小肠健康和肠炎发病密切关联于肠干细胞（ISC）的稳态，这些细胞对饮食变化敏感。然而，对于食品添加剂对ISC池的影响知之甚少。在这里，我们证明了长期接触低剂量二氧化钛纳米粒子（一种常用的食品添加剂），能通过特别削弱Wnt信号传导，严重干扰人类和小鼠ISC导出的基体形成和生长。在机制上，TiO2 NPs改变了Wnt受体LRP6的内吞过程，并阻止β-catenin的核入。值得注意的是，膳食中的TiO2 NPs会使健康的肠道产生温和的慢性压力，并且通过干扰ISC稳态，在体内严重阻碍放射性肠炎的恢复。我们的研究结果揭示了TiO2 NP暴露对ISC稳态和放射性肠炎恢复的健康隐忧。这些发现强调了治疗放射性肠炎需时刻谨慎，并为食品添加剂与ISC相互作用提供了新的见解。© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.

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.© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.