研究背景：雙極症為一種情緒疾患，其特徵為周期性的兩極情緒變化，且平穩期的患者認知功能仍比對照者不佳。近年來，腸道菌相被提出透過雙向的腸-腦軸在情緒疾患上扮演重要的角色，而腸道功能失衡的理論(leaky gut)可能為情緒疾患致病的新途徑。然而，腸道菌相的組成和治療成果在雙極症患者的關係尚未明確。此外，近年研究指出成纖維細胞生長因子2不僅可以調控血管新生和神經可塑性，在維持腸道壁完整性中亦扮演重要的角色。因此，本研究中第一個研究目的為：探討腸道菌相在平穩期雙極症患者和控制組中的差異，並分析精神藥物使用對於雙極症患者腸道菌相的影響。第二個研究目的為：探討腸道菌相與臨床數值的關聯性，並進一步觀察成纖維細胞生長因子2於其中的角色。
研究方法：本研究經國立成功大學醫學院附設醫院人體研究倫理審查委員會核可，招募符合DSM-5診斷標準的雙極症患者，並從社區招募排除精神相關共病的控制組。受試者於試驗糞便採檢前三個月內，使用益生菌或抗生素會加以排除。臨床檢測的部分會採集受試者空腹血糖偵測其臨床數值，包含血脂、血糖、內分泌和發炎數值。治療反應則是使用Alda量表進行評估。菌相分析使用Illumina次世代定序分析菌相16S rRNA的V3-V4區域，透過Mothur v.1.39.5和QIIME v1.9.0.整合生物資訊。
研究結果：結果顯示菌相組成在平穩期雙極症患者和控制組中顯著不同，Verrucomicrobia和Klebsiella在控制組中有較高的豐富度，而Firmicutes和Lachnospiraceae則在雙極症患者中有較高的豐富度。我們更進一步去評估不同治療對於菌群的影響，發現使用抗精神病藥物和丙戊酸並無差異。而Enterococcaceae 和Paraprevotella分別在使用抗精神病藥物和丙戊酸的患者中有較高的豐富度。後續我們使用Alda量表去評估丙戊酸的治療反應，將雙極症患者分為治療反應差和治療反應佳者。儘管兩組的菌群並無顯著差異，Clostridiaceae 1在治療反應差的患者中有較高的豐富度，而Proteobacteria則在治療反應佳的患者中有較高的豐富度。
此外，我們研究菌相和臨床數值在雙極症患者和控制組的相關性。在血脂的方面，Subdoligranulum和三酸甘油脂及低密度脂肪酸在控制組中呈正相關。而在血糖的相關性，Saccharimonadaceae與胰島素和糖化血色素在雙極症患者中呈正相關。對於發炎數值的相關性，Blautia和 Dorea與腫瘤壞死因子-α在雙極症患者中呈負相關。而在認知功能的相關性，Lachnospiraceae和Leuconostoc與遮蔽的持續性表現測驗呈正相關。此外，平穩期雙極性患者相對控制組有較高的成纖維細胞生長因子2，並且與疾病病程呈負相關。而成纖維細胞生長因子2濃度在雙極症患者中與Lachnospiraceae呈正相關，而與Akkermansia呈負相關。
結論：本研究指出腸道菌相組成在平穩期雙極症患者和控制組中有顯著差異，並且會受到丙戊酸和抗精神病藥物治療的影響。此外，腸道菌相的改變與代謝、發炎指標和認知功能具有相關性。另外一方面，我們發現在平穩期雙極症患者中有較高的成纖維細胞生長因子2濃度，而其濃度在雙極症患者中與腸道菌相具有相關性。因此，由本研究可以得知腸道菌相對雙極症患者的影響，然而後續需基礎研究輔助驗證菌相在生理機能中的角色，將其作為潛在的治療標靶。

Background. Bipolar disorder (BD) is a mood disorder, characterized by unusual shifts in mood (depression, hypomania, and mania), and caused the impairments of cognitive function even in euthymic stage. Recently, gut microbiota was reported to be a key role through the bidirectional brain-gut-microbiota axis in mental illness, and leaky gut theory became novel explaination of mood disorder. However, the relation of gut microbiota composition and treatment outcomes in BD patients remains unclear. Besides, recent studies suggested fibroblast growth factor 2 (FGF2) not only regulated angiogenesis and neuroplasticity but also played an important role in maintaining the gut barrier. Therefore, the first objective of the current study was to investigate the microbiota composition in euthymic BD patients and the controls, and to analyze the effect of the psychotropic drugs on the microbiota in BD patients. The secondary objective was to correlate the gut microbiota with clinical indices, and further to investigate the role of FGF2 in gut microbiota.
Materials and Methods
Subjects. This study proposal was approved by the institutional review boards at the National Cheng Kung University Hospital. We recruited patients with BD (n=77) who met DSM-5 criteria from outpatient settings at the National Cheng Kung University Hospital and the controls (n=36) without psychiatric disorder history from the community. All participants were required not to use probiotics and antibiotics for at least 3 months before the fecal sample collection.
Measurements. Fasting blood samples were collected to detect clinical indices (include lipid, sugar, inflammatory profiles and endocrine). Treatment response of BD patients was assessed by Alda scale.
Fecal microbiota analysis. The microbial profile was analyzed by the V3-V4 regions of the bacterial 16S ribosomal RNA (rRNA) gene with next-generation sequencing (Illumina MiSeq 16S Metagenomics). Bioinformatics analysis of the 16S rRNA gene sequence data was performed together with Mothur v.1.39.5 and QIIME v1.9.0.
Results. The results showed that the microbiota compositions were significantly different between BD patients and controls (ANOSIM: p = 0.013*). Verrucomicrobia and Klebsiella were dominant in controls, and Firmicutes and Lachnospiraceae were dominant in BD patients. We further estimated the effect of different treatments on the microbial profile, and there was no significant difference in microbial compositions between antipsychotics (AP) and valproate (VPA) treatment. Enterococcaceae and Paraprevotella were dominant in the AP treatment and the VPA treatment, respectively. Then, we used the Alda scale to assess the VPA treatment response, and classified the BD patients into non-responder and responder groups. Although there was no significant difference in microbial compositions, Clostridiaceae 1 was dominant in non-responder group, and Proteobacteria was dominant in responder. Besides, we investigated the correlation between microbiota and clinical indices in BD patients and controls. For lipid profile, Subdoligranulum was positively correlated with triglycerides and low-density lipoprotein cholesterol (LDL) in controls. For sugar profile, Saccharimonadaceae was positively correlated with insulin and HbA1c in BD patients. For inflammatory profile, Blautia and Dorea were negatively correlated with tumor necrosis factor-α (TNF-α) in BD patients. For cognitive function, the relative abundance of Lachnospiraceae and Leuconostoc were positively correlated with mask CPT. Furthermore, the level of FGF2 was significantly lower in euthymic BD patients than the controls (6.7±6.5 vs 15.8±13.7, p = 0.009**), and was negatively correlated with duration of illness. The level of FGF2 was positively correlated with Lachnospiraceae, and negatively with Akkermansia in BD patients.
Conclusion.
Our findings indicated that gut microbiota composition was significantly different in euthymic BD and control subjects, and was altered by VPA and AP treatment. Besides, VPA-treatment response had influence on the gut microbiota composition. In addition, change of gut microbiota was correlated with the metabolic, inflammatory profile and cognitive function. On the other hand, we found the euthymic BD patients had significantly lower levels of FGF2 than control subjects, and the FGF2 was correlated with gut microbiota in euthymic BD patients. Thus, we understood the influence of gut microbiota on BD patients. However, further studies are needed to investigate the mechanism of gut microbiota in pathology of BD. Gut microbiota can be a potential therapeutic target in the future.

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