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

The Effect of Second-Generation Antipsychotics to Gut Microbiome and Metabolic Index in Rat Model

劉育安(Yu-An Liu)

指導教授 ： 林亮音

共同指導教授 ： 劉韻如

國立臺灣大學/醫學院/醫學檢驗暨生物技術學研究所/碩士(2019年)

https://doi.org/10.6342/NTU201900108

摘要

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。

關鍵字

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 ； Olanzapine ； Aripiprazole (Abilify)

並列摘要

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.

並列關鍵字

schizophrenia ； atypical antipsychotics ； second-generation antipsychotics ； metabolic syndrome ； gut microbiota ； olanzapine ； aripiprazole (abilify)

參考文獻

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