溃疡性结肠炎和菌血症的代谢组NMR研究

发布时间：2018-03-15 01:04

  本文选题：代谢组学　切入点：炎症性肠病　出处：《中国科学院研究生院（武汉物理与数学研究所）》2013年博士论文　论文类型：学位论文

【摘要】：炎症性肠病(IBD)主要分为克罗恩病和溃疡性结肠炎(UC),因其高的致死率已成为严重的公共健康问题。目前,IBD的发病机制尚未完全阐明,普遍接受的是遗传、环境影响和免疫异常等相互作用共同导致IBD的发生。现今有着大量关于IBD易感基因和环境因素的研究,但是对其下游调节机制,尤其是与IBD相关的系统性代谢应答至今却少有人报道。动物模型因操作简便、可多时间点采样和组织器官的获得,成为生物医学不可或缺的研究对象。研究表明UC病发会导致肠道组织结构的改变,肠道细菌会通过破坏的肠道组织入侵宿主血液。为了探究细菌入侵血液引发宿主的代谢应答,本论文随后又研究了肺炎克雷伯菌感染的菌血症。菌血症是指外界的细菌经由体表或是感染的入口进入血液系统。侵入血液的细菌随着血液的流动在全身扩散并激发炎症反应,随后产生大量的炎症因子因而导致全身炎症反应综合征(SIRS)和多器官功能障碍综合症(MODS)。菌血症引发SIRS时宿主产生可检测的代谢物水平上的变化,鉴定并监视与菌血症的发生和发展相关的代谢组变化有助于深入地了解其发病机制,与此同时也打开了一扇对疾病进行营养支持的窗口。 为此,本论文使用了以核磁共振(NMR)为基础的代谢组分析技术并结合多变量数据分析手段,研究葡聚糖硫酸钠(DSS)诱导的急性溃疡性结肠炎小鼠的代谢组变化和肺炎克雷伯菌感染所致的菌血症大鼠的代谢应答。 首先,本论文采用了基于NMR的代谢组分析并结合组织病理学和临床血生化数据研究了DSS诱导的急性溃疡性结肠炎小鼠体液和各脏器的变化。研究发现急性溃疡性结肠炎导致了小鼠血浆中氨基酸含量的显著升高,结肠中与膜合成相关的代谢物以及多种核苷酸、碱基、核苷含量的显著下降。与此同时,溃疡性结肠炎也导致了小鼠肝脏中核苷酸含量的升高和葡萄糖含量的显著降低,脾脏中氧化谷胱甘肽含量的升高以及牛磺酸含量的显著降低。此外,DSS诱导的溃疡性结肠炎也引发了小鼠尿样中肠道菌群共代谢物含量的显著减少和三羧酸循环的中间产物的显著增加。这些研究结果表明溃疡性结肠炎的发生扰乱了机体的脂类和能量代谢,导致结肠和肝脏的受损,引发了机体的抗氧化和抗炎症反应以及扰乱肠道微生物的平衡。本研究结果提供了葡聚糖硫酸钠诱导的急性溃疡性结肠炎动态和全局性的代谢组变化,有助于IBD新治疗靶标的发现。 其次,本论文还采用基于NMR的代谢组分析技术并结合多变量数据分析手段研究了大鼠对肺炎克雷伯菌感染引发的代谢应答。研究发现肺炎克雷伯菌感染的菌血症扰乱了机体的能量代谢,主要表现在促进了糖酵解、三羧酸循环,脂质的氧化和磷酸肌酸的分解。此外,肺炎克雷伯菌感染的菌血症诱导了宿主的抗细菌内毒素,抗炎症和抗氧化反应。最后,菌血症也导致了宿主肠道菌群的紊乱。另外研究结果表明额外的补充葡萄糖和富含高脂和高胆碱的食物摄入可以有效地缓解菌血症病人的病情。 综上所述,本论文提供了DSS诱导的小鼠急性溃疡性结肠炎随时间变化和组织特异性的代谢组信息。此外,本论文还利用代谢组分析方法研究了肺炎克雷伯菌感染引发的宿主血浆和尿样随时间变化的代谢反应。
[Abstract]:Inflammatory bowel disease (IBD) mainly consists of Crohn's disease and ulcerative colitis (UC), because of its high mortality rate has become a serious public health problem. At present, the pathogenesis of IBD has not been fully elucidated, is widely accepted that genetic, environmental impact and immunological interactions lead to the occurrence of IBD. Today there are a large number of IBD susceptibility genes and environmental factors, but the downstream regulatory mechanism, especially the systemic metabolic response associated with IBD has rarely reported. The animal model because of its convenient operation, can obtain multi time point sampling and organs, as the research object. The research showed that biomedical indispensable UC attack will cause the intestinal tissue structure change, intestinal bacteria may be through the destruction of intestinal tissue invasion of host blood. In order to explore the bacteria invade the bloodstream causing metabolic response of the host, this paper then studies The Klebsiella pneumoniae infection and bacteremia. Bacteremia refers to the outside through the body surface or bacteria into the blood system infection. The bacteria invade the blood entrance with the blood flow induced systemic inflammation in diffusion and subsequent generation of numerous inflammatory factors resulting in systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) SIRS host. Bacteremia caused by changes in metabolite levels can be detected on the identification and monitoring and bacteremia and development related metabolic changes contribute to the in-depth understanding of the pathogenesis, but also open the door to disease nutritional support window.
Therefore, this paper used in nuclear magnetic resonance (NMR) metabolomics based analysis techniques combined with multivariate data analysis method, study on dextran sulfate sodium (DSS) metabolic response in rats caused by bacteria blood metabolic changes and Klebsiella pneumoniae induced acute ulcerative colitis in mice infected.
First of all, this thesis adopts NMR analysis and changes of metabolic and biochemical data of blood on DSS induced acute ulcerative colitis in mice humoral and organs combined with pathology. Based on the study found that acute ulcerative colitis resulted in significantly increased amino acid content in mouse plasma and colon associated with membrane synthesis the metabolites and a variety of nucleotide bases, nucleosides content significantly decreased. At the same time, ulcerative colitis also resulted in significantly reduced nucleotide content in liver were increased and the content of glucose and oxygen in the spleen of glutathione content increased and the content of taurine significantly decreased. In addition, DSS induced ulcerative colitis caused significantly increased significantly to reduce the intestinal flora in mice co metabolites in urine and three intermediate acid cycle. These results show that ulcer The occurrence of colitis disrupts lipid and energy metabolism, resulting in damage to the colon and liver, causing antioxidant and anti-inflammatory responses and disrupt the intestinal microbial balance. The results of this study provide acute ulcerative colitis dynamic and comprehensive metabolic changes induced by dextran sodium sulfate, contribute to the new IBD the discovery of therapeutic targets.
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