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研究生:劉育安
研究生(外文):Yu-An Liu
論文名稱:以大鼠模型探討第二代抗精神病藥物對腸道微生物菌相與代謝相關指數的影響
論文名稱(外文):The Effect of Second-Generation Antipsychotics to Gut Microbiome and Metabolic Index in Rat Model
指導教授:林亮音劉韻如
口試委員:廖淑貞歐大諒顧雅真
口試日期:2019-01-24
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:中文
論文頁數:80
中文關鍵詞:思覺失調症非典型抗精神病藥物第二代抗精神病藥物代謝性症候群腸道微生物菌相OlanzapineAripiprazole (Abilify)
DOI:10.6342/NTU201900108
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思覺失調症患者的死亡率為一般人的2~3倍,而由第二抗精神病藥物所造成的代謝症候群及心血管疾病成為了高死亡率的主因。此外,多項研究指出思覺失調症與代謝性疾病都會出現慢性全身發炎的情形。近幾年來的研究亦發現腸道微生物菌相在精神疾病以及代謝性症候群的形成皆有重要的作用。因此本實驗旨在探討 Olanzapine (OLZ) 和 Aripiprazole (ARI) 對代謝、發炎和腸道微生物菌相的影響。
本實驗透過持續管餵大鼠六週第二代抗精神病藥物-OLZ和ARI,以及生理食鹽水作為控制組後,發現大鼠體重和腹部的皮下及內臟脂肪確實較控制組有顯著增加,但此影響並非透過改變大鼠的飼料攝食量以及享樂攝食行為。基因表現方面,OLZ組肝臟Srebp-1c、Acc和Fas表現量皆下降,但ARI組只有Acc和Fas表現量皆較控制組低。另外,分析腹部白色脂肪組織CD68 mRNA的表現量,發現ARI組及OLZ組的CD68表現量皆較控制組高,表示兩組實驗組皆有巨噬細胞聚集在脂肪組織的現象。然而,OLZ及ARI並沒有顯著影響大鼠的血糖、三酸甘油酯、總膽固醇、高密度脂蛋白膽固醇、胰島素、細胞激素和糖尿病生物標記,僅趨化因子中的MIP-3a有顯著降低。
腸道菌相的分析的部分,首先從控制組的腸道檢體發現盲腸、結腸和直腸黏膜之間的菌相組成並沒有差異;盲腸、結腸和直腸內糞便之間的菌相組成亦無差異,但腸黏膜與腸內糞便的菌相組成卻顯著不同,且發現益生菌似乎較易存在腸黏膜中。而在服用OLZ和ARI後,盲腸糞便及盲腸黏膜的菌相多樣性顯著降低,且菌相組成分佈明顯與控制組不同,尤以盲腸黏膜更為顯著。
在本論文中,發現大鼠服用第二代抗精神病藥物OLZ和ARI後,盲腸黏膜的菌相多樣性會減少,並且盲腸黏膜的菌相組成會與肥胖或具有代謝症候群的動物模型或人類的腸道菌相相似,表示在第二代抗精神病藥物引起肥胖的潛在機制中,腸道菌相扮演了重要的角色。
Patients with schizophrenia suffer from two-fold to three-fold higher mortality rates compared with the general population. Metabolic syndrome and cardiovascular disease due to the side effect of second-generation antipsychotics become the major causes of mortality. Furthermore, several studies have indicated found that schizophrenia and metabolic syndrome both represent chronic systemic inflammation. In addition, recent studies have reported that gut microbiota play a critical role in development of psychotic disease and metabolic syndrome. Thus, we investigated the impact of olanzapine (OLZ) and aripiprazole (ARI) treatment on metabolic, inflammatory and gut microbiome parameters.
In this study, we treated female Sprague–Dawley rats with OLZ, ARI and saline by oral gavage for 6 weeks. We found that OLZ and ARI both induced significant body weight gain and increased abdominal subcutaneous and visceral fat; however, the effect was independent of food intake and hedonic hunger test. OLZ and ARI group tended to reduce locomotor activity compare to mock. In addition, OLZ down-regulated expression of hepatic Srebp-1c, Acc and Fas mRNA, whereas ARI only reduced Acc and Fas mRNA expression. Besides, analysis of CD68 mRNA expression indicated that OLZ and ARI induced macrophage infiltration in adipose tissue. Nevertheless, plasma glucose, triglyceride, total-cholesterol, HDL-C, insulin, cytokines and diabetes markers were not affected by ARI or OLZ. Only plasma MIP-3a significantly reduced in OLZ and ARI group.
On the other hand, we analyzed mock gut mucosal and stool microbiota at first, and found that the species richness and microbiota composition displayed similar distribution among mucosa of caecum, colon and rectum, and caecal, colonic, rectal stool microbiota composition also showed similar distribution, whereas microbiota composition was significant difference between mucosa and stool, and probiotics seem to mainly survive in large intestine mucosa. Following OLZ and ARI treatment, decrease of species richness (α-diversity) and altered microbiota profile (β-diversity) were observed in caecal stool and mucosa, especially significant in caecal mucosa.
In this study, we found that the species richness of rat caecal mucosa was decreased and the microbiota composition was altered into obesity- or metabolic syndrome-related microbiota profile in animal models or human. This finding indicated gut microbiota play a critical role in the underlying mechanism of second-generation antipsychotics induced obesity.
誌謝 I
摘要 III
ABSTRACT V
圖目錄 XI
表目錄 XII
第一章 研究背景 1
1. 思覺失調症 (SCHIZOPHRENIA) 1
1.1 思覺失調症簡介 1
1.2 病因與致病機轉 2
1.3 思覺失調症與代謝性症候群 4
1.4 思覺失調症與代謝性症候群之共同機制-慢性發炎反應 5
1.5 治療 6
2. 第二代抗精神病藥物 (SECOND­GENERATION ANTIPSYCHOTICS) 7
2.1 第二代抗精神病藥物簡介 7
2.2 第二代抗精神病藥物之副作用 8
3. 腸道微生物菌相 (GUT MICROBIOTA) 9
3.1 腸道微生物菌相與精神疾病 9
3.2 腸道微生物菌相與第二代抗精神病藥物 10
3.3 腸道微生物菌相與代謝性症候群 10
3.4 腸道微生物菌相與發炎反應 11
第二章 研究目標 13
第三章 材料與方法 14
1. 材料與試劑 14
1.1 實驗動物 14
1.2 藥物與試劑 14
1.3 器材與儀器 15
2. 實驗方法 16
2.1 藥物給予方式與劑量 16
2.2 體重測量 16
2.3 食物攝取量 16
2.4 享樂攝食行為 (Hedonic hunger test) 17
2.5 曠野實驗 (Open field test) 17
2.6 檢體採集 17
2.7 血漿分析 18
2.8 RNA萃取 18
2.9 反轉錄成互補DNA 19
2.10 基因表現分析 20
2.11 腹部皮下與內臟脂肪分析 21
2.12 糞便菌相DNA萃取 21
2.13 腸黏膜菌相DNA萃取 22
2.14 16S rDNA 基因庫 (Library) 製備 23
2.15 腸道微生物菌相分析 25
2.16 統計方法 26
第四章 結果 27
1. ARI 及 OLZ 對大鼠體重之影響 27
2. ARI 及 OLZ 對大鼠腹部皮下及內臟脂肪之影響 27
3. ARI 及 OLZ 對大鼠飼料攝食量及享樂攝食行為之影響 28
4. ARI 及 OLZ 對大鼠運動活性及焦慮行為之影響 28
5. ARI 及 OLZ 對大鼠肝臟脂質新生基因之影響 29
6. ARI及OLZ對大鼠腹部白色脂肪組織CD68表現之影響 29
7. ARI 及 OLZ對大鼠血糖、血脂生化數值之影響 30
8. ARI 及 OLZ對大鼠細胞激素、趨化因子、生長因子及糖尿病生物標
記之影響 30
9. 控制組大腸前中後段腸黏膜與糞便微生物菌相之分析 31
10. ARI 及 OLZ對大鼠腸道微生物菌相之影響 32
第五章 討論 35
第六章 未來展望 40
第七章 參考文獻 41
圖 50
表 78
附圖 79
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