Dietary titanium dioxide nanoparticles impair intestinal epithelial regeneration by perturbating the function of intestinal stem cells

Intestinal health is closely linked to intestinal stem cells (ISCs), which are highly sensitive to the harmful substances in the lumen. However, there is limited knowledge regarding the effects of food additives on ISCs. This study aims to investigate the impact of dietary titanium dioxide nanoparticles (TiO₂ NPs) compared with titanium dioxide microparticles (TiO₂ MPs) on intestinal health associated with ISCs in response to dextran sodium sulfate (DSS)-induced enteritis in mice, as well as the related mechanism. We found that exposure to 1% (w/w) TiO₂ NPs aggravated DSS-induced enteritis in mice, while this effect could not be observed under exposure to TiO₂ MPs. Additionally, 1% (w/w) TiO₂ NPs exposure under DSS-induced enteritis worsened the ISC-mediated regeneration of intestinal epithelium by decreasing the epithelial cell proliferation and epithelial turnover rate while increasing epithelial cell death. Meanwhile, using a 3D intestinal organoid model, we discovered that 20 μg/mL TiO₂ NPs impaired ISC function and disrupted ISC fate specification both ex vivo and in vitro. Furthermore, TiO₂ NPs hindered the nuclear translocation of β-catenin, reducing the overall output of Wnt signaling. Together, TiO₂ NPs deteriorated the intestinal epithelial regeneration of mice with DSS-induced enteritis by perturbating ISC function and fate specification through a mechanism involving Wnt signaling. These findings highlight the adverse effect of dietary TiO₂ NPs on ISCs and shed light on the particle size optimization of TiO₂ food additive.