Titanium dioxide nanoparticles disturb glucose homeostasis in association with impaired enteroendocrine cell differentiation

Gut hormones secreted by enteroendocrine cells play a critical role in maintaining glucose homeostasis. However, the adverse endocrine effects related to glucose homeostasis caused by food additives are not well understood. This work aims to investigate the effects of titanium dioxide nanoparticles (TiO 2 NPs) in comparison to titanium dioxide microparticles (TiO 2 MPs) on glucose homeostasis, with a specific focus on the enteroendocrine cells and gut hormones. Our research found that exposure to 1% (w/w) TiO 2 NPs, unlike TiO 2 MPs, resulted in elevated blood glucose levels and impaired glucose tolerance in mice. Notably, 1% (w/w) TiO 2 NPs significantly influenced the differentiation of the intestinal epithelium while not causing any notable histological changes or affecting cell proliferation in the mouse ileum. Furthermore, the levels of gut hormones, including glucagon-like peptide-1 (GLP-1) , peptide YY (PYY) and cholecystokinin (CCK), released from mouse ileum tissues were also significantly reduced following exposure to 1% (w/w) TiO 2 NPs. Using the intestinal organoid model, we also discovered that 20 μg/mL TiO 2 NPs impaired enteroendocrine cell differentiation, reduced basal GLP-1 secretion levels, and disrupted the GLP-1 secretion response to nutrient stimuli. Our research highlights the detrimental effects of TiO 2 NPs as potential intestinal endocrine disruptor and underscores the need to optimize their particle size for safe use in the food industry.