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Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic effects. However, data from several epidemiological studies have found that consumption of NNSs, mainly in diet sodas, is associated with increased risk to develop obesity, metabolic syndrome, and type 2 diabetes. The main purpose of this article is to review recent scientific evidence supporting potential mechanisms that explain how “metabolically inactive” NNSs, which have few, if any, calories, might promote metabolic dysregulation. Three potential mechanisms, which are not mutually exclusive, are presented: 1) NNSs interfere with learned responses that contribute to control glucose and energy homeostasis, 2) NNSs interfere with gut microbiota and induce glucose intolerance, and 3) NNSs interact with sweet-taste receptors expressed …