SOSweet

Habitual excess sugar consumption, such as that via soda-like drinks, contributes to the risk of developing metabolic diseases (obesity, type 2 diabetes) and increases the risk of developing cardiovascular diseases. In an effort to address this, synthetic or natural non-caloric sweeteners (e.g. aspartame, sucralose, acesulfame K, stevia etc.) are commonly used in commercial products, providing consumers with a similar sweet savor to that of sugar, but without the high-caloric content and, subsequent, hyperglycemic peak. These non-nutritive sweeteners are validated by the American Academy of Nutrition and Dietetics, as well as the European Food Safety Agency; and are often promoted as a healthy alternative to added sugars. However, very recent research demonstrates an association between the consumption of products containing non-nutritive sweeteners and increased risk of mortality, including that of cardiovascular origin. Additionally, research has indicated that these sweeteners have adverse effects on glucose metabolism, gut microbiota and/or the control of appetite. Thus, sweeteners may not be biologically inert, but the underlying mechanisms explaining its consequences to human health are not known. Recent work has identified the presence of sweet taste receptors (T1Rs), which are activated by sweeteners, in the pancreas and intestine; and, more surprisingly, in the brain and endothelial cells. In addition, our preliminary results demonstrate impaired vascular function in rats consuming non-nutritive sweeteners within the limit of an acceptable daily intake. Indeed, vascular endothelial dysfunction is well recognized for its early role in the development of atherosclerosis, as well as an early and sensitive marker in the development of obesity and insulin resistance. Thus, we hypothesize that these sweetener-activated T1Rs are involved directly (at the blood vessel level) and indirectly (via brain integration or metabolic modulation) in the disruption of vascular reactivity. This translational research will combine studies in humans and animals with respect to ethical guidelines and the protection of people. First, we will explore, in mice, the effects of habitual non-nutritive sweetener consumption on vascular and gastrointestinal function; in vivo and ex-vivo macrovascular and microvascular reactivity respectively, as well as in vivo and ex-vivo gastrointestinal contractility. A pharmacological modulation of T1Rs and the use of T1Rs knock-out mice will make it possible to explore the mechanisms involved. We will then conduct a randomized, placebo-controlled clinical trial to investigate (1) the effects of consuming non-nutritive sweeteners on macro- and microvascular function in healthy volunteers, using speckle contrast imaging coupled with intradermal microdialysis to determine the influence of the T1R pathway on vascular reactivity; and (2) to understand how oral and/or gastro-intestinal T1Rs are involved in metabolic responses and consequences for vascular function. We will also study the direct effect of sweeteners on blood vessels via activation of T1Rs present in vascular cells in humans and animals. Finally, since non-nutritive sweeteners can act on the metabolic responses or on the control of food intake, we will assess, in vivo, in a model of healthy mice and T1Rs knock-out mice, as well as by pharmacological methodologies, afferent nerve pathways originating from the digestive tract and projecting to the brain. The direct effect of sweeteners on brain T1Rs will also be studied. These neural pathways may, in turn, affect nerve regulation of vascular tone.