許多研究證實牛樟芝具有預防和減輕肝臟疾病、高血壓、糖尿病、發炎反應、致腫瘤性疾病與各種癌症之潛力，同時牛樟芝也可以預防高脂肪飲食引起的肥胖與其發展性脂肪肝，並具有調節腸道菌叢的功能。也有許多研究建議牛樟芝可作為日常補充的保健食品。然而，牛樟芝對於C57BL/6 (B6) 小鼠腸肝軸與腸道菌叢的影響尚不清楚，另外，牛樟芝是否具有抑制瘦素缺乏型小鼠 (Leptin-deficient (ob/ob) mice) 肥胖的能力並不瞭解。因此，本研究主題一為探討牛樟芝對B6小鼠的代謝功能作用機制，二為探討牛樟芝對瘦素缺乏型肥胖小鼠抗肥胖能力。本研究使用B6 小鼠來模擬健康人，而瘦素缺乏型小鼠則作為過度餵食誘導肥胖的動物模型。以牛樟芝餵食B6小鼠與瘦素缺乏型小鼠四週後，利用二維蛋白質電泳 (2D-DIGE) 及基質輔助雷射脫附離子化－飛行時間質譜儀(MALDI-TOF MS)與細菌鑑定質譜系統 (MALDI Biotyper) 等分析平台牛樟芝對於B6小鼠肝臟和腸道組織與腸道菌叢的影響。再以即時聚合酶鏈鎖反應 (Real-time PCR)和免疫印跡 (Immunoblotting) 等分析以闡明牛樟芝抗肥胖機制;另外，我們也利用人類結腸腺癌細胞 (Caco-2) 之單層膜模擬人類腸道上皮以了解牛樟芝與細菌代謝物對人類腸道通透性的影響。在探討牛樟芝對B6小鼠的代謝功能作用機制中，結果顯示B6小鼠的體重、葡萄糖耐受性試驗、每日食物與水分攝入量和糞便與尿液排出量皆不受餵食牛樟芝的影響。而牛樟芝能夠透過促進新陳代謝相關蛋白表現來降低肝脂肪的含量，並可能透過增加氧化還原調節、細胞骨架調節和代謝之蛋白表現來影響腸道通透性。同時牛樟芝，可以增加B6小鼠腸道菌叢中Alistipes shahii的豐富度。腸道菌叢主要是透過細菌分泌代謝物與腸肝軸相互作用，因此我們收集Alistipes shahii之細菌代謝物處理大腸直腸腺癌細胞株(SW480)和高轉移性大腸直腸腺癌細胞株(SW480-I5)，發現Alistipes shahii的代謝物與的大腸直腸腺癌細胞存活力和遷移能力並無直接關聯性。而且，Caco-2之單層膜研究中發現，Alistipes shahii的代謝物可能會增加人類腸道的通透性。接著，在探討牛樟芝對瘦素缺乏型肥胖小鼠抗肥胖能力的研究中，亦發現牛樟芝可以藉由抑制瘦素缺乏型小鼠的肝臟脂肪生成和脂質攝取，並促進附睪白色脂肪組織中的脂肪分解和減少脂肪生成，從而防止脂質沉積在肝臟與脂肪組織中。同時牛樟芝還可以增強腸道屏障的完整性並降低人類腸道的通透性，可作為對瘦素缺乏型小鼠和人類腸道上皮單層膜細胞的預防性保護。本研究顯示，牛樟芝餵食B6小鼠四周之後，腸道菌叢及腸肝軸的蛋白質表現的改變。而在不影響食物攝取量的情況下，牛樟芝餵食因瘦素缺乏引發的肥胖症小鼠，可透過調節肝臟和附睪白色脂肪組織的脂肪代謝並恢復腸道屏障完整性達到有效減少體重的功能。本研究為牛樟芝作為營養保健品提供了全面的評估，試驗結果顯示牛樟芝可以有效地減少因瘦素缺乏引起的肥胖，因此具有作為治療肥胖的營養保健品之潛力。

Many studies suggest that Antrodia cinnamomea (AC) has the potential to prevent or alleviate liver diseases, hypertension, diabetes, inflammatory, tumorigenic diseases, and various cancers. Recently, AC has been shown to prevent metabolic disorders of diet-induced obesity and the development of fatty liver and regulate gut microbiota. Some studies suggest that AC could be a potential prospective nutraceutical in the treatment of obesity or as a daily remedy in the prevention of disease. However, the AC-induced effects on the gut-liver axis and the gut microbial regulation are mostly unknown; meanwhile, whether the AC protects or attenuates the inherited obesity in leptin-deficient (ob/ob) mice is also unclear. Therefore, the two aims of this study, the aim I was to investigate the AC-induced effect in C57BL/6 (B6) mice, and the aim II was to understand the anti-obesity effect of AC in ob/ob mice. In the present study, the B6 mice were used to mimic healthy human and ob/ob mice as an over-feeding animal model. The B6 mice and ob/ob mice were fed with or without AC for 4 weeks. First, the two-dimensional difference gel electrophoresis (2D-DIGE) with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and MALDI Biotyper were used to investigate the comprehensive influence of AC in the gut-liver axis and gut microbiota of B6 mice. Next, the real-time PCR and immunoblotting analysis were performed to elaborate the anti-obesity mechanism of AC. Furthermore, we used Caco-2 cells as a human intestinal epithelial barrier model to examine the effect of AC and metabolite of bacteria on intestinal permeability. The results of AC-induced effects in B6 mice showed that the body weight, glucose tolerance test (GTT), daily food/water intake and fecal/urine weight were unaffected. Besides, AC supplementation might decrease hepatic lipid content by increasing metabolism and interacting intestinal permeability by increasing redox regulation, cytoskeleton regulation and metabolism in B6 mice. Meanwhile, AC treatment increased the abundance of Alistipes shahii (AS) in the gut microbiota of B6 mice. The gut microbiota might interact with the gut-liver axis mainly thought metabolites of bacteria, therefore, we utilized the metabolite of Alistipes shahii (MAS) to understand the effect on colorectal cancer cells SW480, high-invasive colorectal cancer cells SW480-I5 and Caco-2 cell barrier model. The results showed that MAS was not obviously correlated with cell viability and migration ability on SW480 and SW480-I5, and the MAS might increase intestinal permeability in Caco-2 cells. Next, the results of AC-induced anti-obesity ability in ob/ob mice indicated that AC supplementation suppressed hepatic lipogenesis and lipid uptake and facilitated lipolysis and reduces lipogenesis to prevent fat deposition in the epididymal white adipose tissue (EWAT). AC also reinforced intestinal barrier integrity and reduced intestinal permeability as preventive protection in ob/ob mice and the Caco-2 cell barrier model. Taken together, our study elaborated that AC-induced mechanisms on gut microbiota alteration and differential protein expression of the gut-liver axis in B6 mice. Simultaneously, AC supplementation effectively reduced leptin-deficiency-mediated obesity by regulating metabolism in the liver and EWAT and restoring the gut barrier integrity without any significant compromise on food intake. Thus, our study provides a comprehensive assessment for AC as the nutraceutical, and the AC extract effectively reduced obesity caused by leptin-deficiency and could potentially be used as a nutraceutical for treating obesity.

中文摘要-------------------------------------------------------------------------------------------------------------------------I
Abstract------------------------------------------------------------------------------------------------------------------------III
Acknowledgement-----------------------------------------------------------------------------------------------------------------V
Table of Contents---------------------------------------------------------------------------------------------------------------VI
List of Figures-----------------------------------------------------------------------------------------------------------------X
List of Tables------------------------------------------------------------------------------------------------------------------XII
Abbreviations-------------------------------------------------------------------------------------------------------------------XIII
Chapter 1 Introduction-------------------------------------------------------------------------------------------------------1
1.1 Overview of Antrodia cinnamomea------------------------------------------------------------------------------------------1
1.2 Overview of gut-liver axis-----------------------------------------------------------------------------------------------3
1.3 Overview of gut microbiota-----------------------------------------------------------------------------------------------5
1.4 C57BL/6 mice-------------------------------------------------------------------------------------------------------------7
1.5 Overview of obesity------------------------------------------------------------------------------------------------------8
1.6 Leptin-deficient obese mice----------------------------------------------------------------------------------------------9
1.7 Aim of this study--------------------------------------------------------------------------------------------------------10
Chapter 2 Materials and Methods----------------------------------------------------------------------------------------------11
2.1 The scheme of experiment-------------------------------------------------------------------------------------------------11
2.2 Chemicals and reagent----------------------------------------------------------------------------------------------------13
2.3 Mice---------------------------------------------------------------------------------------------------------------------14
2.4 Glucose tolerance test (GTT)---------------------------------------------------------------------------------------------15
2.5 Sample collection and histological observation---------------------------------------------------------------------------15
2.6 Immunohistochemistry (IHC)-----------------------------------------------------------------------------------------------15
2.7 2D-DIGE and gel image analysis-------------------------------------------------------------------------------------------16
2.8 Protein staining---------------------------------------------------------------------------------------------------------18
2.9 In-gel digestion---------------------------------------------------------------------------------------------------------18
2.10 MALDI-TOF MS analysis---------------------------------------------------------------------------------------------------19
2.11 Microbial identification of MALDI-TOF MS and microbial quantification---------------------------------------------------20
2.12 Fecal DNA extraction and real time PCR----------------------------------------------------------------------------------22
2.13 RNA extraction and real time PCR----------------------------------------------------------------------------------------24
2.14 Metabolite of Alistipes shahii (MAS) collection-------------------------------------------------------------------------26
2.15 Transwell migration assay-----------------------------------------------------------------------------------------------26
2.16 Immunoblotting----------------------------------------------------------------------------------------------------------27
2.17 Cell culture------------------------------------------------------------------------------------------------------------28
2.18 Ethanol extraction of Antrodia cinnamomea (EEAC)------------------------------------------------------------------------29
2.19 Cell viability----------------------------------------------------------------------------------------------------------29
2.20 Transepithelial electrical resistance (TEER)----------------------------------------------------------------------------30
2.21 Immunofluorescence------------------------------------------------------------------------------------------------------30
2.22 Statistical analysis----------------------------------------------------------------------------------------------------30
Chapter 3 Results------------------------------------------------------------------------------------------------------------32
3.1 Proteomic and Microbial Assessments on the Effect of Antrodia cinnamomea in C57BL/6 Mice---------------------------------32
3.1.1 AC reduces the liver weight without changed bodyweight and GTT in B6 mice----------------------------------------------32
3.1.2 AC may reduce hepatic lipid content and not change intestinal morphology in B6 mice------------------------------------36
3.1.3 2D-DIGE and MALDI-TOF MS analyze AC-induced proteomic alterations of the liver tissues in B6 mice----------------------39
3.1.4 2D-DIGE and MALDI-TOF MS analyze AC-induced proteomic alterations of the intestine tissue in B6 mice-------------------45
3.1.5 AC increases the abundance of Alistipes shahii (AS) in the gut microbiota of B6 mice-----------------------------------51
3.1.6 Metabolite of Alistipes shahii (MAS) may not affect cell viability and migration ability of colorectal cancer cells----55
3.1.7 Metabolite of Alistipes shahii (MAS) may increase intestinal permeability in Caco-2 barrier model----------------------58
3.2 Antrodia cinnamomea Confers Obesity Resistance and Restores Intestinal Barrier Integrity in Leptin-deficient Obese Mice--60
3.2.1 AC has an anti-obesity effect in ob/ob mice----------------------------------------------------------------------------60
3.2.2 AC reduces hepatic lipid accumulation and lipid deposition in EWAT in ob+/+ and ob/ob mice-----------------------------62
3.2.3 AC downregulates fatty acid uptake and lipogenesis-related genes and proteins in the liver of ob+/+ and ob/ob mice-----65
3.2.4 AC reduced hepatic inflammation in ob/ob mice--------------------------------------------------------------------------68
3.2.5 AC facilitates lipolysis-related protein expression in EWAT of ob/ob mice----------------------------------------------69
3.2.6 AC may restore the intestinal barrier in ob/ob mice--------------------------------------------------------------------71
3.2.7 Ethanol extracts of A. cinnamomea decrease intestinal permeability in Caco-2 cells-------------------------------------74
3.2.8 The potential mechanism of AC reduced obesity on the liver and EWAT in ob/ob mice--------------------------------------76
Chapter 4 Discussion---------------------------------------------------------------------------------------------------------78
Chapter 5 Conclusion---------------------------------------------------------------------------------------------------------86
Chapter 6 Reference----------------------------------------------------------------------------------------------------------87
Appendix------------------------------------------------------------------------------------------------------------------------100
Peer Reviewed Publications------------------------------------------------------------------------------------------------------130

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