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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84292完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 沈立言(Lee-Yan Sheen) | |
| dc.contributor.author | Rou-An Chen | en |
| dc.contributor.author | 陳柔安 | zh_TW |
| dc.date.accessioned | 2023-03-19T22:07:54Z | - |
| dc.date.copyright | 2022-07-05 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-06-15 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84292 | - |
| dc.description.abstract | 抗生素被廣泛使用於畜牧業作為生長促進劑和疾病預防之用途。因此，動物性食品中可檢出抗生素也成為一項隱憂。過去文獻指出，兒童肥胖與其尿液中檢出的動物用抗生素有關，然而目前尚未有文獻探討飲食暴露於抗生素之食品安全議題。本研究之目的為以動物模式探討暴露於食物中殘留之抗生素生長促進劑-泰黴素 (tylosin)是否透過影響腸道菌及其代謝物而引起代謝症候群。本研究結果顯示，理論每人最大一日攝取量 (theoretical maximal daily intake, TMDI, 0.047 mg/kg bw)之tylosin可促進高脂飲食造成之肥胖和胰島素阻抗，並且改變小鼠腸道菌相組成。接著，本研究以糞菌移植實驗探討TMDI劑量之tylosin是否透過影響腸道菌而引起代謝異常，並發現肥胖表徵可透過菌相之移植而轉移給無菌接受鼠，顯示殘留劑量的tylosin可透過改變腸道菌群而引起肥胖和胰島素阻抗。由於生命早期為腸道菌建立之關鍵期，此時期暴露抗生素可能將改變腸道菌組成而對宿主代謝有長遠之影響。本研究發現生命早期暴露TMDI劑量之tylosin足以使小鼠成年後體重和體脂肪上升、出現胰島素阻抗，並改變小鼠腸道菌中與宿主代謝相關之特定菌種之豐富度。此外，生命早期暴露TMDI劑量之tylosin改變腸道中一級膽酸和二級膽酸之比例，並可能透過影響其下游FGF15分子訊息路徑而引起代謝異常。綜上所述，本研究顯示無論時持續暴露或是生命早期暴露飲食中殘留之抗生素生長促進劑皆可能透過影響腸道菌群及其代謝物組成進而對宿主之代謝產生長遠的影響。本研究點出抗生素殘留限量標準之制定應考量到其對腸道菌群及宿主代謝之影響，抗生素殘留相關規範可能有重新檢視之必要。 | zh_TW |
| dc.description.abstract | Antibiotics have been widely used as growth promotor and zoonotic diseases prevention in livestock. For this reason, they have been detected in the animal source food, which is a hidden risk for humans. Previous studies found that veterinary antibiotics detected in the urine of children were associated with obesity. However, there is a lack of evidence on the safety issue of exposure to a low-dose antibiotic in food. This research aimed to demonstrate whether exposure to residual dose of antibiotic growth promoter (AGP)—tylosin— in food could lead to metabolic disorders and its mechanistic effect through intestinal microbiota and its metabolites in vivo. Theoretical maximal daily intake (TMDI; 0.047 mg/kg bw) doses of tylosin were found to facilitate high-fat diet-induced obesity, induce insulin resistance, and perturb gut microbiota composition in mice. To investigate whether TMDI tylosin induced metabolic disorders through altering the gut microbiota, a fecal microbiota transplantation (FMT) study was performed. The obesity-related phenotypes were transferrable to germ-free recipient mice, indicating that the effects of a TMDI dose of tylosin on obesity and insulin resistance occurred mainly via alteration of the gut microbiota. Early-life is the critical window of the gut microbiota development. Exposure to antibiotic in early-life may disturb the gut microbiota and lead to long-term metabolic dysfunction in later life. The study demonstrated that TMDI dose of tylosin exposure restricted to early life was sufficient to increase body weight and relative fat mass, induce insulin resistance as well as alter the abundance of specific bacteria related to host metabolic homeostasis later in life. Moreover, early life exposure to tylosin TMDI was sufficient to modify the ratio of primary to secondary bile acids, thereby inducing lasting metabolic consequences via the downstream FGF15 signaling pathway. Altogether, these findings demonstrate that exposure to very low-doses of antibiotic residues, whether continuously or in early life, could exert long-lasting effects on host metabolism by altering gut microbiota and its metabolites. This study underscores the establishment of permissible exposure levels in food should take into account its effects on the gut microbiota, and the relevant regulation might need to be re-evaluated. | en |
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| dc.description.tableofcontents | 口試委員審定書 I 誌謝 II 中文摘要 V 英文摘要 VI 第一章 文獻回顧 1 1.1 腸道菌與人體健康之關係 1 1.2 腸道菌影響宿主代謝的機制 2 1.3 抗生素為對腸道菌的影響 3 1.4 生命早期為腸道菌群最易受波動之時期 4 1.5 飲食中微量抗生素暴露和兒童肥胖的關係 6 1.6 抗生素殘留於食物中的原因-作為經濟動物之生長促進劑 7 1.7 抗生素的生長促進機制 8 1.8 Tylosin的生長促進作用 9 1.9 我國動物用抗生素管理機制 10 1.10 食物殘留抗生素可能為新興的食品安全的議題 11 第二章 研究目的、研究假說與實驗設計 13 2.1 研究背景 13 2.2 研究目的 13 2.3 研究假說 14 2.4 研究設計 15 2.4.1 動物實驗一：飲食暴露之抗生素生長促進劑對小鼠體組成和腸道菌相之影響 15 2.4.2 動物實驗二：以糞菌移植驗證飲食暴露之抗生素生長促進劑透過影響腸道菌相而引起小鼠肥胖 17 2.4.3 動物實驗三：飲食暴露之抗生素生長促進劑透過影響小鼠腸道菌代謝物和其相關代謝機轉而造成小鼠肥胖 18 第三章 材料與方法 20 3.1 實驗藥品 20 3.2 體組成測定 20 3.3 呼吸代謝測定 20 3.4 血糖耐受試驗 21 3.5 血清胰島素測定 21 3.6 脂肪肝病理分析 21 3.7 脂肪細胞直徑測定 21 3.8 血清生化測定 22 3.9 血清酯多醣測定 22 3.10 血清細胞激素測定 22 3.11 腸道通透性檢測 23 3.12 DNA萃取與16S rRNA 23 3.12.1 擴增子製備 23 3.12.2 定序文庫製備與次世代定序 23 3.12.3 微生物物種組成分析 24 3.13 相關性分析 24 3.14 糞便短鏈脂肪酸含量測定 24 3.15 糞便膽酸含量測定 25 3.16 西方墨點法 26 3.16.1 萃取組織蛋白 26 3.16.2 蛋白定量 26 3.16.3 配置定量樣品 26 3.16.4 製作膠片 27 3.16.5 電泳（Running） 28 3.16.6 轉漬（Transfer） 28 3.16.7 阻斷（Blocking） 28 3.16.8 抗體反應 29 3.16.9 定量分析 29 3.17 肝門靜脈FGF15測定 35 3.18 統計分析 35 第四章 結果 36 4.1 暴露於安全劑量之抗生素生長促進劑對小鼠體組成和生理代謝的影響 36 4.1.1 體重 36 4.1.2 體脂肪與瘦體組織率 36 4.1.3 脂肪重量與細胞大小 37 4.1.4 肝臟病理切片分析 37 4.1.5 血清生化分析 37 4.1.6 血糖與胰島素恆定性 38 4.1.7 生理代謝分析 38 4.1.8 血清內毒素與細胞激素分析 38 4.2 食物中殘留之低劑量的抗生素生長促進劑對小鼠腸道菌相豐富度與組成的影響 40 4.2.1 腸道菌相 -多樣性 40 4.2.2 腸道菌相 -多樣性 40 4.2.3 腸道菌群組成差異分析 41 4.2.4 以相關分析探討小鼠肥胖和微量抗生素暴露改變之腸道菌相的相關性 41 4.3 以無菌鼠糞菌移植模式探討抗生素生長促進劑透過影響腸道菌而引起小鼠肥胖的因果性 43 4.3.1 體重、體組成與脂肪重量 43 4.3.2 肝臟病理切片分析 43 4.3.3 血清生化分析 43 4.3.4 血糖與胰島素恆定性 43 4.3.5 血清內毒素與腸道通透性分析 44 4.4 生命早期暴露於殘留劑量的抗生素生長促進劑使小鼠體組成和生理代謝的影響 45 4.4.1 體重與體組成 45 4.4.2 肝臟病理切片分析 45 4.4.3 血糖與胰島素恆定性 45 4.5 生命早期暴露於殘留劑量的抗生素生長促進劑對腸道菌和其代謝物之影響 46 4.5.1 腸道菌相 -多樣性分析 46 4.5.2 腸道菌相熱點圖與相關性分析 46 4.5.3 糞便短鏈脂肪酸組成分析 47 4.5.4 盲腸膽酸組成分析 47 4.6 生命早期暴露於殘留劑量的抗生素生長促進劑對膽酸下游分子路徑的影響 48 4.6.1 腸道FGF15-肝門靜脈FGF15-肝臟FGFR4表現量 48 4.6.2 腸道及肝臟FXR表現量 49 第五章 討論 50 5.1 抗生素生長促進劑-tylosin 在安全劑量下仍具有促進肥胖的作用 50 5.2 生命早期暴露殘留劑量之tylosin促進小鼠肥胖 51 5.3 食物中殘留之低劑量的抗生素生長促進劑在長期暴露下影響腸道菌相 51 5.4 生命早期暴露殘留劑量之tylosin對小鼠腸道菌群之影響可持續至成年 53 5.5 食物中殘留的抗生素生長促進劑影響腸道菌和其代謝物組成，可能引起小鼠肥胖 54 第六章 結論 56 第七章 未來規劃 57 第八章 縮寫及中英對照表 108 第九章 參考文獻 109 | |
| dc.language.iso | zh-TW | |
| dc.subject | 肥胖 | zh_TW |
| dc.subject | 膽酸代謝 | zh_TW |
| dc.subject | 飲食暴露 | zh_TW |
| dc.subject | 生命早期 | zh_TW |
| dc.subject | 食品安全 | zh_TW |
| dc.subject | 腸道菌 | zh_TW |
| dc.subject | 低劑量抗生素 | zh_TW |
| dc.subject | 代謝異常 | zh_TW |
| dc.subject | dietary exposure | en |
| dc.subject | obesity | en |
| dc.subject | metabolic disorder | en |
| dc.subject | low-dose antibiotic | en |
| dc.subject | gut microbiota | en |
| dc.subject | food safety | en |
| dc.subject | early life | en |
| dc.subject | bile acid metabolism | en |
| dc.title | 暴露於食物中殘留之抗生素生長促進劑透過改變腸道菌群及膽酸組成引起代謝異常 | zh_TW |
| dc.title | Dietary Exposure to Antibiotic Residues Facilitates Metabolic Disorder by Altering the Gut Microbiota and Bile Acid Composition | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 徐丞志(Cheng-Chih Hsu) | |
| dc.contributor.oralexamcommittee | 吳明賢(Ming-Shiang Wu),賴信志(Hsin-Chih Lai),莊曉莉(Hsiao-Li Chuang),詹長權(Chang-Chuan Chan) | |
| dc.subject.keyword | 膽酸代謝,飲食暴露,生命早期,食品安全,腸道菌,低劑量抗生素,代謝異常,肥胖, | zh_TW |
| dc.subject.keyword | bile acid metabolism,dietary exposure,early life,food safety,gut microbiota,low-dose antibiotic,metabolic disorder,obesity, | en |
| dc.relation.page | 114 | |
| dc.identifier.doi | 10.6342/NTU202200827 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-06-17 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 食品科技研究所 | zh_TW |
| dc.date.embargo-lift | 2022-07-05 | - |
| 顯示於系所單位： | 食品科技研究所 | |
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