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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蘇佳雅(Supitchaya Traisaeng) 查詢紙本館藏

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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
(Effects of butyric acid-producing probiotic bacteria on atopic dermatitis and type 1 diabetes)

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摘要(中)

大多數患有異位性皮膚炎（AD）有90％以上的患者被金黃色葡萄球菌（金黃色葡萄球菌）定植/感染，金黃色葡萄球菌是一種伺機性細菌，與皮膚炎症惡化有關。但是，目前對AD的治療是有限的。目前在益生菌（共生菌可以在宿主中預防病原體定植）的研究中已發揮作用，已被證明是一種有前途的預防和治療感染的方法。來自微生物組體的代謝產物被用於開發創新藥物。表皮葡萄球菌（S. epidermidis，皮膚益生菌）當其發酵後的短鏈脂肪酸，發酵代謝產物之一丁酸。本研究的第一個目的是證明丁酸類似物對來自於AD患者皮膚（AD S. aureus）和炎症的金黃色葡萄球菌過度生長的影響。表皮葡萄球菌經甘油發酵產生丁酸，在體外和體內皆能有效抑制來自於異位性皮膚炎患者皮膚病變中分離出的金黃色葡萄球菌菌株的生長。但是，該方法不太可能應用在治療上，因為丁酸具有氣味，並且需要mM範圍內的高最低殺菌濃度（MBC）才能抑制金黃色葡萄球菌的生長。因此丁酸的衍生物BA-NH-NH-BA，是通過將兩個丁酸與-NH-O-NH-接頭兩端綴合而合成的。 BA-NH-NH-BA降低了AD金黃色葡萄球菌的丁酸MBC含量。丁酸和BA-NH-NH-BA當組蛋白脫乙酰基酶（HDAC）抑製劑，以誘導人類角質形成細胞中組蛋白H3賴氨酸9（AcH3K9）的乙酰化。此外，BA-NH-NH-BA可以改善金黃色葡萄球菌誘導的IL-6的產生，並顯著降低小鼠皮膚中金黃色葡萄球菌的定殖。這些結果表明，皮膚微生物組發酵代謝產物的新型衍生物丁酸具有金黃色葡萄球菌的殺菌活性和對抗金黃色葡萄球菌感染所產生的消炎作用。
補充益生菌可以減少產生糖尿病的風險。在患有第1型糖尿病兒童身上的細菌所產生丁酸的定殖率較低。因此我們假設從蒙古凝乳乾酪中產生丁酸菌株Leuconostoc mesenteroides（L. mesenteroides）EH-1可以降低糖尿病患者的血糖，為了確認短鏈脂肪酸受體2（Ffar2）是否介導丁酸的作用，因此使用Min6細胞及第1型糖尿病小鼠研究Ffar2對腸系膜腸球菌L. mesenteroides EH-1的血糖調節中的作用，Ffar2的抑製作用是否可調控第1型糖尿病小鼠血糖和胰島素的血中濃度。在體外和體內實驗中L. mesenteroides EH-1的葡萄糖發酵皆誘導了高濃度的丁酸生成。用丁酸處理Min6細胞後，可檢測到胰島素分泌，但是當Ffar2被siRNA抑制時，胰島素的分泌被顯著抑制。補充L. mesenteroides EH-1及丁酸在小鼠實驗中可以增強老鼠血液胰島素，降低血糖和白介素（IL）-6的水平。結果顯示 L. mesenteroides EH-1 調控了Ffar2的抑製作用降低第1型糖尿病小鼠的血糖。

摘要(英)

Most patients (up to 90%) with atopic dermatitis (AD) are colonized/infected with Staphylococcus aureus (S. aureus), an opportunistic bacteria implicated in worsening skin inflammation. However, the current treatments for AD are limited. Probiotic bacteria, in which commensal bacteria can function in the prevention of the host from pathogen colonization, is a promising modality for the prevention and treatment of infections. The metabolites from microbiome were used for the development of innovative drugs. One of the short-chain fatty acid fermentation metabolites by Staphylococcus epidermidis (S. epidermidis, the skin probiotic bacterium) is butyric acid. The first object of this study was to demonstrate the effect of butyric acid analog on the overgrowth of S. aureus that isolated from inflammatory AD skin (AD S. aureus). Glycerol fermentation by S. epidermidis resulted in the production of butyric acid and effectively inhibited the growth of S. aureus isolated strain from lesional skin with AD in vitro and in vivo. However, this approach is unlikely to be therapeutically useful since butyric acid is malodorous and requires the mM range of a high minimum bactericidal concentration (MBC) for suppression of AD S. aureus growth. A derivative of butyric acid, names BA-NH-NH-BA, was synthesized by conjugation of two butyric acids to a -NH-O-NH- linker both ends. BA-NH-NH-BA lowered the significant butyric acid MBC for AD S. aureus. Butyric acid and BA-NH-NH-BA functioned as a histone deacetylase (HDAC) inhibitor to induce acetylation of Histone H3 lysine 9 (AcH3K9) in human keratinocytes. Furthermore, BA-NH-NH-BA could ameliorate AD S. aureus-induced production of interleukin (IL)-6 and remarkably decreased the AD S. aureus colonization in mouse skin. These results indicate that a novel derivative butyric acid of a skin microbiome fermentation metabolite exhibits S. aureus bactericidal and anti-inflammatory activities caused by S. aureus infection.
Probiotic bacterial supplementary diet can prevent the risks of diabetes. Whereas, type 1 diabetic children showed the low colonization of bacteria producing butyrate. We
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hypothesize that a butyric acid-producing Leuconostoc mesenteroides (L. mesenteroides) EH-1 strain from Mongolian curd cheese can reduce blood glucose in diabetic individuals and aim to examine if free fatty acid receptor 2 (Ffar2) mediates the action of butyric acid in the regulation of blood levels of glucose and insulin in a type 1 diabetes mice. The inhibition of Ffar2 in Min6 cells or type 1 diabetic mice, was conducted to examine the involvement of Ffar2 in the blood glucose regulation by L. mesenteroides EH-1. The glucose fermentation (in vitro) and feeding (in vivo) of L. mesenteroides EH-1 induced a high concentration of butyric acid production. The secretion of insulin was detected after treatment of Min6 cells with butyric acid but considerably suppressed when Ffar2 was knocked down by siRNA. Supplementation of streptozotocin (STZ)-induced type 1 diabetic mice with butyric acid or L. mesenteroides EH-1 boosted the blood insulin and lowered the levels of blood glucose and IL-6. Inhibition of Ffar2 significantly reduced the action of butyric acid or L. mesenteroides EH-1 for blood glucose reduction in type 1 diabetic mice. Therefore, Ffar2 mediated the probiotic activity of butyric acid-producing by L. mesenteroides EH-1 on reduction of blood glucose in diabetic mice.

關鍵字(中)

★ 特應性皮炎
★ 丁酸
★ 發酵
★ 益生菌
★ 一型糖尿病

關鍵字(英)

★ atopic dermatitis
★ butyric acid
★ fermentation
★ Probiotic bacteria
★ Type 1 diabetes

論文目次

Abstract in Chinese ........................................................................................................ i
Abstract in English ....................................................................................................... iiii
Acknowledgment...........................................................................................................iv
Table of Contents ..........................................................................................................vi
List of Figures ...............................................................................................................xi
Abbreviations .............................................................................................................. xiii
Chapter 1 Literature review ........................................................................................ 1
1.1. Atopic dermatitis (AD) ........................................................................................ 1
1.2. Beneficial effects of probiotic bacteria in AD ...................................................... 2
1.3. Staphylococcus aureus (S. aureus) colonization in AD ..................................... 2
1.4. Inflammation in AD with S. aureus colonization ................................................. 3
1.5. Short-chain fatty acids (SCFAs) and anti-inflammatory activity ......................... 5
1.6. SCFAs and anti-bacterial activity ....................................................................... 5
1.7. Type 1 diabetes ................................................................................................. 6
1.8. Type 1 diabetes and gut probiotic bacteria ........................................................ 8
1.9. Diabetes and free fatty acid receptor 2 (Ffar2) .................................................. 8
1.10. Rationale of the present study ....................................................................... 10
1.10.1. Aims of the present study ..................................................................... 10
1.10.2. Questions raised in the present study .................................................. 11
1.10.3. Structure of the thesis .......................................................................... 12
Chapter 2 An analog of butyric acid, like the fermentation metabolite of S. epidermidis, inhibits an AD skin isolated S. aureus strain growth ......................... 13
2.1. Abstract ........................................................................................................... 13
2.2. Introduction ...................................................................................................... 14
2.3. Materials and Methods .................................................................................... 16
2.3.1. Ethics Statement .................................................................................... 16
2.3.2. Bacterial culture ..................................................................................... 16
2.3.3. Bacterial sampling with tape strips ......................................................... 16
2.3.4. Co-culture of AD S. aureus and S. epidermidis in vitro .......................... 17
2.3.5. In Vivo effects of S. epidermidis glycerol fermentation on skin colonization of AD S. aureus ............................................................................ 17
2.3.2. Synthesis of BA–NH–NH–BA ................................................................. 18
2.3.3. Suppression of bacterial growth ............................................................. 19
2.3.4. Cell culture ............................................................................................. 19
2.3.5. Western blotting ..................................................................................... 19
2.3.6. Keratinocytes treated with bacterial lysates in the presence or absence of BA-BNH-NH-BA ............................................................................................... 20
2.3.7. Administration of 3,3′-Diindolylmethane (DIM) as HDAC inhibitor into mice ................................................................................................................. 20
2.3.8. Gas chromatography (GC) analysis ....................................................... 21
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2.3.9. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay ................................................................................................................ 21
2.3.10. Statistical analysis ................................................................................ 21
2.4. Results and discussion .................................................................................... 22
2.4.1. High abundance of S. aureus colonization was observed in lesional skin of AD patients ................................................................................................... 22
2.4.2. S. epidermidis-induced glycerol fermentation inhibits AD S. aureus growth in vitro ................................................................................................... 24
2.4.3. Glycerol fermentation of S. epidermidis suppresses AD S. aureus growth in mouse skin ................................................................................................... 26
2.4.4. Butyric acid and butyric acid analog (BA-NH-NH-BA) have an anti-AD S. aureus activities ............................................................................................... 28
2.4.5. BA–NH–NH–BA can Inhibit HDAC activity and AD S. aureus growth .... 32
2.4.6. BA-NH-NH-BA reduces AD S. aureus-induced IL-6 production in keratinocytes and mice .................................................................................... 35
2.4.7. HDAC antagonist can suppress IL-6 production but not affect the number of AD S. aureus in the HDAC-depleted mice .................................................... 36
2.5. Conclusions ..................................................................................................... 38
Chapter 3 Butyric acid production of L. mesenteroides fermentation mediates Ffar2 to regulate blood glucose and insulin in type 1 diabetic mice ...................... 39
3.1. Abstract ........................................................................................................... 39
3.2. Introduction ...................................................................................................... 40
3.3. Methods ........................................................................................................... 41
ix
3.3.1 Bacterial culture and identification ........................................................... 41
3.3.2. Glucose fermentation of L. mesenteroides EH-1 .................................... 41
3.3.3. Min6 cell treatments ............................................................................... 42
3.3.4. Streptozotocin (STZ)-induced type 1 diabetic mice ................................ 43
3.3.5. Diabetic mice treated with butyric acid ................................................... 43
3.3.6. Feeding mice with L. mesenteroides EH-1 ............................................. 44
3.3.7. HPLC analysis ........................................................................................ 44
3.3.9. Effects of temperatures and pH values on L. mesenteroides EH-1 growth ......................................................................................................................... 46
3.3.10. Glucose tolerance test (OGTT) ............................................................ 46
3.3.11. RT-PCR ................................................................................................ 46
3.3.12. Statistical analysis ................................................................................ 47
3.4. Results and discussion .................................................................................... 48
3.4.1. L. mesenteroides EH-1 .................... can ferment glucose to produce butyric acid 48
3.4.2. Butyric acid stimulated insulin secretion from Min6 cells via Ffar2 ......... 52
3.4.3. Butyric acid mediates blood glucose and insulin regulations via Ffar2 in the in type 1 diabetic mice ................................................................................ 54
3.4.4. Butyric acid-producing L. mesenteroides EH-1 mediates blood glucose and insulin regulations via Ffar2 in the in type 1 diabetic mice......................... 58
3.4.5. The role of butyric acid-producing by L. mesenteroides EH-1 in IL-6 production of STZ-induced type 1 diabetic mice .............................................. 63
x
3.5. Conclusions ..................................................................................................... 65
Chapter 4 Summary, concluding remarks, and future aspects ............................... 66
References ................................................................................................................... 70
Appendix 1 Conference presentations ...................................................................... 91
Appendix 2 Abstract of conference presentations ................................................... 92
Appendix 3 List of publications ................................................................................. 98

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指導教授

黃俊銘莊宗顯(Chun-Ming Huang Tsung-Hsien Chuang)

審核日期

2020-10-12

推文