Metformin藉由改變腸道菌相而改善第2型糖尿病的血糖控制

Metformin improves glycemic control in type 2 diabetes through alterations of gut microbiota

周佩萱(Pei-Syuan Jhou)

指導教授 ： 洪薇鈞

高雄醫學大學/醫學院/醫學研究所碩士班/碩士(2019年)

摘要

第2型糖尿病的全球罹病率大大增加，且發病的年齡變得更年輕。Metformin是第2型糖尿病治療的第一線藥物。儘管其在肝臟中的作用機制已被充分研究，但對腸道機轉的研究仍然有限。因此，本研究目標是了解短期和長期使用metformin後對腸道微生物之影響。共有14名為第2型糖尿病新診斷患者和26名診斷為第2型糖尿病兩年以上的患者被納入本研究，其生化數值納入統計分析。我們抽取患者糞便DNA用於腸道微生物組分析。第2型糖尿病新診斷患者在metformin治療之前以及之後1個月和3個月（M0，M1和M3）收集糞便。26名診斷為第2型糖尿病兩年以上患者則分為metformin單藥治療成功（n = 14）和失敗（n = 12），並收集其糞便，再進行微生物組分析，包括α-diversity（Chao1和Shannon），β-diversity（PCoA）和LefSe。針對所選特定物種則進行Q-PCR測試。第一部分分析比較了14名新診斷為第型糖尿病患者在M0，M1和M3的變化。結果顯示，和M0 與M1相比，M3中Escherichia coli的比例更高。第二部分比較了短期服用 metformin 3個月與長期服用metformin之第2型糖尿病患者之生化數值與腸道微生物相分析。結果顯示，與metformin單藥治療成功組相比，短期服用metformin3個月組具有較低比例的Gammaproteobacteria與較高比例的Bacteroidetes。第三部分分析比較metformin單藥治療成功與失敗兩組。結果顯示metformin單藥治療失敗組可能生成較多的acetate，原因為有較多的Streptococcus，metformin單藥治療成功組則有較多Actinetobacter。第四部份觀察當加入metformin後是否會影響E. coli (BCRC 11509)、Klebsiella pneumoniae (BCRC 10692)或A. johnsonii (BCRC 14853)生長，結果顯示三者並未受到metformin的刺激而增加其生長。從以上研究可知在metformin治療後會改變腸道微生物群組，包括增加Gammaproteobacteria，這或許與metformin之副作用有關。與metformin單藥治療失敗組相比，長期使用metformin單藥治療成功組在腸道微生物群中具有獨特的組成。Metformin 重塑腸道微生物之作用機制仍有待後續研究。

關鍵字

二甲雙胍 ； 第2型糖尿病 ； 腸道菌

並列摘要

The prevalence of type 2diabetes (T2D) is greatly increasing in the globe, and the onset age of T2D has become younger. Metformin is a first-line medication in the management of T2D. Although its mechanisms in liver have been well studied, studies on mechanisms in gut are still limited. Therefore, we aim to provide better understanding of the effects of short- and long-term use of metformin in the gut microbiota. A total of 14 T2D-newly diagnosed patients and 26 T2D patients diagnosed for more than two years were included in this study. Fecal DNAs were extracted for gut microbiome analysis. Biochemical characteristics were gathered for statistical analysis. Feces of T2D-newly diagnosed patients were collected before and after metformin treatment for 1 and 3 months (M0, M1, and M3). The remaining 26 patients were divided into success (n=14) and failure (n=12) of metformin monotherapy and collected feces once. Microbiome analysis including α-diversity (Chao1 and Shannon), β-diversity (PCoA) and LefSe were carried out. Q-PCR were performed for selected species. The first part of analysis compared M0, M1, and M3 of the 14 T2D-newly diagnosed patients. The results showed higher proportions of Escherichia coli in M3 compared to M0 and M1 by Q-PCR. The second part of analysis compared the Success of metformin monotherapy group and M3. The results showed that M3 had lower proportions of Gammaproteobacteria and higher proportion of Bacteroidetes compared to the Success of metformin monotherapy group by microbiome analysis. The third analysis compared the two groups of success and Failure of metformin monotherapy group. The results showed acetate production might be enhanced in the metformin monotherapy failure group, because Streptococcus species was increased. For metformin monotherapy success group, Acinetobacter species was increased. The fourth part of the analysis observed whether the addition of metformin affects the growth of E. coli (BCRC 11509), Klebsiella pneumoniae (BCRC 10692) or A. johnsonii (BCRC 14853). The results showed that the three species were not stimulated their growth by metformin. The above analyses revealed that gut microbiota composition was reshaped after metformin treatment, including increase of Gammaproteobacteria that might contribute to metformin side effect. Success in metformin monotherapy of long-term use has unique composition in gut microbiota compared to failure in metformin monotherapy. Mechanisms of metformin action in reshaping get microbiota remains unclear.

並列關鍵字

Metformin ； Type 2 diabetes ； Gut microbiota

參考文獻

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