Perturbation of intestinal stem cell homeostasis and radiation enteritis recovery via dietary titanium dioxide nanoparticles

Small intestinal health and enteritis incidence are tightly coupled to the homeostasis of intestinal stem cells (ISCs), which are sensitive to dietary alterations. However, little is known about the impact of food additives on ISC pool. Here, we demonstrate that chronic exposure to low‐dose TiO2 NPs, a commonly used food additive, significantly hampers primary human and mouse ISC‐derived organoid formation and growth by specifically attenuating Wnt signal transduction. Mechanistically, TiO2 NPs alter the endocytic trafficking of the Wnt receptor LRP6 and prevent the nuclear entry of β‐catenin. Notably, dietary TiO2 NPs elicit modest chronic stress in healthy intestines and considerably impede the recovery of radiation enteritis by perturbing the homeostasis of ISCs in vivo. Our results identify a health concern of TiO2 NP exposure on ISC homeostasis and radiation enteritis recovery. These findings suggest extra precaution during the treatment of radiation enteritis and provide new insights into food additive‐ISC interaction. Titanium dioxide nanoparticles (TiO2 NPs), one of the most widely used food additives, propel the Wnt signalling receptor LRP6 from caveolin‐mediated endocytosis to clathrin‐mediated endocytosis to weaken the Wnt signalling activity, which is essential for the homeostasis of small intestinal stem cells (ISCs). Chronic intake of waterborne TiO2 NPs perturbs the homeostasis of ISCs and impedes the recovery of radiation enteritis.