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To review the recent work on potential mechanisms underlying a paradoxical positive association between the consumption of non-nutritive sweeteners (NNS) and weight gain.Several potential mechanisms, not mutually exclusive, are hypothesized. First, by dissociating sweetness from calories, NNS could interfere with physiological responses that control homeostasis. Second, by changing the intestinal environment, NNS could affect the microbiota and in turn trigger inflammatory processes that are associated with metabolic disorders. Third, by interacting with novel sweet-taste receptors discovered in the gut, NNS could affect glucose absorptive capacity and glucose homeostasis. The latter mechanism that has received the most attention recently. Some animal studies, but not all, found that NNS activate gut sweet-taste pathways that control incretin release and upregulate glucose transporters. Human studies found that, at least for healthy fasted individuals, the sole interaction of NNS with sweet-taste gut receptors is insufficient to elicit incretin responses. The reasons for discrepancy between different studies are unknown but could be related to the species of mammal tested and the dose of NNS used.Whether NNS are metabolically inactive, as previously assumed, is unclear. Further research on the potential effects of NNS on human metabolism is warranted.