Significance Statement
The consumption of low doses of fluoride in the drinking water may increase insulin sensitivity or reduce blood glucose levels. However, the exact mechanisms by which fluoride influences glucose homeostasis remain unclear. Considering that the small gut is central to glucose homeostasis, here we investigated the proteomic changes induced by low doses of fluoride (similar to those added to the drinking water) in the ileum of non-obese-diabetic mice. We found an increase in gastrotropin, histones and antioxidant enzymes, and decrease in enzymes involved in energy metabolism. These results indicate an adaptive response of the organism to preserve protein synthesis in the ileum, despite significant alterations in energy metabolism, therefore highlighting the safety of controlled fluoridation of water supplies.