腸道菌群與NAFLD發(fā)生發(fā)展的關(guān)聯(lián)代謝機制研究
發(fā)布時間：2018-11-04 19:58
【摘要】：研究背景隨著肥胖及其相關(guān)代謝綜合征全球化的流行趨勢,非酒精性脂肪性肝病(NAFLD)現(xiàn)已成為威脅全球人類健康的慢性肝病。目前越來越多的研究證據(jù)表明腸道菌群(IM)紊亂在NAFLD的發(fā)生發(fā)展中起重要作用。但相關(guān)研究尤其是人群實驗數(shù)量有限,而且菌群失調(diào)如何影響機體代謝尚未見報道。肝臟是參與機體代謝的重要器官,膽汁酸和氨基酸代謝是肝臟的兩個主要代謝通路,并且與NAFLD的發(fā)生發(fā)展相關(guān)。我們前期預(yù)實驗發(fā)現(xiàn)NAFLD患者IM顯著影響宿主的代謝表型,初步發(fā)現(xiàn)膽汁酸和氨基酸代謝異常。因此,本研究將進—步深入探索膽汁酸、氨基酸代謝與IM之間的聯(lián)系及其在NAFLD發(fā)生發(fā)展中所起的作用。研究方法本研究以非酒精性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)患者以及健康對照(HC)個體為研究對象;利用分子生態(tài)學(xué)方法研究NAFLD患者腸道菌群結(jié)構(gòu)和功能改變;通過高效液相色譜—串聯(lián)質(zhì)譜法(UPLC-MS/MS)和核磁檢測技術(shù)(NMR)檢測NAFLD患者小分子代謝譜變化,重點檢測患者血清和糞便膽汁酸以及血清氨基酸水平;運用生物信息統(tǒng)計分析,初探IM改變與患者膽汁酸和氨基酸代謝變化的潛在關(guān)聯(lián)。研究結(jié)果1.從菌群分析結(jié)果上看,NASH患者IM結(jié)構(gòu)和功能較NAFL和HC組出現(xiàn)顯著變化。NASH組的腸道菌群生物多樣性顯著降低,菌群結(jié)構(gòu)變化表現(xiàn)為:與HC相比,在門的水平上,NASH患者擬桿菌門顯著降低,而變形菌門和放線菌門顯著增加;在科的水平上,擬桿菌科在NASH組腸道中降低,而腸桿菌科顯著增加;在屬的水平上,擬桿菌屬在NASH患者腸道中顯著降低,而Blautia屬顯著增加。擬桿菌、腸桿菌科及Blautia屬改變與膽汁酸.代謝異常密切相關(guān)。通過功能代謝分析發(fā)現(xiàn),NASH患者腸道中氨基酸、碳水化合物、多聚糖、脂質(zhì)、輔酶因子和維他命代謝相關(guān)基因表達顯著減少。2.與HC和NAFL組相比較,NASH患者糞便和血清中初級膽汁酸(膽酸和鵝去氧膽酸)水平顯著增高(P0.05),次級膽汁酸(脫氧膽酸和石膽酸)在NASH患者中有降低的趨勢。另外,血清纈氨酸、丙氨酸、酪氨酸和苯基丙氨酸水平在NAFLD患者中顯著增高(P0.05),并且隨著疾病進展逐漸增高。3.腸道差異菌與糞便膽汁酸、血清氨基酸水平以及肝臟生化指標(biāo)之間存在顯著相關(guān)性,提示IM可能通過改變機體膽汁酸和氨基酸代謝來影響NAFLD的疾病進展;并且血清纈氨酸、丙氨酸、酪氨酸和苯基丙氨酸組合可用于NAFL與NASH的鑒別診斷(AUC=0.863)。結(jié)論NAFLD尤其是NASH患者腸道菌群結(jié)構(gòu)及功能發(fā)生顯著改變,失衡的腸道微生態(tài)影響機體腸道中初級膽汁酸向次級轉(zhuǎn)化這一過程,因此,NASH患者糞便中初級膽汁酸顯著增高,而次級膽汁酸水平降低,從而影響NAFLD的疾病過程。腸道微生態(tài)失衡還可能引起機體氨基酸代謝異常;血清氨基酸水平檢測可為鑒別診斷NAFL與NASH提供新方法。
[Abstract]:Background with the globalization of obesity and its associated metabolic syndrome, (NAFLD) has become a chronic liver disease threatening human health worldwide. There is more and more evidence that intestinal (IM) disorder plays an important role in the occurrence and development of NAFLD. However, there is a limited number of relevant studies, especially in the population, and there are no reports on how the dysbacteriosis affects the metabolism of the body. Liver is an important organ involved in metabolism. Bile acid and amino acid metabolism are two main metabolic pathways of liver and are related to the occurrence and development of NAFLD. Our preliminary study showed that IM significantly affected the metabolic phenotype of the host in patients with NAFLD, and initially found abnormal metabolism of bile acids and amino acids. Therefore, this study will further explore the relationship between bile acid, amino acid metabolism and IM and its role in the development of NAFLD. Methods in this study, (NAFL), patients with non-alcoholic fatty liver and healthy individuals with (HC) were selected as subjects, and the structure and function of intestinal microflora in NAFLD patients were studied by molecular ecology method. High performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and nuclear magnetic detection (NMR) were used to detect the changes of small molecule metabolic spectrum in patients with NAFLD, especially the serum and fecal bile acids and serum amino acids. To explore the potential association between changes of IM and changes of bile acid and amino acid metabolism by statistical analysis of biological information. Results 1. The results of microflora analysis showed that the structure and function of IM in NASH patients were significantly different from those in NAFL and HC groups. The intestinal microflora biodiversity in NASH group was significantly lower than that in NAFL and HC groups. In NASH patients, Bacteroides significantly decreased, while Proteus and Actinomycetes increased significantly. In the family level, Bacteroides decreased in the intestinal tract of the NASH group, but increased significantly in the Enterobacteriaceae group. At the generic level, the Bacteroides decreased significantly in the intestinal tract of NASH patients, while the Blautia genus increased significantly. Changes and bile acids in Bacteroides, Enterobacteriaceae and Blautia genera. Metabolic abnormalities are closely related. The expression of amino acids, carbohydrates, polysaccharides, lipids, coenzyme factors and vitamin metabolism-related genes in the intestine of patients with NASH was significantly decreased by functional metabolism analysis. Compared with HC and NAFL groups, the levels of primary bile acids (cholic acid and chenodeoxycholic acid) in feces and serum of NASH patients were significantly increased (P0.05), and secondary bile acids (deoxycholic acid and lithocholic acid) tended to decrease in NASH patients. In addition, the serum levels of valine, alanine, tyrosine and phenylalanine were significantly increased in NAFLD patients (P0.05), and gradually increased with the disease progression. There is a significant correlation between intestinal bacteria and fecal bile acid, serum amino acid level and liver biochemical index, suggesting that IM may affect the disease progression of NAFLD by changing the metabolism of bile acid and amino acid. The combination of valine, alanine, tyrosine and phenylalanine can be used in differential diagnosis of NAFL and NASH (AUC=0.863). Conclusion the structure and function of intestinal flora in patients with NAFLD, especially in patients with NASH, are significantly changed. The imbalance of intestinal microecology affects the process of primary bile acid transformation from primary bile acid to secondary bile acid in intestinal tract. Therefore, the fecal primary bile acid in NASH patients is significantly increased. The level of secondary bile acids decreased, thus affecting the disease process of NAFLD. The imbalance of intestinal microecology may also lead to abnormal metabolism of amino acids, and the detection of serum amino acids may provide a new method for differential diagnosis of NAFL and NASH.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R575.5
[Abstract]:Background with the globalization of obesity and its associated metabolic syndrome, (NAFLD) has become a chronic liver disease threatening human health worldwide. There is more and more evidence that intestinal (IM) disorder plays an important role in the occurrence and development of NAFLD. However, there is a limited number of relevant studies, especially in the population, and there are no reports on how the dysbacteriosis affects the metabolism of the body. Liver is an important organ involved in metabolism. Bile acid and amino acid metabolism are two main metabolic pathways of liver and are related to the occurrence and development of NAFLD. Our preliminary study showed that IM significantly affected the metabolic phenotype of the host in patients with NAFLD, and initially found abnormal metabolism of bile acids and amino acids. Therefore, this study will further explore the relationship between bile acid, amino acid metabolism and IM and its role in the development of NAFLD. Methods in this study, (NAFL), patients with non-alcoholic fatty liver and healthy individuals with (HC) were selected as subjects, and the structure and function of intestinal microflora in NAFLD patients were studied by molecular ecology method. High performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and nuclear magnetic detection (NMR) were used to detect the changes of small molecule metabolic spectrum in patients with NAFLD, especially the serum and fecal bile acids and serum amino acids. To explore the potential association between changes of IM and changes of bile acid and amino acid metabolism by statistical analysis of biological information. Results 1. The results of microflora analysis showed that the structure and function of IM in NASH patients were significantly different from those in NAFL and HC groups. The intestinal microflora biodiversity in NASH group was significantly lower than that in NAFL and HC groups. In NASH patients, Bacteroides significantly decreased, while Proteus and Actinomycetes increased significantly. In the family level, Bacteroides decreased in the intestinal tract of the NASH group, but increased significantly in the Enterobacteriaceae group. At the generic level, the Bacteroides decreased significantly in the intestinal tract of NASH patients, while the Blautia genus increased significantly. Changes and bile acids in Bacteroides, Enterobacteriaceae and Blautia genera. Metabolic abnormalities are closely related. The expression of amino acids, carbohydrates, polysaccharides, lipids, coenzyme factors and vitamin metabolism-related genes in the intestine of patients with NASH was significantly decreased by functional metabolism analysis. Compared with HC and NAFL groups, the levels of primary bile acids (cholic acid and chenodeoxycholic acid) in feces and serum of NASH patients were significantly increased (P0.05), and secondary bile acids (deoxycholic acid and lithocholic acid) tended to decrease in NASH patients. In addition, the serum levels of valine, alanine, tyrosine and phenylalanine were significantly increased in NAFLD patients (P0.05), and gradually increased with the disease progression. There is a significant correlation between intestinal bacteria and fecal bile acid, serum amino acid level and liver biochemical index, suggesting that IM may affect the disease progression of NAFLD by changing the metabolism of bile acid and amino acid. The combination of valine, alanine, tyrosine and phenylalanine can be used in differential diagnosis of NAFL and NASH (AUC=0.863). Conclusion the structure and function of intestinal flora in patients with NAFLD, especially in patients with NASH, are significantly changed. The imbalance of intestinal microecology affects the process of primary bile acid transformation from primary bile acid to secondary bile acid in intestinal tract. Therefore, the fecal primary bile acid in NASH patients is significantly increased. The level of secondary bile acids decreased, thus affecting the disease process of NAFLD. The imbalance of intestinal microecology may also lead to abnormal metabolism of amino acids, and the detection of serum amino acids may provide a new method for differential diagnosis of NAFL and NASH.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R575.5
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