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研究生:陳奕勳
研究生(外文):Yi-Hsun Chen
論文名稱:利用已知菌動物模式探討微生物對於非酒精性肝臟疾病發展的影響
論文名稱(外文):The roles of microbes on development of non-alcoholic fatty liver disease in gnotobiotic mouse model
指導教授:陳德勛黃彥智黃彥智引用關係
指導教授(外文):Ter-Hsin ChenYen-Te Huang
口試委員:廖俊旺王裕智莊曉莉
口試委員(外文):Jiunn-Wang LiaoYu-Chih WangHsiao-Li Chuang
口試日期:2020-01-13
學位類別:博士
校院名稱:國立中興大學
系所名稱:獸醫病理生物學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:41
中文關鍵詞:腸道菌非酒精性脂肪肝
外文關鍵詞:Gut microbiotanon-alcoholic fatty liver disease
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非酒精性脂肪肝疾病(NAFLD)是一種肝臟疾病,易發生於體重過重人群中,又與代謝症候群和肥胖症密切相關。NAFLD的病因複雜,目前尚不清楚。腸道菌群組成的變化(稱為腸道菌失衡)與NAFLD的發展和非酒精性脂肪肝炎(NASH)的發展是密切相關的。先前的研究得知,來自非腸道棲息地的微生物可在腸道內定植。我們生活的環境中會接觸到許多微生物,目前尚無研究釐清環境菌對NAFLD的影響。因此,本研究目的之一是利用已知菌動物模式證明環境菌對NAFLD的影響。另外,在NAFLD的臨床研究和動物模型顯示腸道菌群會從擬桿菌門(Bacteroidetes)轉變為厚壁菌門(Firmicutes)。但是,這些腸道菌群對NAFLD的影響仍然存在爭議。因此,本研究的另一目的是釐清這些微生物對於NAFLD的影響。
試驗一:八週大無菌小鼠(C57BL/6JNarl)定植從環境中分離出的Lysinibacillus xylanilyticus和Paenibacillus azoreducens,並餵食齧齒類標準飼料(LabDiet 5010,對照組)或含60%豬油(L組)或大豆沙拉油(S組)的飲食,連續18個月。結果顯示三組之間的體重不具顯著差異,但S組的白色脂肪組織囤積有增加。在肝損傷指數如天冬氨酸轉氨酶(AST)和丙氨酸轉氨酶(ALT)以及促炎性細胞因子如白介素6(IL-6)和腫瘤壞死因子-α(TNF-α)的表現量也無顯著差異。組織染色結果顯示雖L組相較於其他兩組有較嚴重的肝脂肪變性和脂肪油滴但不具顯著差異。脂肪酸合成酶(FAS),羥甲基戊二酰輔酶A還原酶(HMGCR),固醇調節元素結合蛋白2(SREBP2)和過氧化物酶體增殖物活化受體激活γ(PPARγ)的表現量有增加的趨勢。通過與先前的研究進行比較,這些結果顯示環境細菌可能不會影響肝脂質代謝,但會對肝炎症和脂質分佈產生影響。
  試驗二:四週大無菌小鼠(C57BL/6JNarl)分別定植從人體糞便中分離出的兩種擬桿菌(B組)或五種厚壁菌(F組)。定植四週之後餵食標準飲食(STD)或高脂飲食(HFD)16週。給予HFD的飲食,F組的體重,肝臟重量和肝脂肪變性增加。在HFD和STD中,F組均顯示出CD36(又稱為脂肪酸轉位酶)的表現量皆高於B組,顯示F組可能增加肝臟從血液循環中攝取脂肪酸。在給予HFD時,肝臟的脂肪新生相關基因在F組的表現量與B組相比較是增加的,包括FAS,硬脂酰輔酶A去飽和酶1(SCD1)和二酯酰甘油酰基轉移酶2(DGAT2)。此外,在F組的miR802-5p的表現量在肝臟中也是增加的。這些結果顯示,厚壁菌類可能通過調節肝臟吸收脂肪酸和脂質新生而誘發肝臟脂肪變性。
  綜合以上的結果得知腸道中存在的特定微生物影響NAFLD的致病過程是藉由影響肝臟基因表現進而引發肝臟脂肪變性導致肝臟的發炎反應。
Non-alcoholic fatty liver disease (NAFLD) is a liver disease largely occurs in overweight people and strongly related with the metabolic syndrome and obesity. The etiology of NAFLD is complex and remains unclear. Changes in composition of gut microbiota which is called as dysbiosis has been implicated in the development of NAFLD and progression of non-alcoholic steatohepatitis (NASH). Previous studies indicated that bacteria taxa from non-gut habitats can colonize in gut. Considering the many microorganisms we are exposed to in the environment, there is no study to clarify the effects of these environmental bacteria on NAFLD. Therefore, the effects of environmental bacteria on NAFLD were also investigated. Clinical studies and animal models have exhibited a shift of gut microbiota from Bacteroidetes to Firmicutes. However, the effects of these gut microbiota on NAFLD still remains controversial.
First experiment investigated the effects of environmental bacteria on NAFLD under different diets. C57BL/6JNarl mice were inoculated with Lysinibacillus xylanilyticus and Paenibacillus azoreducens and then fed either a normal diet (LabDiet 5010, control group) or a diet containing 60% lard (L-group) or soybean oil (S-group) for 18 months. Although there were no significant differences on body weight between these three group, S-group exhibited massive amounts of white adipose tissue compared to other groups. No significant differences between these three groups on hepatic injury index such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and expression levels of pro-inflammatory cytokine such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). However, L-group displayed more hepatic steatosis and fatty droplets paralleled with elevated expression levels of fatty acid synthase (FAS), hydroxymethylglutaryl-coenzyme A reductase (HMGCR), sterol regulatory element-binding protein 2 (SREBP2), and peroxisome proliferator-activated receptor gamma (PPARγ) than other groups. By comparing with previous studies, these data suggested that environmental bacteria may not affect hepatic lipid metabolism but has some impacts on hepatic inflammation and lipid distribution.
Second experiment was performed to elucidate the effects of Bacteroidetes and Firmicutes on NAFLD. Germ-free mice were inoculated with two species of Bacteroidetes (B-group) or five species of Firmicutes (F-group) which were isolated from healthy individuals. F-group exhibited increased body weight, liver weight, and hepatic steatosis compared to B-group under high-fat diet (HFD) condition. F-group showed the increasing expression level of cluster of differentiation 36 (CD36, as known as fatty acid translocase) compared to B-group both in HFD and standard diet (STD) which indicated elevated hepatic fatty acid influx in F-group. F-group also showed increasing de novo lipogenesis-related gene expression in liver including FAS, stearoyl-CoA desaturase-1 (SCD1) and diacylglycerol O-acyltransferase 2 (DGAT2) compared to B-group while under HFD condition. Additionally, elevated expression level of hepatic miR802-5p was also shown in F-group. These results indicated that these species of Firmicutes may induce more hepatic steatosis by modulating fatty acid influx and de novo lipogenesis compared to those of Bacteroidetes.
In conclusion, the results revealed that the specific microbies present in the intestines can cause hepatic steatosis and even the inflammatory response by affecting the expression of several genes. From these experiments, we can better understand the effects of microbes on the pathogenesis of NAFLD.
中文摘要 i
Abstract ii
目次 iv
圖表目次 vi
第一章 文獻探討 1
第一節 非酒精性脂肪肝臟疾病(Non-alcoholic fatty liver disease, NAFLD) 1
第二節 肝臟脂肪代謝(Hepatic lipid metabolism) 1
第三節 飲食對於NAFLD的影響 2
第四節 腸道菌(gut microbiota)對於NAFLD的影響 3
第二章 材料與方法 5
第一節 探討不同油脂來源的高脂飲食對環境菌定植小鼠脂質儲存和分佈的影響 5
一、動物 5
二、微生物移植(microbiota transplantation)及實驗設計 5
三、組織病理學評估 5
四、油紅O(Oil-red O)染色 5
五、血清生化學(serum biochemistry)分析 6
六、即時聚合酶連鎖反應(Real-time reverse transcription-PCR, qRT-PCR) 6
七、西方點墨法(western blotting) 6
八、利用高效液相層析(high performance liquid chromatography, HPLC)方式進行糞便短鏈脂肪酸分析 6
九、統計分析 7
第二節 探討擬桿菌門及厚壁菌門對宿主的脂肪代謝及NAFLD的影響 7
一、動物 7
二、微生物的分離,接種和實驗設計 7
三、組織病理學評估 8
四、油紅O(Oil-red O)染色 8
五、血清生化學分析 8
六、 mRNA的萃取及即時聚合酶連鎖反應 8
七、miRNA的萃取以及即時聚合酶連鎖反應 9
八、統計分析 9
第三章 實驗結果 11
第一節 探討不同油脂來源的高脂飲食對環境菌定植小鼠脂質儲存和分佈的影響 11
一、在環境菌的存在下,不同油脂來源的HFD對體重、肝臟重量、脂肪墊(fat pad)的影響 11
二、在環境菌的存在下,不同油脂來源的HFD對肝臟和脂肪組織組織學的影響 11
三、在環境菌的存在下,不同油脂來源的HFD對血清生化的影響 11
四、在環境菌的存在下,不同油脂來源的HFD對基因表達的影響 11
五、在環境菌的存在下,不同油脂來源的HFD對糞便中短鏈脂肪酸的影響 12
第二節 探討擬桿菌門及厚壁菌門對宿主的脂肪代謝及NAFLD的影響 12
一、F組微生物定植的小鼠̄表現出較嚴重的高脂飼料誘發肥胖 12
二、F組微生物定植的小鼠̄在HFD餵養下呈現較重的肝臟重量 12
三、F組微生物引起更嚴重的肝脂肪變性 12
四、F組和B組微生物群對血清生化的影響 13
五、F組和B組微生物群對肝臟脂質代謝和炎症的影響 13
六、F組微生物誘發肝臟miR-802-5p表現量 13
第四章 討論 14
第一節 探討不同油脂來源的高脂飲食對環境菌定植小鼠脂質儲存和分佈的影響 14
第二節 探討擬桿菌門及厚壁菌門對宿主的脂肪代謝及NAFLD的影響 15
第三節 結論 17
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