- 學位論文
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
Dietary Exposure to Antibiotic Residues Facilitates Metabolic Disorder by Altering the Gut Microbiota and Bile Acid Composition
摘要
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。
並列摘要
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.