腸道共生黴菌與酒精性肝病的相關性

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姓名

楊安民(An-ming Yang) 查詢紙本館藏

畢業系所

系統生物與生物資訊研究所

論文名稱

腸道共生黴菌與酒精性肝病的相關性
(The Association of Intestinal Fungi and Alcoholic Liver Disease)

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摘要(中)

在台灣地區，由於病毒性肝炎的盛行，慢性肝病及肝硬化是一個重要的課題。最近幾年來由於B型肝炎疫苗接種的普及及病毒性B型及C型肝炎治療的大幅度進展，因病毒性肝炎所導致的肝硬化及其併發症已經明顯的下降，相較之下，酒精濫用所導致的肝病及肝硬化卻明顯上升，酒精性肝硬化所導致的失能與死亡數在台灣也節節上升，在美國大約有一半的肝硬化所導致的死亡與酒精濫用相關，酒精導致的肝病的發生率正在明顯的上升，其重要性不言可喻。
慢性的酒精濫用而導致慢性酒精性肝病的病理機轉已被證實與腸道共生菌的生態失調有關、然而人類腸道共生的微生物並非只有細菌、腸道共生的黴菌在酒精性肝病扮演的角色並沒有被研究過。
在這個研究中，我們利用小鼠模式證明了慢性的酒精過量攝取會導致腸道共生黴菌的增生並導致黴菌細胞壁的Beta-葡聚糖轉移到血液循環中；對小鼠投以口服抗黴菌藥物會減少腸道黴菌的增生、減少血液循環中Beta-葡聚糖的量，從而減輕酒精性肝傷害；接下來我們藉由小鼠的骨髓移植製造了骨髓崁合體小鼠，並證明了Beta-葡聚糖經由與肝臟庫氏細胞或其他骨髓衍生細胞的CLEC7A受體結合來引發肝臟的發炎反應，引發了後續的IL-1β的表現及分泌增加並導致了肝發炎、惡化了酒精性肝病的程度。
在人體實驗上，我們觀察到酒精依賴患者表現出較低的腸道共生黴菌的多形性並合併念珠菌的增生；相較於健康個體及非酒精相關的肝硬化患者，酒精性肝硬化患者對黴菌所產生的系統性免疫反應也明顯增加，更甚者，我們發現個體對腸道外黴菌暴露的增加及其免疫反應與酒精性肝硬化的死亡率相關。
簡言之，慢性酒精的過量攝取會改變腸道中黴菌的生態平衡並增加黴菌細胞相關產物轉移至血液循環中，藉由操縱腸道中黴菌生態的平衡可能是一個有效減輕酒精性肝傷害的方法。

摘要(英)

Chronic liver disease with cirrhosis is a major medical problem in Taiwan, mainly because of endemic of viral hepatitis. In recent years, with the enforcement of universal vaccination for hepatitis B and the advance of treatment for both viral hepatitis B and C, the burden of viral hepatitis related cirrhosis is decreased significantly. In the contrast, alcohol related liver disease and cirrhosis is significantly increased. In the United States, alcoholic liver disease accounts for approximately half of all cirrhosis deaths. The prevalence of alcohol related liver disease is increasing and the importance cannot be overemphasized.
Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin–like receptor CLEC7A on Kupffer cells and possibly other bone marrow–derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non–alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.

關鍵字(中)

★ 酒精性肝病
★ 黴菌
★ 腸道共生菌
★ 肝臟免疫學

關鍵字(英)

★ Alcoholic liver disease
★ Mycobiome
★ Intestinal commensal microorganism
★ Hepatic immunology

論文目次

Table of contents
中文摘要…………………………………….i
Abstract …………..………………………iii
Acknowledgement ..…………………………v
Table of contents ..………………………vi
List of figures ………………………….vii
List of tables and.appendage………….viii
I : Introduction
1-1 Rationale of research…………….…1
1-2 Literature review…………………..2
1-3 Comments and specific aims…………4
II : Material and Method
2-1 Basic laboratory experiments and sequencing…..5
2-2 Animal experiments………………………………….11
2-3 Human clinical studies…………………………..…13
2-4 Statistics and study approval…………………….16
III : Results
3-1 In vivo experiments………………………………….18
3-2 In vitro experiments…………………………………24
3-3 Human clinical………………………………………..26
IV : Discussion.…………………………………………..28
V : Conclusion………..……………………………………31
Reference…………………..……………………………….32
Figures………………………………………………………40
Tables…………………………..….……………………..67
Appendage………………………….………………………..69

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指導教授

陳健生(Chien-shen Chen)

審核日期

2017-6-5

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