雙極症為一種嚴重且功能失調的情緒疾患。流行病學指出，使用丙戊酸治療的雙極症患者會增加其代謝異常的風險。雖然雙極症的病理生理學尚未被完全了解，據近年研究發現腸道菌相和多巴胺轉運子可能會影響大腦功能和周邊代謝。然而，目前研究針對微生物-腸-腦軸線和多巴胺轉運子，與丙戊酸的治療成效之關聯性，尚未定論。因此，本研究假設腸道菌相與多巴胺轉運子為丙戊酸治療中，作為與腦部治療成效及周邊代謝系統的共同調節因子。本研究使用7週齡雄性C57BL / 6N小鼠，為了誘導小鼠出現雙極症類似行為，施予社交挫敗壓力10天，而後於老鼠腹腔注射為期三週的350mg / kg 丙戊酸或10ml / kg生理食鹽水。本研究透過強迫游泳測試及社會偏好測試，檢測小鼠是否具憂鬱及社交異常行為。收集血液用於三酸甘油脂檢測和葡萄糖耐受性試驗。在丙戊酸治療前後分別收集新鮮糞便檢體，以Illumina次世代定序分析菌相16S rRNA的V3-V4區域，進一步透過線性判別分析（LEfSe），QIIME v1.80和mothur v.1.39.5整合生物資訊。我們利用西方墨點法測試小鼠紋狀體中多巴胺轉運子蛋白表現。統計顯著設於p <0.05。本研究結果顯示社交挫敗壓力誘導小鼠出現雙極症類似行為，包含社會迴避和類憂鬱行為。使用丙戊酸造成對照小鼠和社交挫敗小鼠其腸道微生物分布顯著不同。此外，Escherichia-Shigella屬在社交挫敗小鼠中含量顯著降低，而Enterobacter屬則顯著增加。藉由抗生素操弄腸道菌相可逆轉由壓力所誘導的憂鬱及社交異常行為，以及減緩在社交挫敗小鼠中由丙戊酸引起的高三酸甘油酯。除此之外，本研究亦發現社交挫敗小鼠腦部紋狀體的多巴胺轉運子表現量增加。使用丙戊酸處理後，社交挫敗小鼠的三酸甘油脂升高伴隨著多巴胺轉運子表現量下降，且三酸甘油脂與多巴胺轉運子的表現量具有顯著的負相關關係。根據以上結果，本研究推論腸道菌相和多巴胺轉運子在壓力狀態下扮演重要的角色，並提供雙極症疾患一個有潛力的新治療標的。

Bipolar disorder (BD) is a severe and dysfunctional mood disorder. Epidemiologic evidences have indicated increased risk of the metabolic abnormalities in BD patients treated with valproic acid (VPA). Although the pathophysiology of BD is not fully understood, recent reports suggested that gut microbiota and dopamine transporter (DAT) activity could affect brain function and metabolic status. Moreover, literatures about the potential role of the microbiota-gut-brain axis and DAT in the therapeutic effect of VPA is unknown. Thus, we hypothesized that gut microbiota and DAT could be common mediators to regulate therapeutic effects in the brain and influence metabolism in the peripheral tissue after VPA treatment. We used seven-week-old male C57BL/6N mice. To mimic bipolar disorder-like behaviours, the mice were under social defeat stress (SD) for 10 days, and then they were injected 350mg/kg VPA or 10ml/kg saline intraperitoneally for 3 weeks. There were two domains to confirm BD-like behaviour, including depression-like (forced swim test) and social behaviour (social preference test). The blood was collected for triglyceride detection and glucose tolerance test. Fresh fecal samples were individually collected at baseline and after VPA treatment. The microbial profiles of the samples were analyzed the V3-V4 regions of the bacterial 16S rRNA gene with next generation sequencing by Illumina. Bioinformatics analyses were performed using linear discriminant analysis effect size (LEfSe), QIIME v1.80 and mothur v.1.39.5. We applied western blotting to verify DAT protein expression on mice striatum. The significance was determined at p<0.05. In the current study, the results showed that social defeat stress developed BD-like behaviors mice, which exhibited social avoidance and depression-like behavior. The composition of gut microbiota was significantly different between saline-treated and VPA-treated control mice and the results were consistent in SD mice. We found that the genus Escherichia-Shigella were significantly less abundant in VPA-treated SD mice, together with the significant increase of Enterobacter when compared with vehicle-treated SD mice. Manipulation of composition of gut microbiota via antibiotic intervention reversed stress-induced depression-like and impaired social behavior, as well as alleviated triglyceride level caused by VPA in SD mice. In addition, SD mice were observed increased DAT expression in striatum. After treated with VPA, SD mice had elevated triglyceride levels along with decreased DAT expression. There was a significant negative correlation between triglyceride level and DAT expression. Taken together, the current study provided evidance of important roles of gut microbiota and DAT under stressful condition, and provided possible new therapeutic strategy in BD.

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