Due to its excellent physicochemical properties and wide applications in consumer goods, titanium dioxide nanoparticles (TiO2 NPs) have been increasingly exposed to the environment and the public. However, the health effects of oral exposure of TiO2 NPs are still controversial. This study aimed to illustrate the hepatotoxicity induced by TiO2 NPs and the underlying mechanisms. Rats were administered with TiO2 NPs (29 nm) orally at exposure doses of 0, 2, 10, 50 mg/kg daily for 90 days. Changes in the gut microbiota and hepatic metabolomics were analyzed to explore the role of the gut-liver axis in the hepatotoxicity induced by TiO2 NPs. TiO2 NPs caused slight hepatotoxicity, including clear mitochondrial swelling, after subchronic oral exposure at 50 mg/kg. Liver metabolomics analysis showed that 29 metabolites and two metabolic pathways changed significantly in exposed rats. Glutamate, glutamine, and glutathione were the key metabolites leading the generation of energy-related metabolic disorders and imbalance of oxidation/antioxidation. 16S rDNA sequencing analysis showed that the diversity of gut microbiota in rats increased in a dose-dependent manner. The abundance of Lactobacillus_reuteri increased and the abundance of Romboutsia decreased significantly in feces of TiO2 NPs-exposed rats, leading to changes of metabolic function of gut microbiota. Lipopolysaccharides (LPS) produced by gut microbiota increased significantly, which may be a key factor in the subsequent liver effects. TiO2 NPs could induce slight hepatotoxicity at dose of 50 mg/kg after long-term oral exposure. The indirect pathway of the gut-liver axis, linking liver metabolism and gut microbiota, played an important role in the underlying mechanisms.

中文翻译：

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口服二氧化钛纳米粒子后对大鼠的肝毒性和肠肝轴的作用。

由于其出色的理化特性和在消费品中的广泛应用，二氧化钛纳米颗粒（TiO2 NPs）越来越暴露于环境和公众。但是，口服TiO2 NPs的健康影响仍存在争议。这项研究旨在说明TiO2 NPs诱导的肝毒性及其潜在机制。每天以0、2、10、50 mg / kg的暴露剂量口服大鼠TiO2 NP（29 nm），共90天。分析了肠道菌群和肝脏代谢组学的变化，以探索肠-肝轴在TiO2 NPs诱导的肝毒性中的作用。在50 mg / kg的亚慢性口腔暴露后，TiO2 NPs会引起轻微的肝毒性，包括明显的线粒体肿胀。肝脏代谢组学分析表明，暴露的大鼠中29种代谢物和两种代谢途径发生了显着变化。谷氨酸，谷氨酰胺和谷胱甘肽是导致与能量有关的代谢紊乱和氧化/抗氧化失衡的关键代谢产物。16S rDNA测序分析表明，大鼠肠道菌群的多样性呈剂量依赖性增加。在暴露了TiO2 NPs的大鼠的粪便中，乳酸杆菌的丰度增加，而罗氏菌的丰度显着降低，从而导致肠道菌群的代谢功能发生变化。肠道菌群产生的脂多糖（LPS）显着增加，这可能是随后的肝脏影响的关键因素。长期口服后，以50 mg / kg的剂量使用TiO2 NPs可能会引起轻微的肝毒性。