博碩士論文 105886002 詳細資訊



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姓名 高銘杉(Ming-Shan Kao)  查詢紙本館藏   畢業系所 生醫科學與工程學系
論文名稱 藉由研究皮膚微生物組體為人類疾病之治療與檢測 提供創新概念
(Novel concepts for the treatment and detection of human diseases through the study of skin microbiome)
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摘要(中) 微生物精準編輯：藉以使用選擇性發酵元PEG來對抗耐甲氧西林金黄色葡萄球菌
近來創建的聯合微生物組體計畫目的為了解微生物如何在彼此與人類之間相互作用，當致病菌金黃色葡萄球菌感染皮膚時，細菌與皮膚之間的交互作用將立馬產生，前人研究數據顯示，皮膚上的共生細菌可以藉由發酵作用來對抗一種耐甲氧西林金黄色葡萄球菌（MRSA, USA300）的生長，通過小規模的固態培養基實驗發現聚乙二醇二甲基丙烯酸酯（PEG-DMA）可作為選擇性發酵元只給予特定益生菌-皮膚共生之表皮葡萄球菌做使用，在其發酵中，至少五種短脂肪鍊酸（乙酸、丁酸以及丙酸）產生以對抗USA300，除此之外，包埋表皮葡萄球菌的PEG-DMA水膠還能有效的降低USA300的菌落生成，PEG-DMA及其衍生物具潛力成為新穎的生醫材料、訂製出特定微生物組體以對抗外來病原體。

鼻腔定植表皮葡萄球菌可以減輕SARS-CoV-2核酸殼蛋白在肺部中所引發的白細胞介素-6
嚴重急性呼吸系統綜合症冠狀病毒2（SARS-CoV-2）的感染可以引發過度的白細胞介素-6 （IL-6），導致無數的生物效應，其中包括會因免疫風暴而導致多重器官衰竭的嚴重冠狀病毒疾病2019（COVID-19），藉由小鼠模型，本研究證實鼻腔接種SARS-CoV-2的核酸殼蛋白（NPP）會增加白細胞介素-6在支氣管中的含量，給予表皮葡萄球菌液體椰油醇-辛酸/癸酸酯（LCC）可顯著降低NPP引發的IL-6，除此之外，表皮葡萄球菌藉由發酵LCC產生的電力與丁酸可以用來增進細菌的生長和激活游離脂肪酸受體2（Ffar2），若抑制Ffar2後，則會阻礙表皮葡萄球菌加入LCC以減少NPP誘導IL-6的作用，總而言之，本研究結果支持在改善SARS-CoV-2呼吸道感染所導致的免疫風暴中，表皮葡萄球菌扮演著第一道防線的角色。

受表皮葡萄球菌定植之小鼠鼻腔電訊號的信息相似性分析
人類微生物組體中已有許多細菌被認定為電力活性菌，從活體實驗中獲取複雜的電訊號並加以分析是需仰賴於特徵提取方法，將從人體中分離出的表皮葡萄球菌K1菌株事前定植於小鼠鼻腔中給予液體椰油醇-辛酸/癸酸酯（LCC）後產生電力，以給予生理食鹽水的組別所產生的電訊號為基準，進而發現給予LCC組別的電壓變化較高，其中兩組別的電訊號圖可以被信息相似性分析法明顯的分開，當表皮葡萄球菌K1菌株受添加玫瑰黃色素前處理後，其定植於小鼠鼻腔並給予LCC的電訊號圖則會回到與基準植高度相似，具上述所綜，共生電力活性菌影響著鼻腔電訊號，且所使用的信息相似性分析法是可以用以分析、定量出電訊號之相似性與規律性。

共生微生物在近年來已被證實不論是在人體表面、腸胃道、免疫系統、甚至是在心智上，都影響且代表著人類，藉由研究共生微生物之間是如何交互影響可幫助我們在微生物失衡所導致的疾病當中找到更有效的治療方法，檢測共生微生物之組成更可了解其引發人類疾病之成因、甚至可以其組成代表人類之健康狀態，在本篇論文中，將藉由研究皮膚微生物組體，提出創新的治療與檢測方法來針對人類疾病，並且深入討論其未來之展望與應用。
摘要(英) Microbiome Precision Editing: Using PEG as a Selective Fermentation Initiator Against Methicillin-resistant Staphylococcus aureus
Recent creation of a Unified Microbiome Initiative (UMI) has the aim of understanding how microbes interact with each other and with us. When pathogenic Staphylococcus aureus (S. aureus) infects the skin, the interplay between S. aureus and skin commensal bacteria occurs. Our previous data revealed that skin commensal bacteria can mediate fermentation against the growth of USA300, a community-acquired methicillin-resistant S. aureus MRSA (CA-MRSA). By using a fermentation process with solid media on a small scale, we define poly(ethylene glycol) dimethacrylate (PEG-DMA) as a selective fermentation initiator (SFI) which can specifically intensify the probiotic ability of skin commensal Staphylococcus epidermidis (S. epidermidis) bacteria. At least five SCFAs including acetic, butyric and propionic acids with anti-USA300 activities were produced by PEG-DMA fermentation of S. epidermidis. Furthermore, the S. epidermidis-laden PEG-DMA hydrogels effectively decolonized USA300 in skin wounds in mice. The PEG-DMA and its derivatives may become novel biomaterials to specifically tailor the human skin microbiome against invading pathogens.

Colonization of Nasal Cavities by Staphylococcus epidermidis Mitigates SARS-CoV-2 Nucleocapsid Phosphoprotein-induced Interleukin (IL)-6 in the Lung
Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger excessive interleukin (IL)-6 signaling, leading to a myriad of biological effects including a cytokine storm that contributes to multiple organ failure in severe coronavirus disease 2019 (COVID-19). Using a mouse model, we demonstrated that nasal inoculation of nucleocapsid phosphoprotein (NPP) of SARS-CoV-2 increased IL-6 content in bronchoalveolar lavage fluid (BALF). Nasal administration of liquid coco-caprylate/caprate (LCC) onto Staphylococcus epidermidis (S. epidermidis)-colonized mice significantly attenuated NPP-induced IL-6. Furthermore, S. epidermidis mediated LCC fermentation to generate electricity and butyric acid that promoted bacterial colonization and activated free fatty acid receptor 2 (Ffar2), respectively. Inhibition of Ffar2 impeded the effect of S. epidermidis plus LCC on the reduction of NPP-induced IL-6. Collectively, these results suggest that nasal S. epidermidis is part of the first line of defense in ameliorating a cytokine storm induced by airway infection of SARS-CoV-2.

Information-based similarity analysis of electric signals of nasally pre-colonized Staphylococcus epidermidis in mice
Many bacteria in the human microbiome have been identified as electrogenic microorganisms. Characterization of bacterial electricity from complex electric signals in vivo relies on a feature extraction method. A Staphylococcus epidermidis (S. epidermidis) K1 strain isolated from human was pre-colonized on the nasal cavities of mice and triggered with liquid coco-caprylate/caprate (LCC) to elicit electricity. Intranasal administration of phosphate buffered saline (PBS) was used to establish a base pattern of electric signals. Compared to PBS, LCC induced a higher level of voltage changes in S. epidermidis K1 colonized nasal cavities. The patterns of electric signals elicited by PBS or LCC were distinctly separated by information-based similarity (IBS) analysis. Treatment of S. epidermidis K1 with roseoflavin significantly diminished the electricity production of S. epidermidis K1 and exhibited electric signals with high similarity to a base pattern. Collectively, our results indicated that commensal electrogenic bacteria contributed to nasal electric signals and highlighted that IBS analysis was a quantitative method to analyze the similarity and regularity of bacteria-involved electric signals.

In recent years, microbiome has been shown to affect and represent the human body, whether on the human surface, in the gastrointestinal tract, in the immune system, or even in the mind. By studying the interaction between microbiome, the more effective treatments for diseases caused by microbial imbalance can be found. The causes of several human diseases can be understood through checking the composition of microbiome. It even represents the health status of human. In this dissertation, I will propose innovative therapeutic and detection methods to address human diseases by studying the skin microbiome and discuss the future perspectives and applications.
關鍵字(中) ★ 微生物組體
★ 選擇性發酵
★ 新冠肺炎
★ 電訊號
★ 表皮葡萄球菌		 關鍵字(英) ★ microbiome
★ selective fermentation
★ COVID-19
★ electric signals
★ S. epidermidis
論文目次 Chinese Abstract i
Abstract iii
Acknowledgement vi
Table of Contents ix
List of Figures xii
List of Table xiv
Chapter 1. Introduction 1
1.1. Human microbiome 1
1.2. Interaction between microorganism and human skin 1
1.3. Short-chain fatty acids (SCFAs) 2
1.4. Coronavirus disease 2019 (COVID-19) 3
1.5. Biomedical signals 3
1.6. Dissertation declaration 4
Chapter 2. Microbiome Precision Editing: Using PEG as a Selective Fermentation Initiator Against Methicillin-resistant Staphylococcus aureus 5
2.1. Introduction 5
2.2. Materials and Methods 8
2.2.1. Ethics statement 8
2.2.2. Bacterial culture 8
2.2.3. Bacterial fermentation in solid media 8
2.2.4. Anti-USA300 overlay assays 9
2.2.5. GC-MS analysis 9
2.2.6. The minimum bactericidal concentration (MBC) assays 10
2.2.7. Fabrication of S. epidermidis-laden PEG-DMA hydrogels 10
2.2.8. In vivo anti-USA300 activity of probiotic PEG-DMA hydrogels 10
2.2.9. Bacterial counts in USA300-infected skin 11
2.2.10. Statistical analysis 11
2.3. Results 11
2.3.1. PEG-DMA as a SFI for S. epidermidis 11
2.3.2. Suppression of USA300 growth by PEG-DMA fermentation of S. epidermidis 13
2.3.3. Identification of SCFAs produced by PEG-DMA fermentation by GC-MS 15
2.3.4. Anti-USA300 activities of SCFAs 17
2.3.5. Inhibition of USA300 growth by S. epidermidis-laden PEG-DMA hydrogels 19
2.4. Discussion 21
Chapter 3. Colonization of Nasal Cavities by Staphylococcus epidermidis Mitigates SARS-CoV-2 Nucleocapsid Phosphoprotein-induced Interleukin (IL)-6 in the Lung 26
3.1. Introduction 26
3.2. Materials and methods 28
3.2.1. Ethics statement 28
3.2.2. Sources of nasal swabs 28
3.2.3. NPP cloning, expression and purification 29
3.2.4. Nasal inoculation and IL-6 detection 29
3.2.5. Bacterial electricity detection 29
3.2.6. Isolation of nasal septum and detection of butyric acid by HPLC 30
3.2.7. Colonization of S. epidermidis on mouse nasal cavities 31
3.2.8. Inoculation of NPP into S. epidermidis-colonized mice and inhibition of Ffar2 32
3.2.9. Statistical analysis 32
3.3. Results 32
3.3.1. Nasal inoculation of NPP of SARS-CoV-2 in mice induces an increase in IL-6 in the lung 32
3.3.2. LCC fermentation mediates electricity production that is essential for nasal colonization of S. epidermidis 34
3.3.3. Produced of butyric acid by S. epidermidis-colonized nasal septum 37
3.3.4. S. epidermidis plus LCC attenuates NPP-induced IL-6 production in BALF via activation of free fatty acid receptor 2 (Ffar2) 40
3.4. Discussion 49
Chapter 4. Information-based similarity analysis of electric signals of nasally pre-colonized Staphylococcus epidermidis in mice 56
4.1. Introduction 56
4.2. Materials and methods 58
4.2.1. Ethics statement 58
4.2.2. S. epidermidis colonization on mouse nasal cavities 58
4.2.3. Detection of electricity on S. epidermidis-colonized mouse nasal cavities 58
4.2.4. Inhibition of bacteria-produced electricity 59
4.2.5. IBS analysis 60
4.2.6. Calculation of IBS values 61
4.3. Results 61
4.3.1. Formation of an electrical circuit for detection of electric signals in S. epidermidis K1-colonized mice 61
4.3.2. Dissimilar electric signals analyzed by IBS 63
4.3.3. Inhibition of S. epidermidis-elicited electric signals by roseoflavin 68
4.3.4. Contribution of S. epidermidis to electric signals detected in the upper respiratory tract 70
4.4. Discussion 73
Chapter 5 Conclusion 76
5.1 Key findings and significance 76
5.1.1 Chapter 2 | PEG-DMA hydrogels 76
5.1.2 Chapter 3 | First line of defense in nasal cavity 76
5.1.3 Chapter 4 | Analyzation of biomedical signals 77
5.2 Future study 78
Reference 80
Appendix 1: List of Publication 91
Appendix 2: Published Articles and Manuscript 92
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指導教授 黃俊銘 王孫崇(Chun-Ming Huang Sun-Chong Wang) 審核日期 2022-7-25
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