本文選題：代謝組學(xué)　切入點(diǎn)：炎癥性腸病　出處：《中國科學(xué)院研究生院（武漢物理與數(shù)學(xué)研究所）》2013年博士論文　論文類型：學(xué)位論文

【摘要】：炎癥性腸病(IBD)主要分為克羅恩病和潰瘍性結(jié)腸炎(UC),因其高的致死率已成為嚴(yán)重的公共健康問題。目前,IBD的發(fā)病機(jī)制尚未完全闡明,普遍接受的是遺傳、環(huán)境影響和免疫異常等相互作用共同導(dǎo)致IBD的發(fā)生。現(xiàn)今有著大量關(guān)于IBD易感基因和環(huán)境因素的研究,但是對(duì)其下游調(diào)節(jié)機(jī)制,尤其是與IBD相關(guān)的系統(tǒng)性代謝應(yīng)答至今卻少有人報(bào)道。動(dòng)物模型因操作簡便、可多時(shí)間點(diǎn)采樣和組織器官的獲得,成為生物醫(yī)學(xué)不可或缺的研究對(duì)象。研究表明UC病發(fā)會(huì)導(dǎo)致腸道組織結(jié)構(gòu)的改變,腸道細(xì)菌會(huì)通過破壞的腸道組織入侵宿主血液。為了探究細(xì)菌入侵血液引發(fā)宿主的代謝應(yīng)答,本論文隨后又研究了肺炎克雷伯菌感染的菌血癥。菌血癥是指外界的細(xì)菌經(jīng)由體表或是感染的入口進(jìn)入血液系統(tǒng)。侵入血液的細(xì)菌隨著血液的流動(dòng)在全身擴(kuò)散并激發(fā)炎癥反應(yīng),隨后產(chǎn)生大量的炎癥因子因而導(dǎo)致全身炎癥反應(yīng)綜合征(SIRS)和多器官功能障礙綜合癥(MODS)。菌血癥引發(fā)SIRS時(shí)宿主產(chǎn)生可檢測的代謝物水平上的變化,鑒定并監(jiān)視與菌血癥的發(fā)生和發(fā)展相關(guān)的代謝組變化有助于深入地了解其發(fā)病機(jī)制,與此同時(shí)也打開了一扇對(duì)疾病進(jìn)行營養(yǎng)支持的窗口。 為此,本論文使用了以核磁共振(NMR)為基礎(chǔ)的代謝組分析技術(shù)并結(jié)合多變量數(shù)據(jù)分析手段,研究葡聚糖硫酸鈉(DSS)誘導(dǎo)的急性潰瘍性結(jié)腸炎小鼠的代謝組變化和肺炎克雷伯菌感染所致的菌血癥大鼠的代謝應(yīng)答。 首先,本論文采用了基于NMR的代謝組分析并結(jié)合組織病理學(xué)和臨床血生化數(shù)據(jù)研究了DSS誘導(dǎo)的急性潰瘍性結(jié)腸炎小鼠體液和各臟器的變化。研究發(fā)現(xiàn)急性潰瘍性結(jié)腸炎導(dǎo)致了小鼠血漿中氨基酸含量的顯著升高,結(jié)腸中與膜合成相關(guān)的代謝物以及多種核苷酸、堿基、核苷含量的顯著下降。與此同時(shí),潰瘍性結(jié)腸炎也導(dǎo)致了小鼠肝臟中核苷酸含量的升高和葡萄糖含量的顯著降低,脾臟中氧化谷胱甘肽含量的升高以及�；撬岷康娘@著降低。此外,DSS誘導(dǎo)的潰瘍性結(jié)腸炎也引發(fā)了小鼠尿樣中腸道菌群共代謝物含量的顯著減少和三羧酸循環(huán)的中間產(chǎn)物的顯著增加。這些研究結(jié)果表明潰瘍性結(jié)腸炎的發(fā)生擾亂了機(jī)體的脂類和能量代謝,導(dǎo)致結(jié)腸和肝臟的受損,引發(fā)了機(jī)體的抗氧化和抗炎癥反應(yīng)以及擾亂腸道微生物的平衡。本研究結(jié)果提供了葡聚糖硫酸鈉誘導(dǎo)的急性潰瘍性結(jié)腸炎動(dòng)態(tài)和全局性的代謝組變化,有助于IBD新治療靶標(biāo)的發(fā)現(xiàn)。 其次,本論文還采用基于NMR的代謝組分析技術(shù)并結(jié)合多變量數(shù)據(jù)分析手段研究了大鼠對(duì)肺炎克雷伯菌感染引發(fā)的代謝應(yīng)答。研究發(fā)現(xiàn)肺炎克雷伯菌感染的菌血癥擾亂了機(jī)體的能量代謝,主要表現(xiàn)在促進(jìn)了糖酵解、三羧酸循環(huán),脂質(zhì)的氧化和磷酸肌酸的分解。此外,肺炎克雷伯菌感染的菌血癥誘導(dǎo)了宿主的抗細(xì)菌內(nèi)毒素,抗炎癥和抗氧化反應(yīng)。最后,菌血癥也導(dǎo)致了宿主腸道菌群的紊亂。另外研究結(jié)果表明額外的補(bǔ)充葡萄糖和富含高脂和高膽堿的食物攝入可以有效地緩解菌血癥病人的病情。 綜上所述,本論文提供了DSS誘導(dǎo)的小鼠急性潰瘍性結(jié)腸炎隨時(shí)間變化和組織特異性的代謝組信息。此外,本論文還利用代謝組分析方法研究了肺炎克雷伯菌感染引發(fā)的宿主血漿和尿樣隨時(shí)間變化的代謝反應(yīng)。
[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.
鍏舵,鏈鏂囪繕閲囩敤鍩轟簬NMR鐨勪唬璋㈢粍鍒嗘瀽鎶，

本文編號(hào)：1613719