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帕金森症患者肠道菌群的结构性变化及其与帕金森症临床表型之间的关联性研究
其他题名Structural Changes of Gut Microbiota in Parkinson's Disease and its Correlation with Clinical Phenotypes
李薇
学位类型博士
导师金锋
2017-04
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业行为遗传学
关键词肠道菌群 帕金森症 Α-突触核蛋白 胃肠道功能失调 肠脑轴 16srrna测序
摘要

帕金森症是一种多发于中老年期的,慢性的、进行性的、可致残的神经系统退行性疾病。尽管研究已经发现了影响帕金森症的15 个基因和遗传位点, 但流行病学的调查认为遗传因素只能解释大约 10%的帕金森病例,而绝大多数的散发性帕金森症都与环境因素有关。在环境因素中,肠道菌群的作用是不可忽视的一环。近年越来越多的研究表明肠神经系统和副交感神经可能是最早出现α-突触核蛋白病理现象并深受其影响的神经系统。在帕金森患者中胃肠道功能障碍,比如便秘可能早于其运动症状数年出现。 而肠道菌群在维持胃肠道的微生态平衡中的作用至关重要, 并可能通过肠神经和迷走神经等途径与中枢神经系统和自主神经系统产生交互作用。 因此我们推测肠道菌群可能与帕金森患者的胃肠道症状乃至病理改变发生发展都有着一定的关系。 本研究的目的就是通过分析帕金森患者和健康对照人群的肠道菌群的结构性差异,来探索肠道菌群与帕金森症之间的关系。
本研究选取24例帕金森患者和14例健康对照志愿者的粪便样本为研究对象, 利用 Miseq 高通量测序平台和多元统计学方法检测细菌16SrRNA 基因V3-V5 区的多样性。本研究发现帕金森患者的肠道菌群整体结构与健康对照人群具有显著的差异, 帕金森患者的肠道菌群结构失衡主要表现为降解纤维素菌的显著减少和条件致病菌的显著增加。本研究发现,在PD 患者组中,主要降解纤维素的菌属 Blautia(2.14v.s.0.52,p<0.05),粪杆菌(Faecalibacterium)(5.18 v.s.2.48,p<0.05)和瘤胃球菌(Ruminococcus)(3.68 v.s. 1.10,p<0.05)的相对丰度和健康对照组比显著减少, 这些菌属主要以抗性淀粉和膳食纤维为底物,代谢产生大量的短链脂肪酸,是肠道细胞的重要营养来源以及调节肠道免疫应答重要因素。 帕金森患者肠道菌群结构失衡的另一明显特征是条件性致病菌志贺氏菌(Escherichia-Shigella)(0.55v.s 2.2,p<0.05)、 链球菌(Streptococcus)(0.09v.s0.33,p<0.05)、变形杆菌(Proteus)(0.001 v.s 0.2,p<0.05)和肠球菌(Enterococcus)(0.008v.s0.25,p<0.01)的相对丰度和健康对照组比显著增加。这些条件致病菌的异常增多可导致体内长期的慢性的炎症反应, 并代谢产生大量内毒素和神经毒素,可能诱发帕金森病理改变的发生。
本研究还尝试把肠道菌群的结构性变化与帕金森症的常见临床表型,如UPDRS评分, 病程年限、 HY评级、 非运动症状评分 (NMSS) 、Wexner 便秘程度评分和焦虑抑郁程度评分 (HAMA/HAMD)等放在一起做相关性分析。相关性分析的结果主要有两点:一是上述发现的主要降解纤维素的菌属Blautia,粪杆菌(Faecalibacterium)和瘤胃球菌(Ruminococcus)不仅在 PD患者组中显著降低,而且这种变化的趋势还与被试的UPDRS评分以及PD的病程年限成显著负相关关系,而同时与年龄、性别和 BMI 指数变化没有明显的相关关系。提示这种降解纤维素类的菌属的显著减少与帕金森症的病理变化有关。 二是上述发现的条件致病菌中肠球菌属(Enterococcus)、志贺氏菌属(EscherichiaShigella)、和变形杆菌属(Proteus)不仅在PD 患者组中显著升高,而且这种变化趋势还与被试的 UPDRS 评分以及PD的病程年限成显著正相关关系。 提示这些条件致病菌的异常增殖可能与帕金森症的病理变化有关。
之前的研究曾发现 PD患者的粪便样本中的 Blautia和Faecalibacterium菌属与PD 病程年限有显著相关关系,但与 UPDRS评分的显著相关关系尚属首次发现。 研究曾报道过条件致病菌肠球菌属(Enterococcus)、志贺氏菌属(EscherichiaShigella)在结直肠癌患者肠道中的异常增多,以及变形杆菌Proteus mirabills在自闭症儿童中的异常增多。 然而在帕金森患者人群中报道条件致病菌的异常增多及其与帕金森临床表型的关系也是首次发现。
本论文的研究成果提示, 肠道菌群在帕金森症病理改变中的作用,可能体现在两方面: 一是降解纤维素菌的减少会影响肠道的正常功能代谢,减少短链脂肪酸的产生,不利于对体内的炎症反应和氧化应激的调控; 二是条件致病菌的增多加剧了体内的炎症反应和氧化应激水平,更容易产生大量的内毒素和神经毒素,可能成为诱发症帕金森病理变化的环境因素。 帕金森症患者的肠道菌群与健康对照之间有显著差异,提示从改善肠道菌群的角度入手,通过益生菌干预来恢复肠道微生态的平衡可能成为治疗帕金森症的一种新方法。

其他摘要

Parkinson’s disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only about ten percent of cases. Epidemiologic studies have found that the majority of sporadic PD were associated with environmental factors. The role of gut microbiota is undisputable among all environmental factors. Accumulating evidences demonstrated that in the course of Parkinson’s disease (PD), the enteric nervous system (ENS) and parasympathetic nerves are among the structures earliest and most frequently affected by alpha-synuclein pathology.  Accordingly, gastrointestinal dysfunction, in particular  constipation often precedes the onset of motor symptoms by years. Recent research has shown that gut microbiota is critical in maintaining gastrointestinal homeostasis, and may interact with the autonomic and central nervous system via diverse pathways including the ENS and vagal nerve. Thus, we hypothesized that the gut microbiota was related with the gastrointestinal dysfunction in PD patients, as well as the development of PD pathology. The aim of this study is to analyze the structural change of gut microbiota in PD patients in comparison to healthy controls, and to explore the correlations between gut microbiota and Parkinson’s disease.
The study recruited 24 PD patients and 14 healthy volunteers, and collected their fecal samples for research. The isolated fecal DNA was used as a template for the amplification of the V3-V5 region of 16S rRNA gene on Miseq platform, and the multivariate statistical methods were employed to evaluate the diversity and structural changes  of gut microbiota. The study found significant differentiation between the PD group and healthy controls. The gut microbiota of PD group is generally dysbiosis in comparison with the healthy controls. The characteristic of this structural change is the increase of cellulose degraders and the decrease of conditional  pathogens. The genera  Blautia(2.14v.s.0.52, p<0.05),  Faecalibacterium(5.18 v.s.2.48, p<0.05) and  Ruminococcus (3.68 v.s. 1.10,p<0.05), which were mainly responsible for cellulose degrading in the colon, were significantly decreased in PD group comparing to healthy controls. These genera facilitated the fermentation of resistant starch and cellulose in the colon, and produced short-chain-fatty-acids (SCFAs) as their metabolite. The SCFAs  were trophic factors for enteric epithelial cells and were critical for regulating enteric immune response. Another important characteristic is the increase of conditional pathogens. The genera Escherichia-Shigella(0.55 v.s 2.2,p<0.05),  Streptococcus(0.09v.s0.33,p<0.05), Proteus(0.001 v.s 0.2,p<0.05), and Enterococcus(0.008v.s0.25,p<0.01)were significantly increased in PD group comparing to healthy controls. The proliferation of these conditional pathogens may cause chronic inflammation and produce endotoxins and neurotoxins, and may induce PD pathology thereby.
The study further correlated the structural change of gut microbiota with common clinical phenotypes  of PD, such as UPDRS, duration, NMSS, constipation, HAMA and HAMD. The correlation analysis found that the structural change of cellulose degraders(Blautia, Faecalibacterium and Ruminococcus) were negatively correlated with UPDRS score and PD duration, but not with the age, gender and BMI index, indicating the decrease of cellulose degraders in the gut microbiota may related with PD pathology. We also found the structural changes of conditional pathogens (Enterococcus, Escherichia-Shigella and Proteus) were positively correlated with UPDRS score and PD duration, indicating the proliferation of these conditional pathogens may related with PD pathology.
Earlier studies on the gut microbiota of PD have reported that Blautia and  Faecalibacterium were both negatively correlated with PD duration, but our study is the first to report that  Blautia and Faecalibacterium were both negatively correlated with UPDRS score. Research has found that  Enterococcus and EscherichiaShigella were significantly increased in colorectal cancer patients. Another  research found that  proteus mirabills  were significantly increased in autism children. But it's the first time that the significant increase of these conditional pathogens were reported in PD patients and correlated with PD phenotypes.
The result of this study suggested that the gut microbiota may influence PD pathology from two aspects: first, the decrease of cellulose degraders may affect the metabolic function in the gut, reduce  the production of SCFAs, thus, influence the regulation of inflammatory response and oxidative stress; second, the increase of conditional pathogens may stimulate the inflammation and oxidative stress in the host, produce more endotoxins and neurotoxins, which may facilitate the occurrence of PD pathology. After all, the structural change of gut microbiota may become sensitive biomarkers to predict and evaluate the risk for PD, and may provide a new solution for the early diagnosis and treatment for PD.

语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/21346
专题健康与遗传心理学研究室
作者单位中国科学院心理研究所
推荐引用方式
GB/T 7714
李薇. 帕金森症患者肠道菌群的结构性变化及其与帕金森症临床表型之间的关联性研究[D]. 北京. 中国科学院研究生院,2017.
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