肝臟和腸道損傷活化第四型類鐸受體介導細胞內發炎反應誘導肝臟疾病及發炎性腸道疾病的進程，並伴隨著腸道微生物菌叢生態的失衡。已知法尼醇X受體在肝臟疾病中負責調節能量新陳代謝與發炎反應，近年來許多研究指出法尼醇X受體在腸道發炎反應中參與改善腸道屏壁功能並調節腸道微生物菌叢生態，但是其參與之機制仍不清楚。本研究的目的是探討法尼醇X受體在肝臟和腸道損傷中調節發炎反應以及腸道微生物菌叢的機制。本研究使用C57BL/6正常小鼠及法尼醇X受體缺陷小鼠，經腹腔注射脂多醣(5 mg/kg)，12小時後腹腔注射法尼醇X受體激動劑GW4064 (20 mg/kg)兩次。研究結果顯示，相較於正常小鼠，脂多醣處理後顯著增加血清丙氨酸轉氨酶含量、肝臟及腸道細胞中促發炎因子(包括腫瘤壞死因子-α、白介素1β和白介素6)的基因表現。此外，脂多醣誘發小鼠肝臟及腸道的第四型類鐸受體、p38 絲裂原激活蛋白激酶和核因子活化B細胞κ輕鏈增強子蛋白質以及凋亡誘導因子(B細胞淋巴瘤2相關X蛋白和半胱氨酸蛋白酶3)的基因表現。GW4064在正常小鼠肝臟及腸道顯著降低脂多醣促進第四型類鐸受體訊號路徑、細胞發炎反應以及凋亡現象，但是GW4064對於法尼醇X受體缺陷小鼠並無顯著的改善效果。進一步觀察腸道屏障蛋白表現(包括緊密連接蛋白-1和閉鎖小帶蛋白-1)，結果顯示GW4064顯著改善脂多醣導致正常小鼠腸道緊密連接蛋白-1和閉鎖小帶蛋白-1減少的表現量，但是對於法尼醇X受體缺陷小鼠則無顯著的改善效果。有趣的是，GW4064在脂多醣處理的正常小鼠腸道中顯著改善了腸道菌叢的多樣性和組成，並且顯著降低由於脂多醣導致變形桿菌、γ變形菌、多形擬桿菌的增加。然而，GW4064對於脂多醣處理的法尼醇X受體缺陷小鼠腸道菌叢則無顯著的影響。總體而言，GW4064治療可藉由抑制脂多醣誘發的第四型類鐸受體訊號路徑抑制肝臟和腸道的發炎反應，並且改善腸道屏障以及調節腸道微生物菌叢生態，因此也許可作為治療肝炎以及大腸炎之嶄新策略。

Liver disease and inflammatory bowel disease (IBD) caused by toll-like receptor (TLR) 4-mediated intracellular inflammatory response, while following gut microbial dysbiosis. It is known that farnesoid X receptors (FXR) plays a central role in the regulation of energy metabolism and inflammatory response in liver disease. Recent studies indicated that FXR activation prevents gut barrier dysfunction and shapes the gut microbiota; however, the underlying mechanisms for theses improved phenotypes are not fully understood. The aim of this study was to investigate the action mechanisms of FXR in the regulation of inflammatory responses and gut microbial flora in liver and intestinal injury. In this study, male C57BL/6J wild-type (WT) mice and FXR knock (KO) mice were intraperitoneally (i.p.) injected with a single dose of lipopolysaccharide (LPS, 5 mg/kg), and 12 hours after LPS injection, mice were treated with FXR agonist GW4064 twice (20 mg/kg i.p.). The results showed that GW4064 alleviated LPS-induced increases in serum aspartate aminotransferase content and the mRNA expressions of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β and -6 in WT mice. In addition, TLR4, p38 mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein levels, B-cell lymphoma-2-associated X protein (BAX) and caspase 3 mRNA expression were decreased in WT mice receiving LPS with simultaneous GW4064 administration compared with those receiving LPS alone, while these changes were not observed in FXR KO mice. Furthermore, GW4064 improved LPS-induced decrease in the protein level of intestine epithelial tight junctional claudin-1 and zonula occludens-1 (ZO-1) in WT mice, but not in FXR KO mice. Interesting, GW4064 improved LPS-induced relative abundance of Proteobacteria, Gammaproteobacteria, Bacteroides thetaiotaomicron and altered intestinal microbial diversity and composition in the LPS-challenged WT mice, but not in FXR KO mice. In conclusion, GW4064 improved LPS-induced gut microbiota dysbiosis, tight junction disruption and TLR4 signaling-mediated inflammatory responses in WT mice. Therefore, GW4064 may become a new strategy therapy for liver disease and colitis.

目錄
誌謝…………………………………………………i
中文摘要…………………………………………………iii
英文摘要…………………………………………………v
中英文對照以及縮寫表…………………………………………………vii
目錄…………………………………………………xix
圖目錄…………………………………………………xxiv
表目錄…………………………………………………xxvi
附圖目錄…………………………………………………xxvii
第一章 緒論…………………………………………………1
1.1. 肝臟損傷…………………………………………………1
1.1.1. 肝臟疾病與第四型類鐸受體訊號傳遞路徑…………………………………………1
1.1.2. 非酒精脂肪肝疾病(non-alcoholic fatty liver diseases，NAFLD)…………………………………………………2
1.1.3. 酒精脂肪肝炎(Alcoholic steatohepatitis)………………………4
1.1.4. 自身免疫性肝病…………………………………………………4
1.1.5. 肝纖維化…………………………………………………5
1.1.6. 肝硬化…………………………………………………6
1.1.7. 脂多醣在肝臟致病機轉…………………………………………………6
1.2. 法尼醇X受體在肝臟的角色…………………………………………………7
1.3. FXR扮演的角色…………………………………………………11
1.4. 發炎性腸道疾病(Inflammatory bowel disease，IBD)………17
1.4.1. 克隆氏症…………………………………………………18
1.4.2. 潰瘍性結腸炎…………………………………………………21
1.4.3. 發炎性腸道疾病與TLR4相關訊號傳遞路徑…………………25
1.5. 腸道微生物菌叢與疾病相關性…………………………………………………27
1.5.1. 腸內微生物菌叢依據生物分類法分類………………………………………………… 28
1.5.2. 腸道微生物菌叢與發炎性腸道疾病…………………………………………………36
1.6. 脂多醣與發炎性腸道疾病…………………………………………………37
第二章 研究動機與目的…………………………………………………39
第三章 實驗材料與方法…………………………………………………40
3.1. 實驗設計…………………………………………………40
3.1.1. 實驗使用小鼠…………………………………………………40
3.2. 實驗分析流程…………………………………………………42
3.2.1. 組織學…………………………………………………42
3.2.1.1. 石蠟切片…………………………………………………42
3.2.1.2. 蘇木紫-伊紅染色…………………………………………………42
3.2.1.3. 免疫組織化學染色…………………………………………………43
3.2.2. 丙氨酸轉氨酶(alanine transaminase，ALT)濃度測定…………44
3.2.3. 總膽汁酸 (total bile acid，TBA)濃度測定…………44
3.2.4. 萃取組織的RNA以及合成cDNA…………45
3.2.5. 即時定量聚合酶鏈式反應(quantitative polymerase chain reaction, qPCR)…………46
3.2.6. 萃取組織的細胞核和細胞質內蛋白質…………46
3.2.7. 西方墨點法(western blot，WB)…………46
3.2.8. 從糞便樣本中萃取DNA…………48
3.2.9. 16S rRNA基因擴增和系統演化分析…………49
3.2.10. 腸道微生物菌叢主成分分析(principal components analysis，PCA)…………50
3.2.11. 統計方法…………50
第四章 實驗結果…………51
4.1. GW4064減緩脂多醣誘發血清ALT增加以及肝臟損傷…………51
4.2. GW4064在肝損傷小鼠提升肝臟內FXR蛋白質以及其下游SHP基因表現…………52
4.3. GW4064抑制脂多醣誘發肝臟損傷小鼠肝臟內TLR4訊號傳遞路徑…52
4.4. GW4064抑制脂多醣誘發肝臟損傷小鼠肝臟細胞凋亡…………53
4.5. GW4064提升迴腸炎小鼠迴腸內FXR蛋白質以及其下游SHP mRNA表現 …………54
4.6. GW4064改善脂多醣導致迴腸炎小鼠迴腸組織損傷和緊密連結蛋白損壞…………55
4.7. GW4064改善脂多醣誘發大腸炎小鼠大腸組織損傷以及FXR蛋白質表現量…………56
4.8. GW4064改善脂多醣誘發大腸炎小鼠腸道微生物菌叢多樣性之改變 …………57
4.9. GW4064對於脂多醣處理的正常和FXR缺陷小鼠腸道微生物菌叢的影響…………58
4.10. GW4064調節脂多醣誘發大腸炎小鼠腸道微生物菌叢組成比例……59
4.11. GW4064調節脂多醣誘發大腸炎小鼠血清和大腸總膽汁酸濃度……62
4.12. GW4064調節脂多醣誘發大腸炎小鼠大腸膽汁酸運輸因子表現……62
4.13. GW4064減緩迴腸炎小鼠迴腸巨噬細胞浸潤 ……65
4.14. GW4064減緩脂多醣導致迴腸炎小鼠迴腸TLR4和MyD88蛋白質表現 ……65
4.15. GW4064減緩脂多醣誘發大腸炎小鼠大腸TLR4訊號傳遞路徑……65
4.16. GW4064改善脂多醣誘發迴腸炎小鼠迴腸發炎反應以及細胞凋亡表現……66
4.17. GW4064減緩脂多醣誘發大腸炎小鼠大腸發炎反應、內質網壓力以及細胞凋亡表現……67
4.18. GW4064改善脂多醣誘發大腸炎小鼠大腸細胞凋亡表現……68
4.19. GW4064改善脂多醣誘發迴腸炎小鼠迴腸粒線體損傷……69
4.20. GW4064減緩脂多醣誘發大腸炎小鼠大腸促癌因子β-catenin和C-Myc蛋白質表現……70
4.21. GW4064改善脂多醣誘發大腸炎小鼠大腸血管新生……70
第五章 討論……72
參考文獻 ……83
實驗結果圖……107
表……142
附圖……146


圖目錄
圖一、GW4064減緩脂多醣誘發小鼠肝臟損傷和發炎反應………………………..107
圖二、GW4064降低脂多醣誘發肝臟損傷小鼠肝臟內發炎反應…………………108
圖三、GW4064提升脂多醣誘發肝臟損傷小鼠肝臟FXR以及其下游SHP表現 .109
圖四、GW4064減緩脂多醣誘發肝臟損傷小鼠肝臟內TLR4/MyD88/p38 MAPK/NF-κB信號路徑………………………………………………………...110
圖五、GW4064減緩脂多醣誘發肝臟損傷小鼠肝臟內細胞凋亡路徑之活化…… 112
圖六、GW4064提升脂多醣誘發迴腸炎小鼠迴腸FXR以及SHP表現之減少…. 113
圖七、GW4064改善脂多醣誘發迴腸炎小鼠迴腸組織和緊密連結蛋白損傷…… 115
圖八、GW4064改善脂多醣誘發大腸炎小鼠大腸損傷以及FXR蛋白質表現….. 116
圖九、GW4064改善脂多醣誘發大腸炎小鼠腸道屏障受損……………………… 117
圖十、GW4064影響腸道微生物菌叢多樣性……………………………………… 118
圖十一、GW4064對於脂多醣處理的正常和FXR缺陷小鼠腸道微生物菌叢的影響 …………………………………………………………………………………...119
圖十二、GW4064影響腸道微生物菌叢門類階段組成分布……………………… 121
圖十三、GW4064影響腸道微生物菌叢綱類階段組成分布……………………… 122
圖十四、GW4064影響腸道微生物菌叢目類階段組成分布……………………… 123
圖十五、GW4064影響腸道微生物菌叢種類階段組成分布……………………… 124
圖十六、GW4064調節腸道膽汁酸動態平衡和膽汁酸運輸因子mRNA表現….. 127
圖十七、GW4064調節膽汁酸運輸因子蛋白質表現……………………………… 129
圖十八、GW4064減緩脂多醣誘發迴腸炎小鼠迴腸巨噬細胞浸潤……………… 130
圖十九、GW4064減緩脂多醣誘發迴腸炎小鼠迴腸TLR4和MyD88蛋白質表現 …………………………………………………………………………………...132
圖二十、GW4064減緩脂多醣誘發大腸炎小鼠大腸TLR4訊號傳遞路徑……… 133
圖二十一、GW4064改善脂多醣誘發迴腸炎小鼠迴腸發炎反應以及細胞凋亡表現 …………………………………………………………………………………...135
圖二十二、GW4064減緩脂多醣誘發大腸炎小鼠大腸發炎反應、內質網壓力以及細胞凋亡 …………………………………………………………………………...136
圖二十三、GW4064減緩脂多醣誘發大腸炎小鼠大腸細胞凋亡因子Caspase 3蛋白質表現 …………………………………………………………………………...137
圖二十四、GW4064改善脂多醣誘發迴腸炎小鼠迴腸粒線體損傷 ………………......................................................................................................138
圖二十五、GW4064減緩脂多醣誘發大腸炎小鼠大腸促癌因子β-catenin和C-Myc蛋白質表現……………………………………………………………………... 139
圖二十六、GW4064減緩脂多醣誘發大腸炎小鼠大腸血管新生相關蛋白質表現 141

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