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系統識別號 U0026-2208201914421000
論文名稱(中文) 益生菌對改善胰十二指腸切除術後病人腸內菌相失衡與控制膽道感染療效之評估
論文名稱(英文) Beneficial Effects of Probiotics on Improvement of Gut Dysbiosis and Postoperative Ascending Cholangitis in Patients with Pancreaticoduodenectomy
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所碩士在職專班
系所名稱(英) Institute of Clinical Medicine(on the job class)
學年度 107
學期 2
出版年 108
研究生(中文) 吳忠翰
研究生(英文) Jhong-Han Wu
學號 S97051103
學位類別 碩士
語文別 英文
論文頁數 42頁
口試委員 指導教授-沈延盛
指導教授-陳炯瑜
口試委員-林錫璋
召集委員-陳芃潔
中文關鍵字 術後膽管炎  胰十二指腸切除術  腸道菌相  16S rRNA基因定序 
英文關鍵字 postoperative ascending cholangitis  pancreaticoduodenectomy  gut microbiota  dysbiosis  16S rRNA gene sequencing 
學科別分類
中文摘要 研究背景:
術後膽管炎對於接受胰十二指腸切除術的病人來說,是一個常見的併發症。Oddi 括約肌是位於膽管、胰管及十二指腸交界部位的一個可以抵抗腸道細菌進入膽道的重要屏障,而在病患接受胰十二指腸切除術時會被切除,因而可能是造成術後膽管炎的一個重要原因。本研究主要目的是著重在胰十二指腸切除術與腸道菌相之間的相關變化及其與術後膽管炎之間的關聯性。另外,也進一步研究益生菌的介入是否可對術後膽管炎及術後腸道菌相失衡的現象有所改善。

研究方法:
首先,我們回顧在 2014 年至 2016 年間於成大醫院接受胰十二指腸切除術及胰臟體尾切除術的病例,並進行術後膽管炎發生機率、嚴重程度及常見菌種的評估。接著,用前瞻性研究的方式,收集 2015 年 1 月至 12 月於本院接受胰十二指腸切除術(共收錄 16 人)及胰臟體尾切除術(共收錄 3 人)的病人。我們收集這些病人在術前及術後的糞便檢體並進行完整的分析與比較。最後,我們會以含有益生菌的優酪乳作為介入的方式,來進行評估益生菌對開完胰十二指腸切除術超過六個月的病人的腸道菌相及術後膽管炎的影響。糞便檢體的收集會在病人服用益生菌之前、服用益生菌一個月後及停止使用益生菌兩個月之後這三個時間點完成。糞便檢體經處理後會由 Illumina Miseq platform 來進行 16S rRNA 的基因定序。

研究結果:
首先,本次研究總共回顧了 138 個接受胰十二指腸切除術的病人及 65 個接受胰臟體尾切除術的病人。在接受胰十二指腸切除術的病人當中,術後膽管炎的發生比率是18.8%,其中 92.3%的術後膽管炎病例都在手術後兩年內發生。Escherichia coli 是造成術後膽管炎病人發生菌血症最常見的菌種。接受胰臟體尾切除術的病人當中,無人發生術後膽管炎。其次,我們用前瞻性的研究方式收錄了 16 個接受胰十二指腸切除術的病人及 3 個接受胰臟體尾切除術的病人。在接受這兩種術式的病人當中,我
們發現其術前及術後的腸道菌相組成皆並無明顯不同。然而,在分析接受胰十二指腸切除術的病人術前術後糞便檢體時,我們發現術後的病人檢體當中 Escherichia-Shigella 菌屬顯著增加。最後,益生菌的使用,對接受胰十二指腸切除術的病人來說,並無法有效地造成腸道菌相的改變。然而在本研究中,使用益生菌一個月之後,可以增加胰十二指腸切除術後病人腸道中 Bifidobacterium/Escherichia-Shigella 的比例。

結論:
本研究證實接受胰十二指腸切除術的病人術後會有腸道菌相失衡的現象,進而可能造成術後膽管炎發生。短期使用益生菌可以有效提升 Bifidobacterium/Escherichia-Shigella 在腸道內的比例。然而,長期使用益生菌是否能有效改善術後膽管炎的發生仍需進一步的研究來證實。
英文摘要 Introduction:
Postoperative ascending cholangitis (POAC) represents one of the most common late complications of pancreaticoduodenectomy (PD). The disappearance of sphincter of Oddi is considered a possible cause of POAC after PD due to loss of mechanical barrier to prevent
bacterial reflux from the duodenum. Gut dysbiosis after PD may play a role in the occurrence of POAC. This study aims to clarify the change of gut microbiota after PD and its association with POAC. Furthermore, we prescribe probiotics to evaluate its effect on gut microbiota in patients after PD.

Methods:
First, we retrospectively reviewed the medical records in patients received PD and distal pancreatectomy (DP) from January 1, 2014 to December 31, 2016 to evaluate the condition of PAOC in National Cheng Kung University Hospital. Second, we prospectively enrolled patients that received PD (16 patients) and DP (three patients) between January 1, 2015 and December 31, 2015. Fecal samples of these patients at pre-surgery and post-surgery time
points were collected. Third, probiotics-containing yogurt were prescribed prospectively in patients, who have received PD (20 patients) for more than 6 months. We collected fecal samples at before probiotics, after taking probiotics for 1 month and after stopping probiotics
for 2 months. Fecal samples were sent for 16S rRNA gene sequencing on Illumina Miseq platform.

Results:
First, total 138 patients with PD and 65 patients with DP were enrolled retrospectively. POAC occurred in 18.8% of patients in PD group and 92.3 % of these patients developed in 2 years after PD. Escherichia coli is the most common pathogen of POAC related bacteremia. No patient in DP group developed POAC. Second, the α diversity and β diversity showed no significant difference between pre-PD and post-PD group, or between pre-DP and post-DP group. However, genera Escherichia-Shigella increased significantly in post-PD group compared with pre-PD group. Third, selected patients with good effects of taking probiotics revealed no significant difference in α diversity, β diversity, or
differential abundance of bacterial genera between different time points of fecal sample collection. The ratio of Bifidobacterium/Escherichia-Shigella increased after taking probiotics for 1 month.

Conclusion
Dysbiosis of gut microbiota occurs after PD and may be responsible for the development of POAC. Probiotics could induce a transient effect of increased ratio of Bifidobacterium/Escherichia-Shigella. Further studies are necessary to prove the beneficial effects after long-term use of probiotics on the improvement of POAC.
論文目次 Abstract…………………………………………………………………………II
Chinese Abstract……………………………………………………IV
Acknowledgement………………………………………………………VI
Thesis Contents……………………………………………………VII
Table Contents……………………………………………………VIII
Figure Contents………………………………………………………IX
Abbreviation Index…………………………………………………X
Introduction…………………………………………………………………1
Patients and Methods……………………………………………4
Results………………………………………………………………………………9
Discussion……………………………………………………………………11
Conclusion……………………………………………………………………16
References……………………………………………………………………17
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