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研究生： 邱鈞瑋
Chiu, Chun-Wei
論文名稱： 去氧羥四環素在困難梭狀桿菌感染老鼠模型中的作用
Role of doxycycline in a mouse model of Clostridioides difficile infection
指導教授： 柯文謙
Ko, Wen-Chien
蔡佩珍
Tsai, Pei-Jane
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床醫學研究所碩士在職專班
Institute of Clinical Medicine(on the job class)
論文出版年： 2021
畢業學年度： 109
語文別： 英文
論文頁數： 35
中文關鍵詞： 困難梭狀桿菌 、去氧羥四環素 、小鼠模型 、治療
外文關鍵詞： Clostridioides difficile, doxycycline, mouse model, treatment
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    • 困難梭狀桿菌感染的主要危險因子是抗生素的濫用所造成，臨床上以甲硝唑以及萬古黴素做為困難梭狀桿菌感染的治療藥物，然而這兩種抗生素的治療容易造成困難梭狀桿菌感染的高復發率，以及萬古黴素抗藥性腸球菌的產生。因此臨床上一直在尋找對困難梭狀桿菌有殺菌力，又能降低對腸道菌叢影響的新抗生素。去氧羥四環素是四環黴素的衍生物，而文獻報告也顯示此抗生素不會增加困難梭狀桿菌感染的風險。在體外試驗中已證實去氧羥四環素對困難梭狀桿菌有抑菌力，但是仍不清楚是否可作為治療困難梭狀桿菌感染的新治療選項。我們以實驗小鼠建立了體外跟體內困難梭狀桿菌感染實驗，用以評估去氧羥四環素的暴露對困難梭狀桿菌在腸道菌相中生長的影響，以及去氧羥四環素的暴露對之後造成困難梭狀桿菌感染的影響。最後，以困難梭狀桿菌感染小鼠之動物模式，評估去氧羥四環素治療的效果。在體外實驗中，曾暴露去氧羥四環素的腸道菌相並不會增加困難梭狀桿菌的生長能力；同時在體內實驗中，相對應於高風險的克林達黴素，曾暴露去氧羥四環素的小鼠，感染困難梭狀桿菌的疾病症狀並不嚴重。此外，感染困難梭狀桿菌腹瀉的小鼠動物模式中，去氧羥四環素的治療不但可以減輕腹瀉的嚴重程度，而且去氧羥四環素的治療效果跟甲硝唑以及萬古黴素的療效不相上下。經由我們的小鼠實驗，去氧羥四環素的暴露並不是困難梭狀桿菌感染的危險因子，而去氧羥四環素治療可減輕困難梭狀桿菌感染嚴重度。

    Antibiotic overuse is the major risk factor for Clostridioides difficile infection (CDI), and metronidazole and vancomycin are commonly used to treat CDI in clinical patients. However, antibiotic treatment for CDI favors the fecal colonization of vancomycin-resistant enterococci and cannot preclude recurrent CDI. Discovery of new antibiotics that do not impair gut microbiota and can eliminate C. difficile in intestinal tract is required. Doxycycline is a derived compound of tetracycline and will not increase the risk of CDI development. In vitro studies have revealed that doxycycline display antibacterial activity against clinical C. difficile isolates. However, the efficacy of doxycycline in treating CDI is not clear. Here utilized experimental ex vivo and in vivo models to investigate the effect of pre-exposure to doxycycline on the growth of C. difficile and on the severity of CDI. Besides, therapeutic effect of doxycycline was examined in an established mouse model of CDI. Pre-exposure of doxycycline did not promote the cecal growth of C. difficile, as compared with pre-exposure of clinidamycin, in the ex vivo model. Meanwhile, pre-exposure of doxycycline did not lead to more body weight loss in the in vivo model. In addition, doxycycline, like metronidazole or vancomycin, therapy can ameliorate body and cecal weight loss in C. difficile-infected mice. Throughout our study, recent doxycycline exposure did not predispose the hosts to CDI as clindamycin, and oral administration of doxycycline can alleviate the disease severity of CDI, like metronidazole or vancomycin, in the mouse model.

    中文摘要 i Abstract ii Acknowledgements iii Table of Contents iv List of Tables vi List of Figures vii Abbreviations ix Chapter 1. Introduction 1 1.1 The prevalence and mortality of Clostridioides difficile infection 1 1.2 Limitations of traditional antibiotic therapy against C. difficile infection 1 1.3 Protective effect of doxycycline for C. difficile infection 2 1.4 Potential therapeutic use of doxycycline for C. difficile infection 3 1.5 Doxycycline susceptibility for clinical Clostridioides difficile isolates in Taiwan 4 1.6 Aims 4 Chapter 2. Materials and methods 6 2.1 To study the effect of doxycycline treatment on the growth of C. difficile by an ex vivo experiment 6 2.2 To study the impact of intraperitoneal doxycycline administration as a preventive or predisposing factor on CDI by an in vivo assay. 7 2.3 To assess effect of doxycycline therapy on C. difficile-infected mice. 7 2.4 Experimental materials and procedures 8 Bacterial strain and drugs 8 Gene expression analysis 8 Histopathologic examination 9 Data processing and statistical analysis 9 Chapter 3. Results 10 3.1 Exposure of doxycycline did not promote the growth of C. difficile in an ex vivo assay. 10 3.2 Doxycycline administration less aggravates C. difficile infection in an in vivo assay. 10 3.3 The effect of doxycycline therapy on C. difficile-infected mice 11 Chapter 4. Discussions 13 4.1 Exporsure of doxycycline exposure does not promote the growth of C. difficile 13 4.2 Alleviation of colonic epithelial permeability and inflammation in C. difficile-infected mice by doxycycline therapy 13 4.3 Doxycycline therapy in C. difficile-infected mice 14 4.4 Limitations and further researches 14 Chapter 5. Conclusions 17 References 18

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