The Probiotic Activity of Human Microbiome Against Methicillin-Resistant Staphylococcus aureus Infection and Obesity

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楊杰龍(John Jackson Yang) 查詢紙本館藏

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論文名稱

(The Probiotic Activity of Human Microbiome Against Methicillin-Resistant Staphylococcus aureus Infection and Obesity)

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★ 產生丁酸的益生菌對異位性皮膚炎和第一型糖尿病的影響

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摘要(中)

益生菌，一種共生細菌能用於防止病原體在宿主體內定殖，已顯示出是一種預防及治療感染有前途的方法。耐甲氧西林金黃色葡萄球菌（S. aureus）（MRSA）已成為對公共衛生和軟組織感染的主要威脅。由於其對多種傳統抗生素的強大耐藥性，開發有效的MRSA治療方法仍是一項尚未解決的挑戰。第一項研究表明，從人皮膚中分離出的共生金黃色葡萄球菌具有介導甘油發酵產生短鏈脂肪酸（SCFA）的能力，短鏈脂肪酸可被定義為皮膚先天免疫力的一部分，可抑制USA300的生長。透過蛋白質組學定量分析甘油發酵中酶的表達，共生金黃色葡萄球菌中六種酶包括3-磷酸甘油脫氫酶（GPDH）和磷酸甘油酸變位酶（PGM）的表達水平比普通USA300高三倍。蛋白質印跡表明USA300、MRSA252（一種醫院獲得的MRSA菌株）和非抗藥性金黃色葡萄球菌（MSSA）中GPDH的低表達水平。在甘油存在下，共生金黃色葡萄球菌在體外和體內均能有效抑制USA300的生長。用共生金黃色葡萄球菌的裂解物或重組α-溶血素主動免疫小鼠，或用中和血清被動免疫可提供針對USA300皮膚感染的免疫保護。由於抗體可以提供抗金黃色葡萄球菌感染的保護，因此我們推測，共生金黃色葡萄球菌激發血液中的天然抗體是宿主適應性免疫的重要組成部分，可防止USA300 MRSA的生長。為傷口選擇合適的敷料，包括定植或感染MRSA的傷口，應根據患者的無菌類型和濕潤傷口癒合的原則來確定。由於水凝膠的特殊特性，例如對生理環境高度敏感，親水性，類軟組織水含量和足夠的柔韌性，使其成為生物醫學應用的極佳候選者。
在第二項研究中，我們製作了一個能夠吸收和釋放銅的半胱氨酸水凝膠，銅是一種具有抑制USA300生長能力的離子。傅立葉變換紅外光譜（FTIR）的分析結果表明，銅與半胱氨酸的水凝膠結合。在癌症研究所（ICR）小鼠背側皮膚上USA300感染的皮膚傷口上局部結合半胱氨酸與銅結合的水凝膠可顯著增強傷口癒合，阻礙USA300的生長並減少促炎物質的產生巨噬細胞炎症蛋白2-alpha（MIP-2）細胞因子。我們證明了新設計的水凝膠結合了一個半胱氨酸分子與銅結合可以螯合各種抗菌金屬，作為一種新型的傷口敷料。不僅在皮膚中，而且腸道益生菌在體內的存在都有有益的作用。腸道益生菌能夠調節整個身體的營養吸收，並調節體重，降低包括肥胖在內的多種疾病的發展。
第三項研究為腸膜腸球菌（Leuconostoc mesenteroides）（L. mesenteroides）對高脂飲食（HFD）誘導的PPAR-γ活化和腹部脂肪的益生作用。分化的3T3-L1脂肪細胞與產丁酸的腸膜腸球菌EH-1可顯著減少油滴的數量。腸膜腸球菌EH-1的口服在盲腸中產生大量（> 1 mM）丁酸，並減弱了HFD誘導的PPAR-γ上調和小鼠腹部脂肪的累積。2％葡萄糖與腸膜腸球菌EH-1的結合增加了丁酸的產生，並增強了腸膜腸球菌EH-1對3T3-L1脂肪細胞中脂滴形成以及HFD-腹部脂肪的益生菌活性餵老鼠。藉由拮抗劑GLPG-0974對游離脂肪酸受體2（Ffar2）的抑製作用，腸膜腸球菌EH-1和葡萄糖對抑制HFD誘導的PPAR-γ和腹部脂肪的益生作用明顯降低。除了證明腸膜腸球菌的益生菌價值外，我們的結果強調了針對丁酸激活的Ffar2途徑以減少腹部脂肪的可能療法。

摘要(英)

Probiotic bacteria, in which commensal bacteria are used to prevent the colonization of the host by pathogens, have been shown to be a promising modality for the prevention and treatment of infections. The methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) has become a major threat to public health and soft tissue infections. It remains an unmet challenge to develop effective therapeutic approaches for MRSA treatment because of its formidable resistance against multiple traditional antibiotics. The first study showed that commensal S. aureus bacteria isolated from human skin demonstrated the ability to mediate the glycerol fermentation to produce short-chain fatty acids (SCFAs), which can be defined as a part of skin innate immunity to inhibited the growth of USA300. Quantitative proteomic analysis of enzymes involved in glycerol fermentation demonstrated that the expression levels of six enzymes, including glycerol-3-phosphate dehydrogenase (GPDH) and phosphoglycerate mutase (PGM), in commensal S. aureus are more than three-fold higher than those in USA300. Western blotting validated the low expression levels of GPDH in USA300, MRSA252 (a strain of hospital-acquired MRSA), and invasive methicillin-susceptible S. aureus (MSSA). In the presence of glycerol, commensal S. aureus effectively suppressed the growth of USA300 in vitro and in vivo. Active immunization of mice with lysates or recombinant α-hemolysin of commensal S. aureus or passive immunization with neutralizing sera provided immune protection against the skin infection of USA300. As antibodies could offer protection against S. aureus infection, we speculated that natural antibodies in the bloodstream provoked by commensal S. aureus are a crucial part of host adaptive immunity to prevent the colonization of USA300 MRSA.
MRSA is often isolated from patient wounds, either in the hospital and community setting. Choosing a suitable dressing for any wound, including those colonized or infected with MRSA, should be determined by the type of wound a patient has in line with the principles of asepsis and moist wound healing. Due to hydrogels′ peculiar properties, such as high-sensitive to physiological environments, hydrophilic nature, soft tissue-like water content, and adequate flexibility, make them excellent candidates for biomedical applications. In the second study, we created a cysteine-capped hydrogel able to absorb and release copper, an ion with the capability of suppressing the growth of USA300, a community-acquired MRSA. The results of the analysis of Fourier transform infrared spectroscopy (FTIR) revealed the binding of copper to a cysteine-capped hydrogel. The topical application of a cysteine-capped hydrogel binding with copper on USA300-infected skin wounds in the dorsal skin of the Institute of Cancer Research (ICR) mice significantly enhanced wound healing, hindered the growth of USA300, and reduced the production of pro-inflammatory macrophage inflammatory protein 2-alpha (MIP-2) cytokine. Our work demonstrates a newly designed hydrogel that conjugates a cysteine molecule for copper binding. The cysteine-capped hydrogel can potentially chelate various antimicrobial metals as a novel wound dressing.
Not only in the skin, but the presence of gut probiotic in the body has beneficial effects. The gut probiotic is capable of regulating nutrients acquisition throughout the body and eventually bodyweight, leading to the development of several diseases, including obesity. The third study aimed to investigate the probiotic effect of Leuconostoc mesenteroides (L. mesenteroides) on high-fat diet (HFD)-induced Peroxisome proliferator-activated receptor gamma (PPAR-γ) activation and abdominal fat depots. Incubation of differentiated 3T3-L1 adipocytes with media of L. mesenteroides EH-1, a butyric acid-producing strain, significantly reduced the amounts of lipid droplets. The oral administration of L. mesenteroides EH-1 produced large amounts (>1 mM) of butyric acid in the cecum and attenuated the HFD-induced upregulation of PPAR-γ and accumulation of abdominal fats in mice. The combination of 2% glucose with L. mesenteroides EH-1 increased the production of butyric acid and potentiated the probiotic activity of L. mesenteroides EH-1 against the formation of lipid droplets in 3T3-L1 adipocytes as well as abdominal fats in HFD-fed mice. The inhibition of free fatty acid receptor 2 (Ffar2) by its antagonist, GLPG-0974, markedly diminished the probiotic effects of L. mesenteroides EH-1 plus glucose on the suppression of HFD-induced PPAR-γ and abdominal fats. Besides demonstrating the probiotic value of L. mesenteroides EH-1, our results highlight the possible therapy targeting the butyric acid-activated Ffar2 pathway to reduce abdominal fats.

論文目次

Table of contents
摘要 ii
Abstract iii
Acknowledgement v
Table of contents vi
List of figures ix
List of table xi
Abbreviations xii
Chapter 1. Literature review 1
1.1. Methicillin-resistant Staphylococcus aureus (MRSA) infection 1
1.2. MRSA infection treatment 1
1.3. Probiotic function in the diseases 2
1.4. Short-chain fatty acids (SCFAs) 3
1.5. Abdominal adipose tissues 4
1.6. Rationale of the present study 5
1.6.1. Aims of the present study 5
1.6.2. Questions raised in the present study 5
1.6.3. Structure of the thesis 6
Chapter 2. Commensal Staphylococcus aureus provokes immunity to protect against skin infection of methicillin-resistant Staphylococcus aureus 8
2.1. Abstract 8
2.2. Introduction 8
2.3. Materials and Methods 11
2.3.1. Ethics statement 11
2.3.2. Bacterial culture, identification, glycerol fermentation and anti-USA300 overlay assays 11
2.3.3. Identification of SCFAs by NMR analysis 12
2.3.4. Mass spectrometric label-free protein quantification 12
2.3.5. Western blot 13
2.3.6. In vivo effects of S. aureus glycerol fermentation on skin infection of USA300 13
2.3.7. Molecular cloning and expression of recombinant α-hemolysin 14
2.3.8. Vaccination, antibody detection and protection against USA300 14
2.3.9. Antibody detection and test strip fabrication 15
2.3.10. Statistical analysis 15
2.4. Results 15
2.4.1. Interference of commensal S. aureus with the growth of USA300 15
2.4.2. Differential expression of enzymes in the pathway of glycerol fermentation 18
2.4.3. SCFAs in fermentation metabolites of commensal S. aureus and suppression of USA300 growth in vivo 21
2.4.4. Protection of skin infection of USA300 by antibodies to α-hemolysin of commensal S. aureus 24
2.5. Discussion 28
Chapter 3. Cysteine-capped hydrogels incorporating copper as effective antimicrobial materials against methicillin-resistant Staphylococcus aureus 32
3.1. Abstract 32
3.2. Introduction 32
3.3. Materials and Methods 35
3.3.1. Ethics statement 35
3.3.2. Synthesis of cysteine methacrylate (CysMA) 35
3.3.3. Preparation of CysMA/copper chloride hydrogel and 3-(acryloyloxy)-2-hydroxypropyl methacrylate/copper chloride hydrogel 36
3.3.4. Fourier transform infrared spectroscopy (FTIR) analysis 36
3.3.5. Copper ion absorption and releasing measurement of hydrogel 36
3.3.6. The antibacterial activity of hydrogel containing copper ions 37
3.3.7. The minimum bactericidal concentration (MBC) assays 37
3.3.8. Wound size infection on a mouse animal model 37
3.3.9. Bacterial counting 37
3.3.10. Statistical analysis 38
3.4. Results and Discussion 38
3.4.1. Preparation of CysMA monomer 38
3.4.2. Preparation of CysMA and MA Hydrogel and the Hydrogel Appearance 39
3.4.3. Absorption and Release Ability of CysMA and MA Hydrogels 41
3.4.4. FTIR Analysis 44
3.4.5. Antibacterial Test 45
3.4.6. Wound Infection Mouse Model 47
Chapter 4. Mouse abdominal fat depots reduced by butyric acid producing Leuconostoc mesenteroides 50
4.1. Abstract 50
4.2. Introduction 50
4.3. Materials and Methods 52
4.3.1. Ethics statement 52
4.3.2. Glucose fermentation of L. mesenteroides EH-1 52
4.3.3. 3T3-L1 cell differentiation and Oil Red O staining 53
4.3.4. Feeding mice with L. mesenteroides EH-1 and Ffar2 inhibition 53
4.3.5. Butyric acid detection by high performance liquid chromatography (HPLC) 54
4.3.6. PPAR-γ expression 54
4.3.7. Statistical analysis 55
4.4. Results 55
4.4.1. Reduction of lipid droplets in differentiated 3T3-L1 adipocytes by L. mesenteroides EH-1 55
4.4.2. In vivo production of butyric acid and reduction of HFD-induced abdominal fats by L. mesenteroides EH-1 57
4.4.3. Suppression of HFD-induced PPAR-γ upregulation by L. mesenteroides EH-1 59
4.4.4. Effects of Ffar2 inhibitor administration with L. mesenteroides EH-1 probiotic diet on PPAR-γ level in high-fat diet mice 60
4.5. Discussion 62
Chapter 5. Summary, concluding remarks, and future aspects 66
5.1. Summary 66
5.2. Concluding remarks 67
5.3. Future study 67
References 69
Appendix 1 77
Appendix 2 78
Appendix 3 81

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指導教授

黃俊銘莊宗顯

審核日期

2020-10-22

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