的一项研究中,富含普雷沃氏菌科的肠型个体中,其便秘发生率最低,且阈下帕金森症发生率最低 [42] 。有研究证实了在PD中乳杆菌和双歧杆菌水平升高以及毛螺菌科水平降低 [43] 。

5.2. 微生物–色氨酸代谢

色氨酸被肠道微生物群分解成吲哚衍生物和犬尿氨酸代谢物,其中吲哚是肠道细菌通过色氨酸酶的作用产生的主要代谢物 [44] ;色氨酸代谢途径其中通过犬尿氨酸3-单加氧酶代谢为3羟基犬尿氨酸(3-OH-KYN)生成3-羟基犬尿氨酸,这两种代谢产物被发现在帕金森脑肠轴中有重要影响 [45] [46] 。同时研究发现在PD患者的血清和脑脊液中,与健康对照组相比,发现PD组KYN/TRT比值增加 [47] 。

5.3. 微生物代谢产物–短链脂肪酸

短链脂肪酸(SCFA)为肠道微生物群的发酵产物,根据膳食纤维的含量,每天大肠产生约500~600 mmol的SCFAS [48] 。其主要包括丁酸、乙酸、丙酸和琥珀酸等 [49] 。对于体内摄入的SCFAS主要由单羧酸转运蛋白(MCT)及钠偶联MCT (SMCT)介导的同向性主动转运被结肠上皮细胞所吸收 [50] 。大量动物研究表明,SCFAS可能参与PD形成关键阶段;例如在帕金森小鼠肠道骨钙素研究中证实了丙酸盐主要通过作用于肠神经元中的FFAR3,来发挥对PD的神经保护作用 [51] 。而在患有PD的动物模型中已被证实粪便及血清中SCFA含量较低 [52] 。与PD相关研究中,嗜黏蛋白阿克曼菌增加及产SCFAS菌减少,会增加肠道通透性和肠道炎症,从而促进肠道神经丛暴露于毒素(如脂多糖),随后将导致α-突触核蛋白原纤维的异常聚集 [53] 。

5.4. 微生物代谢产物–脂多糖

脂多糖(LPS)又称为内毒素,通常被认为是机体免疫应答的有效刺激剂及促炎剂;其是革兰氏阴性菌细胞外膜所特有的重要成分,但发现LPS所引起的反应与微生物种类有关 [54] [55] 。虽然微生物聚集与人体各部位,但90%以上的定居于肠道 [56] 。因此肠道微生物群对于LPS有着显著影响。在健康人血浆中LPS含量较低,在生理浓度下不会对肠上皮产生破坏且调节TJ蛋白,而在PD患者中其血液LPS明显升高 [55] [57] 。且在PD患者与正常人对比中发现:PD患者肠道通透性增加且血浆LPS结合蛋白(LBP)较低 [4] 。与这些发现相一致的是,PD患者肠道中定殖有可产生LPS的微生物菌(如幽门螺旋杆菌等) [58] 。LPS的大量产生通过其上的脂质A与LBP特异性结合,形成LPS-LBP复合物,以促进LPS转移并与巨噬细胞/树突状细胞表面的膜CD14结合(LPS-CD 14复合物),促进其被Toll样受体4 (TLR 4)和骨髓分化-2 (MD-2)受体识别,以促进炎症级联反应;TLR4信号通路的激活导致促炎因子的大量激活及免疫反应的发生,引起PD患者的运动及非运动症状 [4] [54] [55] [57] [58] 。

综上所述,肠道微生物菌群与PD的发生、发展及致病有着密切关系,尤其在帕金森临床前阶段。目前关于肠道微生物群已被作为与PD相关的致病途径或作为PD中特定表型的可能生物标志物来研究,而较少地作为用于治疗目的的潜在靶点来研究 [59] 。因此我们可以通过调控肠道微生物群来预防和治疗PD。目前,较多研究集中于益生菌、粪便移植、饮食疗法对于肠道菌群的调节。

6. 肠道菌群作为帕金森的治疗靶点

6.1. 益生菌干预

在食物益生菌评估指南中将益生菌定义为当给予足够量时,可为宿主带来健康益处的活微生物 [60] 。其通过氧化应激、炎症和抗炎途径以及细胞凋亡,来发挥其抗癌、抗氧化、抗炎和神经保护作用 [35] 。越来越多的证据表明,益生菌补充剂可以显著调节肠道微生物群;且益生菌可预防肠道粘膜上的LPS生长、调节胃肠道粘膜的免疫系统,防止肠道屏障被破坏 [61] [62] 。

第一项关于益生菌改变肠道菌群研究于2011年进行,并证明患有慢性便秘的PD患者接受含有干酪乳杆菌代田株益生菌可显著改善粪便稠度并减少了腹泻、腹胀和腹痛症状 [63] 。既往研究发现,嗜酸乳杆菌和婴儿双歧杆菌对治疗PD胃肠道症状如腹胀和腹痛方面表现出良好的效果 [59] 。在一项随机双盲安慰剂对照试验中,60名PD患者被随机分到益生菌组(含有嗜酸乳杆菌、两歧双歧杆菌、罗伊氏乳杆菌和发酵乳杆菌四种联合菌株)或安慰剂组治疗12周,并且评估干预前后的统一帕金森病评分量表(MDS-UPDRS)评分值,结果显示益生菌组12周后MDS-UPDRS显著降低 [64] 。另一项研究证实植物乳杆菌PS128作为一种特异性乳杆菌,当服用12周后可改善PD生活质量及UPDRS运动评分,其被认为可以作为治疗PD的治疗辅助剂 [65] 。益生元也被认为对于PD胃肠道症状有益 [66] 。如研究证实含有益生菌和益生元的发酵乳可缓解PD便秘 [67] 。然而,目前围绕益生菌在PD中的使用仍存在许多知识空白,对于使用单一菌株与联合菌株,以及何种组合和剂量使用仍需要我们进一步研究。

6.2. 粪便移植

粪便微生物移植(FMT)主要通过将健康供体体内的粪便(即有功能的肠道微生物群),移植到受体中,最终在受体中重建具有健康功能的微生物群 [68] 。

在动物实验中,研究者证实FMT给药可减轻肠道炎症和屏障破坏,从而降低了全身炎症的水平,改善PD小鼠的胃肠功能障碍和运动缺陷 [69] 。如前所述,TLR4信号通路的激活对PD产生重要影响。另一项研究指出,FMT通过减少黑质中小胶质细胞和星形胶质细胞的活化,同时可减少肠道及大脑中TLR4信号通路表达,对PD小鼠起到保护作用 [70] 。截至目前,FMT治疗PD的临床研究尚很少。研究者将健康青年供体的粪便经结肠镜注入到一名71岁的PD患者回盲部,1周后患者腿部震颤几乎消失几乎完全消失且排便通常,虽然2月后右下肢震颤复发,但严重程度与FMT治疗前相比有所下降 [71] 。2021年所报道的较大研究样本中关于FMT治疗PD中,指出FMT可能是重建PD患者肠道微生物群并改善其运动和非运动症状的潜在治疗方法 [72] 。Liu-Jun Xue等人进行了关于不同途径FMT组的自身对照研究,其中10名PD经结肠镜途径接受FMT,另外5例经鼻空肠管途径接受FMT。结果显示相比之下治疗后UPDRS等评分表下降;且经结肠镜途径接受FMT组疗效更好 [73] 。虽然大量动物实验和临床研究均显示出了FMT对PD的治疗作用,但仍存在许多不容忽视的问题。例如FMT的某些不良反应,如腹泻、发热、穿孔、出血、肺炎、诱发慢性疾病等 [74] 。尚且需要更高质量的临床实验对于FMT的疗效和安全性、供体选择、移植途径、移植次数以及伦理问题等问题深入探究。以便FMT能够在PD中得到更广泛应用。

6.3. 饮食疗法

研究表明,PD患者除于疾病严重程度、持续时间有关外,营养状况对其生活质量及日常生活状况直接相关 [75] ,约3%~60%患者存在营养不良风险,且存在营养不良者更易合并吞咽困难、流涎和便秘的症状 [76] 。越来越多研究表明,碳水化合物、蛋白质和脂肪的摄入数量、类型和是否平衡,大量摄入蔬菜、水果、及ω-3脂肪酸;健康的饮食模式,如地中海饮食通过调节肠道微生物群来保护神经,对PD有很强的保护作用 [77] [78] 。一项大型观察性病例对照研究中证实,重视蛋白质摄入的管理,将维持PD患者营养状况,且可以优化左旋多巴胺治疗;其能量摄入量与PD严重程度呈正相关 [79] 。在1053例关于PD横断面研究中,新鲜蔬菜、水果、坚果和种子、非油炸鱼、橄榄油、葡萄酒、椰子油、新鲜草药和香料、辅酶Q10及鱼油与其进展率降低相关;水果和蔬菜罐头、无糖和非无糖汽水、油炸食品、牛肉、冰淇淋、酸奶和奶酪、补充铁剂与其更快进展有关 [80] 。

生酮饮食(KD)一种低碳水化合物和富含脂肪的饮食,提供足够的蛋白质,但不足以满足身体所有代谢需求的碳水化合物 [81] [82] 。Shaafi等人研究发现KD可以改善PD大鼠的运动功能 [82] 。T.B. VanItallie等人对5名PD患者进行28天4:1高生酮饮食(4份脂肪和1份碳水化合物–蛋白质混合物组成)的临床试验中,所有患者UPDRS评分均低于实验前得分 [83] 。另一项临床研究中,47例PD患者被随机分配到低脂饮食组或生酮饮食组,两者保持低脂或生酮饮食8周。结果显示运动和非运动症状方面都有显着改善,但生酮组在非运动症状方面表现出更大的改善 [84] 。既往的研究中人类参与KD的帕金森患者数量相当少,并且现有的研究中治疗持续时间短。尚不能说明这种治疗方法在帕金森治疗上会有多大意义。需要进一步的研究明确长期KD对PD症状和病程的影响。

7. 总结和展望

虽然PD病因复杂,目前尚不完全清楚。越来越多的证据表明,肠道生态失调与PD的发生和发展有关。肠道微生物群异常可引起肠道通透性增加、免疫失衡、肠道微生物群代谢产物致病等多机制,在脑肠轴的作用下在PD发生中发挥着重要作用。基于大量的动物模型及临床研究证实肠道微生物群的重建可延缓PD发病。因此,饮食干预、粪便移植、益生菌等方法,可以作为改变肠道微生物群和调节肠道微生物–脑–肠轴的治疗方案。

肠道微生物群是维持宿主健康和疾病的重要因素之一。虽然国内外对于肠道微生物与PD相关性研究很多,但尚未达成一致性结果。我们仍需要进一步研究肠道微生物群的致病机制。在未找到治愈PD方法之前,我们尚且还有很长的路要走。

NOTES

*第一作者。

#通讯作者。

参考文献

[1] Matziorinis, A.M. and Koelsch, S. (2022) The Promise of Music Therapy for Alzheimer’s Disease: A Review. Annals of the New York Academy of Sciences, 1516, 11-17.
https://doi.org/10.1111/nyas.14864
[2] Tansey, M.G., et al. (2022) Inflammation and Immune Dysfunction in Parkinson Disease. Nature Reviews Immunology, 22, 657-673.
https://doi.org/10.1038/s41577-022-00684-6
[3] Kwon, H.S. and Koh, S.H. (2020) Neuroinflammation in Neu-rodegenerative Disorders: The Roles of Microglia and Astrocytes. Translational Neurodegeneration, 9, Article 42.
https://doi.org/10.1186/s40035-020-00221-2
[4] Forsyth, C.B., et al. (2011) Increased Intestinal Permeability Correlates with Sigmoid Mucosa α-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson’s Disease. PLOS ONE, 6, e28032.
https://doi.org/10.1371/journal.pone.0028032
[5] Wright Willis, A., et al. (2010) Geographic and Ethnic Variation in Parkinson Disease: A Population-Based Study of US Medicare Beneficiaries. Neuroepidemiology, 34, 143-151.
https://doi.org/10.1159/000275491
[6] Tysnes, O.B. and Storstein, A. (2017) Epidemiology of Parkinson’s dis-ease. Journal of Neural Transmission, 124, 901-905.
https://doi.org/10.1007/s00702-017-1686-y
[7] Litvan, I., et al. (2003) Movement Disorders Society Scientific Issues Committee report: SIC Task Force Appraisal of Clinical Diag-nostic Criteria for Parkinsonian Disorders. Movement Disorders, 18, 467-486.
https://doi.org/10.1002/mds.10459
[8] Raza, C., Anjum, R. and Shakeel, N.U.A. (2019) Parkinson’s Disease: Mechanisms, Translational Models and Management Strategies. Life Sciences, 226, 77-90.
https://doi.org/10.1016/j.lfs.2019.03.057
[9] Katzenschlager, R. (2014) Parkinson’s Disease: Recent Advances. Journal of Neurology, 261, 1031-1036.
https://doi.org/10.1007/s00415-014-7308-9
[10] Kim, S., et al. (2019) Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease. Neuron, 103, 627-641.E7.
https://doi.org/10.1016/j.neuron.2019.05.035
[11] Julio-Pieper, M., Bravo, J.A., Aliaga, E. and Gotteland, M. (2014) Review Article: Intestinal Barrier Dysfunction and Central Nervous System Disorders—A Controversial Associ-ation. Alimentary Pharmacology & Therapeutics, 40, 1187-1201.
https://doi.org/10.1111/apt.12950
[12] Lewis, C.V. and Taylor, W.R. (2020) Intestinal Barrier Dysfunction as a Therapeutic Target for Cardiovascular Disease. Ameri-can Journal of Physiology-Heart and Circulatory Physiology, 319, H1227-H1233.
https://doi.org/10.1152/ajpheart.00612.2020
[13] Odenwald, M.A. and Turner, J.R. (2013) Intestinal Permeability Defects: Is It Time to Treat? Clinical Gastroenterology and Hepatology, 11, 1075-1083.
https://doi.org/10.1016/j.cgh.2013.07.001
[14] Yao, C., et al. (2022) Key Regulators of Intestinal Stem Cells: Diet, Microbiota, and Microbial Metabolites. Journal of Genetics and Genomics, 50, 735-746.
[15] Díaz-Coránguez, M., Liu, X. and Antonetti, D.A. (2019) Tight Junctions in Cell Proliferation. International Journal of Molecular Sciences, 20, Ar-ticle 5972.
https://doi.org/10.3390/ijms20235972
[16] Camilleri, M., Lasch, K. and Zhou, W. (2012) Irritable Bow-el Syndrome: Methods, Mechanisms, and Pathophysiology. The Confluence of Increased Permeability, Inflammation, and Pain in Irritable Bowel Syndrome. American Journal of Physiology-Gastrointestinal and Liver Physiology, 303, G775-G785.
https://doi.org/10.1152/ajpgi.00155.2012
[17] Suzuki, T. (2020) Regulation of the Intestinal Barrier by Nutrients: The Role of Tight Junctions. Animal Science Journal, 91, e13357.
https://doi.org/10.1111/asj.13357
[18] Casini, A., et al. (2021) Distribution of α-Synuclein in Normal Human Je-junum and Its Relations with the Chemosensory and Neuroendocrine System. European Journal of Histochemistry, 65, No. 4.
https://doi.org/10.4081/ejh.2021.3310
[19] Fasano, A., et al. (2015) Gastrointestinal Dysfunction in Parkinson’s Disease. The Lancet Neurology, 14, 625-639.
https://doi.org/10.1016/S1474-4422(15)00007-1
[20] Gehart, H. and Clevers, H. (2019) Tales from the Crypt: New Insights into Intestinal Stem Cells. Nature Reviews Gastroenterology & Hepatology, 16, 19-34.
https://doi.org/10.1038/s41575-018-0081-y
[21] Uematsu, S. and Fujimoto, K. (2010) The Innate Immune System in the Intestine. Microbiology and Immunology, 54, 645-657.
https://doi.org/10.1111/j.1348-0421.2010.00267.x
[22] Liddle, R.A. (2018) Parkinson’s Disease from the Gut. Brain Research, 1693, 201-206.
https://doi.org/10.1016/j.brainres.2018.01.010
[23] Chandra, R., et al. (2017) α-Synuclein in Gut Endocrine Cells and Its Implications for Parkinson’s Disease. JCI Insight, 2, e92295.
https://doi.org/10.1172/jci.insight.92295
[24] Dogra, S.K., Doré, J. and Damak, S. (2020) Gut Microbiota Resili-ence: Definition, Link to Health and Strategies for Intervention. Frontiers in Microbiology, 11, Article 572921.
https://doi.org/10.3389/fmicb.2020.572921
[25] Hou, K., et al. (2022) Microbiota in Health and Diseases. Signal Transduction and Targeted Therapy, 7, Article No. 135.
https://doi.org/10.1038/s41392-022-00974-4
[26] Voigt, R.M. and Bishehsari, F. (2021) The Intestinal Microbiota: Determinants of Resiliency? The Lancet Healthy Longevity, 2, e2-e3.
https://doi.org/10.1016/S2666-7568(20)30048-9
[27] Rutsch, A., Kantsjö, J.B. and Ronchi, F. (2020) The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology. Frontiers in Im-munology, 11, Article 604179.
https://doi.org/10.3389/fimmu.2020.604179
[28] Boertien, J.M., Pereira, P.A.B., Aho, V.T.E. and Scheperjans, F. (2019) Increasing Comparability and Utility of Gut Microbiome Studies in Parkinson’s Disease: A Systematic Review. Journal of Parkinson’s Disease, 9, S297-S312.
https://doi.org/10.3233/JPD-191711
[29] Bercik, P., et al. (2009) Role of Gut-Brain Axis in Persistent Abnormal Feeding Behavior in Mice following Eradication of Helicobacter pylori Infection. American Journal of Physiolo-gy-Regulatory, Integrative and Comparative Physiology, 296, R587-R594.
https://doi.org/10.1152/ajpregu.90752.2008
[30] Tan, A.H., Hor, J.W., Chong, C.W. and Lim, S.Y. (2021) Probi-otics for Parkinson’s Disease: Current Evidence and Future Directions. JGH Open, 5, 414-419.
https://doi.org/10.1002/jgh3.12450
[31] Bao, Y., et al. (2023) Quantification of Non-Motor Symptoms in Parkin-sonian Cynomolgus Monkeys. Brain Sciences, 13, Article 1153.
https://doi.org/10.3390/brainsci13081153
[32] Stocchi, F. and Torti, M. (2017) Constipation in Parkinson’s Dis-ease. International Review of Neurobiology, 134, 811-826.
https://doi.org/10.1016/bs.irn.2017.06.003
[33] Ueki, A. and Otsuka, M. (2004) Life Style Risks of Parkinson’s Disease: Association between Decreased Water Intake and Con-stipation. Journal of Neurology, 251, vii18-vii23.
https://doi.org/10.1007/s00415-004-1706-3
[34] 李剑兰, 余璇, 胡青婷, 等. 老年帕金森病与肠道菌群、短链脂肪酸和炎性因子相关性研究[J]. 实用老年医学, 2021, 35(3): 282-285.
[35] Mirzaei, H., et al. (2022) Probiotics and the Treatment of Parkinson’s Disease: An Update. Cellular and Molecular Neurobiology, 42, 2449-2457.
https://doi.org/10.1007/s10571-021-01128-w
[36] Cryan, J.F., et al. (2019) The Microbiota-Gut-Brain Axis. Physiological Reviews, 99, 1877-2013.
https://doi.org/10.1152/physrev.00018.2018
[37] Scheperjans, F., et al. (2015) Gut Microbiota Are Related to Par-kinson’s Disease and Clinical Phenotype. Movement Disorders, 30, 350-358.
https://doi.org/10.1002/mds.26069
[38] Ning, J., et al. (2022) Investigating Casual Associations among Gut Mi-crobiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study. Journal of Alzheimer’s Disease, 87, 211-222.
https://doi.org/10.3233/JAD-215411
[39] Aho, V.T.E., et al. (2019) Gut Microbiota in Parkinson’s Disease: Tem-poral Stability and Relations to Disease Progression. eBioMedicine, 44, 691-707.
https://doi.org/10.1016/j.ebiom.2019.05.064
[40] Heintz-Buschart, A., et al. (2018) The Nasal and Gut Microbiome in Parkinson’s Disease and Idiopathic Rapid Eye Movement Sleep Behavior Disorder. Movement Disorders, 33, 88-98.
https://doi.org/10.1002/mds.27105
[41] dos Santos, E.F., et al. (2009) Evidence That Folic Acid Deficiency Is a Major Determinant of Hyperhomocysteinemia in Parkinson’s Disease. Metabolic Brain Disease, 24, 257-269.
https://doi.org/10.1007/s11011-009-9139-4
[42] Heinzel, S., et al. (2021) Gut Microbiome Signatures of Risk and Prodromal Markers of Parkinson Disease. Annals of Neurology, 90, E1-E12.
https://doi.org/10.1002/ana.26128
[43] Hill-Burns, E.M., et al. (2017) Parkinson’s Disease and Parkinson’s Dis-ease Medications Have Distinct Signatures of the Gut Microbiome. Movement Disorders, 32, 739-749.
https://doi.org/10.1002/mds.26942
[44] Jaglin, M., et al. (2018) Indole, a Signaling Molecule Produced by the Gut Microbiota, Negatively Impacts Emotional Behaviors in Rats. Frontiers in Neuroscience, 12, Article 216.
https://doi.org/10.3389/fnins.2018.00216
[45] O’Farrell, K. and Harkin, A. (2017) Stress-Related Regulation of the Kynurenine Pathway: Relevance to Neuropsychiatric and Degenerative Disorders. Neuropharmacology, 112, 307-323.
https://doi.org/10.1016/j.neuropharm.2015.12.004
[46] Szabó, N., Kincses, Z.T., Toldi, J. and Vécsei, L. (2011) Altered Tryptophan Metabolism in Parkinson’s Disease: A Possible Novel Therapeutic Approach. Journal of the Neuro-logical Sciences, 310, 256-260.
https://doi.org/10.1016/j.jns.2011.07.021
[47] Widner, B., Leblhuber, F. and Fuchs, D. (2002) Increased Neopterin Production and Tryptophan Degradation in Advanced Parkinson’s Disease. Journal of Neural Transmission, 109, 181-189.
https://doi.org/10.1007/s007020200014
[48] Dalile, B., Van Oudenhove, L., Vervliet, B. and Verbeke, K. (2019) The Role of Short-Chain Fatty Acids In Microbiota-Gut-Brain Communication. Nature Reviews Gastroenterology & Hepatology, 16, 461-478.
https://doi.org/10.1038/s41575-019-0157-3
[49] Mirzaei, R., et al. (2021) Role of Microbiota-Derived Short-Chain Fatty Acids in Nervous System Disorders. Biomedicine & Pharmacotherapy, 139, Article ID: 111661.
https://doi.org/10.1016/j.biopha.2021.111661
[50] Vijay, N. and Morris, M.E. (2014) Role of Monocarboxylate Transporters in Drug Delivery to the Brain. Current Pharmaceutical Design, 20, 1487-1498.
https://doi.org/10.2174/13816128113199990462
[51] Hou, Y.F., et al. (2021) Gut Microbiota-Derived Propionate Mediates the Neuroprotective Effect of Osteocalcin in a Mouse Model of Parkinson’s Disease. Microbiome, 9, Article 34.
https://doi.org/10.1186/s40168-020-00988-6
[52] Chen, S.J., et al. (2022) Association of Fecal and Plasma Levels of Short-Chain Fatty Acids with Gut Microbiota and Clinical Severity in Patients with Parkinson Disease. Neurology, 98, e848-e858.
https://doi.org/10.1212/WNL.0000000000013225
[53] Hirayama, M. and Ohno, K. (2021) Parkinson’s Disease and Gut Microbiota. Annals of Nutrition and Metabolism, 77, 28-35.
https://doi.org/10.1159/000518147
[54] Dutta, G., Zhang, P. and Liu, B. (2008) The Lipopolysaccharide Parkinson’s Disease Animal Model: Mechanistic Studies and Drug Discovery. Fundamental & Clinical Pharmacology, 22, 453-464.
https://doi.org/10.1111/j.1472-8206.2008.00616.x
[55] Mohr, A.E., et al. (2022) Lipopolysaccharide and the Gut Microbiota: Considering Structural Variation. FEBS Letters, 596, 849-875.
https://doi.org/10.1002/1873-3468.14328
[56] Góralczyk-Bińkowska, A., Szmajda-Krygier, D. and Kozłowska, E. (2022) The Microbiota-Gut-Brain Axis in Psychiatric Disorders. International Journal of Molecular Sciences, 23, Article 11245.
https://doi.org/10.3390/ijms231911245
[57] Brown, G.C. (2019) The Endotoxin Hypothesis of Neurodegeneration. Journal of Neuroinflammation, 16, Article 180.
https://doi.org/10.1186/s12974-019-1564-7
[58] Deng, I., et al. (2020) Lipopolysaccharide Animal Models of Par-kinson’s Disease: Recent Progress and Relevance to Clinical Disease. Brain, Behavior, & Immunity—Health, 4, Article ID: 100060.
https://doi.org/10.1016/j.bbih.2020.100060
[59] Georgescu, D., Ancusa, O.E., Georgescu, L.A., Ionita, I. and Reisz, D. (2016) Nonmotor Gastrointestinal Disorders in Older Patients with Parkinson’s Disease: Is There Hope? Clin-ical Interventions in Aging, 11, 1601-1608.
https://doi.org/10.2147/CIA.S106284
[60] Gazerani, P. (20190 Probiotics for Parkinson’s Disease. International Journal of Molecular Sciences, 20, Article 4121.
https://doi.org/10.3390/ijms20174121
[61] Corridoni, D., et al. (2012) Probiotic Bacteria Regulate Intestinal Epi-thelial Permeability in Experimental Ileitis by a TNF-Dependent Mechanism. PLOS ONE, 7, e42067.
https://doi.org/10.1371/journal.pone.0042067
[62] Ait-Belgnaoui, A., et al. (2012) Prevention of Gut Leakiness by a Probiotic Treatment Leads to Attenuated HPA Response to an Acute Psychological Stress in Rats. Psychoneuroendo-crinology, 37, 1885-1895.
https://doi.org/10.1016/j.psyneuen.2012.03.024
[63] Cassani, E., et al. (2011) Use of Probiotics for the Treatment of Constipation in Parkinson’s Disease Patients. Minerva Gastroenterologica e Dietologica, 57, 117-121.
[64] Tamtaji, O.R., et al. (2019) Clinical and Metabolic Response to Probiotic Administration in People with Parkinson’s Disease: A Randomized, Double-Blind, Placebo-Controlled Trial. Clinical Nutrition, 38, 1031-1035.
https://doi.org/10.1016/j.clnu.2018.05.018
[65] Lu, C.S., et al. (2021) The Add-On Effect of Lactobacillus planta-rum PS128 in Patients with Parkinson’s Disease: A Pilot Study. Frontiers in Nutrition, 8, Article 650053.
https://doi.org/10.3389/fnut.2021.650053
[66] Alfonsetti, M., Castelli, V. and d’Angelo, M. (222) Are We What We Eat? Impact of Diet on the Gut-Brain Axis in Parkinson’s Disease. Nutrients, 14, Article 380.
https://doi.org/10.3390/nu14020380
[67] Barichella, M., et al. (2016) Probiotics and Prebiotic Fiber for Constipa-tion Associated with Parkinson Disease: An RCT. Neurology, 87, 1274-1280.
https://doi.org/10.1212/WNL.0000000000003127
[68] Antushevich, H. (2020) Fecal Microbiota Transplantation in Disease Therapy. Clinica Chimica Acta, 503, 90-98.
https://doi.org/10.1016/j.cca.2019.12.010
[69] Zhao, Z., et al. (2021) Fecal Microbiota Transplantation Protects Rotenone-Induced Parkinson’s Disease Mice via Suppressing Inflammation Mediated by the Lipopolysaccharide-TLR4 Signaling Pathway through the Microbiota-Gut-Brain Axis. Microbiome, 9, Article No. 226.
https://doi.org/10.1186/s40168-021-01107-9
[70] Sun, M.F., et al. (2018) Neuroprotective Effects of Fecal Micro-biota Transplantation on MPTP-Induced Parkinson’s Disease Mice: Gut Microbiota, Glial Reaction and TLR4/TNF-α Signaling Pathway. Brain, Behavior, and Immunity, 70, 48-60.
https://doi.org/10.1016/j.bbi.2018.02.005
[71] Huang, H., et al. (2019) Fecal Microbiota Transplantation to Treat Parkinson’s Disease with Constipation: A Case Report. Medicine, 98, e16163.
https://doi.org/10.1097/MD.0000000000016163
[72] Kuai, X.Y., et al. (2021) Evaluation of Fecal Microbiota Transplantation in Parkinson’s Disease Patients with Constipation. Microbial Cell Factories, 20, Article No. 98.
https://doi.org/10.1186/s12934-021-01589-0
[73] Xue, L.J., et al. (2020) Fecal Microbiota Transplantation Therapy for Parkinson’s Disease: A Preliminary Study. Medicine, 99, e22035.
https://doi.org/10.1097/MD.0000000000022035
[74] Dailey, F.E., Turse, E.P., Daglilar, E. and Tahan, V. (2019) The Dirty Aspects of Fecal Microbiota Transplantation: A Review of Its Adverse Effects and Complications. Current Opinion in Pharmacology, 49, 29-33.
https://doi.org/10.1016/j.coph.2019.04.008
[75] Fereshtehnejad, S.M., et al. (2014) Motor, Psychiatric and Fatigue Features Associated with Nutritional Status and Its Effects on Quality of Life in Parkinson’s Disease Patients. PLOS ONE, 9, e91153.
https://doi.org/10.1371/journal.pone.0091153
[76] Paul, B.S., et al. (209) Prevalence of Malnutrition in Parkin-son’s Disease and Correlation with Gastrointestinal Symptoms. Annals of Indian Academy of Neurology, 22, 447-452.
https://doi.org/10.4103/aian.AIAN_349_18
[77] Uyar, G. and Yildiran, H. (2019) A Nutritional Approach to Mi-crobiota in Parkinson’s Disease. Bioscience of Microbiota, Food and Health, 38, 115-127.
https://doi.org/10.12938/bmfh.19-002
[78] Solch, R.J., et al. (2022) Mediterranean Diet Adherence, Gut Microbio-ta, and Alzheimer’s or Parkinson’s Disease Risk: A Systematic Review. Journal of the Neurological Sciences, 434, Arti-cle ID: 120166.
https://doi.org/10.1016/j.jns.2022.120166
[79] Barichella, M., et al. (2017) Dietary Habits and Neurological Fea-tures of Parkinson’s Disease Patients: Implications for Practice. Clinical Nutrition, 36, 1054-1061.
https://doi.org/10.1016/j.clnu.2016.06.020
[80] Mischley, L.K., Lau, R.C. and Bennett, R.D. (2017) Role of Diet and Nutritional Supplements in Parkinson’s Disease Progression. Oxidative Medicine and Cellular Longevity, 2017, Ar-ticle ID: 6405278.
https://doi.org/10.1155/2017/6405278
[81] Włodarek, D. (2019) Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease). Nutrients, 11, Article 169.
https://doi.org/10.3390/nu11010169
[82] Shaafi, S., et al. (2016) The Efficacy of the Ketogenic Diet on Motor Functions in Parkinson’s Disease: A Rat Model. Iranian Journal of Neurology, 15, 63-69.
[83] Vanitallie, T.B., et al. (2005) Treatment of Parkinson Disease with Diet-Induced Hyperketonemia: A Feasibility Study. Neurology, 64, 728-730.
https://doi.org/10.1212/01.WNL.0000152046.11390.45
[84] Phillips, M.C.L., et al. (2018) Low-Fat versus Keto-genic Diet in Parkinson’s Disease: A Pilot Randomized Controlled trial. Movement Disorders, 33, 1306-1314.
https://doi.org/10.1002/mds.27390