Long-term exposure to titanium dioxide nanoparticles promotes diet-induced obesity through exacerbating intestinal mucus
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al Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China 2 Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China 3 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China § Xiaoqiang Zhu and Lijun Zhao contribute equally to this work. © Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 8 September 2020 / Revised: 13 October 2020 / Accepted: 22 October 2020
ABSTRACT Titanium dioxide nanoparticles (TiO2-NPs) are commonly used as food additives, including some high-fat foods that are risk factors for obesity. However, little is known about the effects of chronic TiO2-NPs digestion in the population on high fat diet (HFD). Herein, we reported that TiO2-NPs exacerbated HFD-induced obesity by disruption of mucus layer and alterations of gut microbiota. Oral intake of TiO2-NPs significantly increased body weight, liver weight, and amount of adipose tissues, especially in HFD-fed mice. Mechanistic studies revealed TiO2-NPs induced colonic mucus layer disruption and obesity-related microbiota dysbiosis. The damage on mucus was demonstrated through down-regulation of Muc2 gene and the absorption of mucin protein by TiO2-NPs. Consequently, mucus layer damage combined microbiota dysbiosis escalated the low-grade systemic inflammation, which exacerbated HFD-induced obesity. In contrast, gut microbiota depletion eliminated these effects, indicating gut microbiota were necessary for TiO2-NPs-induced inflammation and obesity. All the results stated the alarming role of TiO2-NPs in the HFD-driven obesity and emphasized the reevaluating the health impacts of nanoparticles commonly used in daily life, particularly, in susceptible population.
KEYWORDS titanium dioxide nanoparticles, nanosafety, obesity, mucus layer, gut microbiota
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Introduction
The prevalence of obesity is increasing rapidly in the world with the development of economy and the change of diet [1]. The incidence of obesity is 42.4% in the USA, 12.8% in the European Union, and 12% in China [2–4]. Epidemiologic studies have shown obesity is associated with a number of chronic diseases such as type 2 diabetes, cardiovascular diseases, and nonalcoholic fatty liver diseases [5, 6]. The causes of obesity are complex and are considered to involve genetic and environmental factors. Increasing evidence suggests that consumption of high-fat diet (HFD) is an important reason for development of obesity in the past several decades, and has been demonstrated to induce obesity through altering intestinal microbes [7, 8]. The gut microbiota regulates energy absorption, hepatic lipogenesis, and fat accumulation in the host [9, 10]. Despite HFD, some food additives, such as polysorbate-80 and carboxymethylcellulose, have also been proven to play important roles
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