纳米二氧化铈长期暴露对大鼠肠道微生物的影响研究

With the rapid development of nanotechnology in food, agriculture, and biomedicine, the possibility of nanoparticles accumulation in human gastrointestinal (GI) tract and presence biological effects has been increased. Epidemiological studies indicate that exposure to environmental particulate matter is associated with the occurrence and development of gut inflammation. So, nanosafety, especially for GI system, should be investigated ugently. At present, the study of the effects of nano-sized ceria on intestinal micro-organisms in rats is still blank. Recent studies show that colonized gut microbiomes are significantly correlated with intestine function, and the role of the correlation in nano cerium dioxide, requires further study. Metabonomics, as a powerful tool in complicated metabolic pathways of biological system, is able to reveal components of the metabolites from gut microbiota rapidly, and show the overview of metabolic process of gut microbiota, which could contribute to investigation and analysis of the relationship between the changes of gut microbiota and the host gastrointestinal function. This research aimed to investigate high-throughput molecular mechanism of metabolism which was the underlying relationship with nano cerium dioxide, screen the possible biomarkers that indicated progression of nano cerium dioxide, and establish a safety evaluation system based on metabonomics of nano cerium dioxide.

纳米技术在食品工业、农业、生物医药等领域的广泛应用，使职业人群和普通人群暴露于纳米材料的几率大大增加。流行病学研究显示环境颗粒物的暴露与胃肠道炎症的发生和发展密切相关。因此，对纳米材料的生物安全性，尤其是纳米材料对胃肠道系统的作用亟待研究。目前纳米二氧化铈暴露对大鼠肠道微生物的影响研究尚属空白。近期研究表明肠道定植菌群的结构与肠道功能密切相关，上述相关性是否在纳米二氧化铈与机体作用过程中发挥作用值得深入研究。代谢组学作为研究复杂代谢体系强有力的研究工具，可快速展现菌群相关代谢物的组成，反映肠道菌群代谢的活动概貌，有助于研究和分析肠道菌群的变化与宿主肠道功能的关系。本课题旨在研究纳米二氧化铈相关的高通量分子代谢机制，筛选出反映其发生发展的生物标记物，建立基于代谢组学的纳米二氧化铈安全性评价体系。

纳米二氧化铈（CeO2NPs）兼具纳米材料和稀土材料双重特性，现在越来越多的用于药物载体或诊疗等医药行业，人们与CeO2NPs接触的机会也大大增加。目前，CeO2NPs长期经口暴露后的生物学效应未见报道。因此，本研究以SD雄性大鼠为模式动物，灌胃CeO2NPs90天后观察动物的整体状态，发现CeO2NPs整体毒性小，主要作用器官为回肠和盲肠，并且随着CeO2NPs剂量增加，毒性增加。 当CeO2NPs灌胃暴露剂量大于100mg/kg后，在第45天会引起肠炎，随着给药时间增加，肠道炎症病理学改变加重；同时伴有菌群失调，即有害菌丰度增加，有益菌减少；一些代谢物含量异常导致代谢紊乱。肠炎机制探索发现，使用益生菌干预或治疗后，肠道病理学损伤减轻，有益菌增多，部分代谢物通路恢复正常，说明肠道菌群在肠炎形成过程中起重要作用。生物学信息分析发现摄入CeO2NPs后，有特征性的菌群出现，这些菌群可以为体外评价CeO2NPs生物安全性提供依据。