Mechanistic and Metabolic Impacts of Non-Nutritive Sweeteners

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OVERVIEW. Novel work from my laboratory shows that the regular use of low-dose, non-caloric artificial sweeteners compounds ubiquitous in the Canadian marketplace and widely believed to reduce daily caloric intake, promote satiety, encourage weight loss and facilitate glucoregulation, unintentionally disrupt the balance of the gut microbiota resulting in distorted glucose metabolism.OBJECTIVES. This grant tests the central hypothesis that aspartame consumption either directly or indirectly (via changes in the gut microbiome and its metabolite production) alters glucose management thus contributing to insulin resistance. It will determine the sites of glucose regulation affected and probe the mechanism(s) or metabolites that are communicating this response. Primary aims are as follows:1. Determine the impact of chronic aspartame consumption on the gut microbiota and the means by which aspartame heightens the response to a glucose challenge by examining the intrinsic ability of the liver to both consume and produce glucose. 2. Examine the effects of aspartame-induced glucose-intolerance on whole body and tissue specific glucose disposal and insulin action. 3. Establish the contribution of the gut microbiota to aspartame induced alterations in glucose metabolism and its specific impacts on circulating factors.METHODOLOGY. As aspartame is one of the most commonly consumed artificial sweeteners in Canada, predominantly in the form of diet soda, it will be the primary focus. Fundamental studies will elucidate the mechanistic basis of how a commonly consumed sweetener alters host metabolism. The experimental model that will be used is the well-characterized, chronically catheterized, conscious rat. Rats will be fed a chow or high fat diet in combination with either water or low-dose aspartame. Glucose fluxes will be carefully monitored in vivo employing sophisticated isotopic tracers and euglycemic-hyperinsulinemic clamps. These techniques will provide an indication of whether aspartame either directly or indirectly (via alterations in the gut microbiota, altered production of metabolites) contributes to aberrant hepatic glucose production (gluconeogenesis) or declines in peripheral insulin sensitivity. Sequencing will assess the microbiome at both functional and taxonomical levels while extensive serum and fecal metabolomic profiling will uncover gut-host mediators influencing glucose metabolism. IMPACT. This grant will explore the mechanistic basis of artificial sweetener induced metabolic disturbances. Results have the potential to alter current perceptions that aspartame is a harmless food additive and may have far reaching implications for food industry, agriculture (artificial sweeteners are commonly added to animal starter feeds to encourage food consumption and weight gain), medical professionals and legislators alike.