基于肠道菌群-胆汁酸-法尼醇X受体(FXR)轴线探究氟苯尼考对斑马鱼糖脂代谢的影响及作用机制

The pollution of veterinary antibiotics is becoming increasingly serious in China. Despite of the relatively high detection concentration and frequency in water environment and even human urines, veterinary antibiotic indicators including florfenicol are still not involved in the current standards of water environment quality in China, because of their unclear health hazard effects. Both results of our previous studies and the epidemiological investigation indicate that disturbance on the glucose and lipid metabolism could be the sensitive toxicological endpoint upon exposure of environmental pollutants like florfenicol. Therefore, in the present study, zebrafish is used as the model animal to investigate the detailed influences of florfenicol exposure on glucose and lipid metabolism, at the levels of individual, organ, tissue, cell, and molecule. Then, considering the key role of gut microbiota-bile acids-farnesoid X receptor (FXR) axis on the regulation of metabolism, mechanisms underlying the adverse effects of florfenicol will be further explored from the aspects of: 1) damaging gut microbiota and eventually reducing chenodesoxycholic acid (CDCA) contents in the liver, and 2) directly binding to FXR and inhibiting its function. Results of the present study will provide theoretical basis for the health risk assessment and the establishment of related water quality standard of florfenicol, and also provide new insights into the study on the mechanism of antibiotic toxic effects.

我国面临着日益严峻的兽用抗生素污染形势，其中氟苯尼考在水环境甚至人体尿液中的检出浓度和频率均较高。然而，现行的各类水质标准并未纳入氟苯尼考等兽用抗生素指标，究其原因，主要是因为这类抗生素的健康危害效应并不明确。我们前期的工作和流行病学调查结果提示，诱发葡萄糖和脂质代谢紊乱可能是氟苯尼考等环境污染物暴露的敏感毒性终点。因此，本项目采用斑马鱼为模式生物，首先从个体、器官、组织、细胞和分子水平探讨环境浓度的氟苯尼考长期暴露对机体糖脂代谢的具体影响；然后基于肠道菌群-胆汁酸-法尼醇X受体(FXR)轴线对糖脂代谢调控的关键作用，从杀伤肠道菌群最终减少肝脏中FXR天然配体鹅脱氧胆酸(CDCA)含量、以及直接与FXR结合并拮抗其功能两个方面，阐明氟苯尼考扰乱糖脂代谢的作用机制。本项目研究结果将为氟苯尼考健康风险评价和水环境质量标准建立提供理论基础，同时也为抗生素毒性效应机制的研究提供新的思路。

氟苯尼考是我国用量最大的兽用抗生素，在各种环境介质和人体体液中被广泛检出，然而其健康危害效应并不明确。本研究采用斑马鱼为模式生物，从个体、器官、组织、细胞和分子水平研究了氟苯尼考对斑马鱼糖脂代谢的具体影响，结果发现环境浓度的氟苯尼考暴露斑马鱼早期、全世代或成鱼期，均可显著扰乱机体糖脂代谢平衡；此外，体内、体外实验结果发现扰乱肠道菌群稳态、降低肠道菌群代谢产物短链脂肪酸含量（而非胆汁酸）、继而干扰其下游FFAR3和AMPK信号通路对机体糖脂代谢的调控功能，是氟苯尼考作用的主要机制。本项目研究结果探明了环境浓度的氟苯尼考长期暴露对生物体健康的敏感毒性终点及其作用机制，研究结果不仅将推动氟苯尼考等兽用抗生素的健康风险评价工作，也为抗生素毒性效应机制的研究提供了新的思路。