Mechanistic and Metabolic Impacts of Non-Nutritive Sweeteners

概述。我实验室的新工作表明，在加拿大市场上普遍存在的低剂量、无热量的人工甜味剂化合物的常规使用，被广泛认为可以减少每日热量摄入，促进饱腹感，促进体重减轻，促进血糖调节，无意中破坏肠道微生物群的平衡，导致葡萄糖代谢扭曲。******目的这项拨款验证了一个中心假设，即阿斯巴甜的摄入直接或间接（通过改变肠道微生物群及其代谢物的产生）改变了葡萄糖的管理，从而导致了胰岛素抵抗。它将确定受影响的葡萄糖调节位点，并探索传递这种反应的机制或代谢物。主要目标如下：***1。通过检测肝脏消耗和产生葡萄糖的内在能力，确定长期摄入阿斯巴甜对肠道微生物群的影响，以及阿斯巴甜如何增强对葡萄糖挑战的反应。* * * 2。检查阿斯巴甜诱导的葡萄糖不耐受对全身和组织特异性葡萄糖处理和胰岛素作用的影响。* * * 3。建立肠道菌群对阿斯巴甜诱导的葡萄糖代谢改变的贡献及其对循环因子的特定影响。******方法学。由于阿斯巴甜是加拿大最常见的人工甜味剂之一，主要以无糖汽水的形式存在，因此它将成为主要焦点。基础研究将阐明一种普遍食用的甜味剂如何改变宿主代谢的机制基础。将使用的实验模型是具有良好特征的、长期插管的、有意识的大鼠。大鼠将被喂食与水或低剂量阿斯巴甜混合的食物或高脂肪食物。葡萄糖通量将使用复杂的同位素示踪剂和正糖-高胰岛素钳仔细监测体内。这些技术将提供阿斯巴甜是否直接或间接（通过改变肠道微生物群，改变代谢物的产生）导致肝糖生成异常（糖异生）或外周胰岛素敏感性下降的指示。测序将在功能和分类水平上评估微生物组，而广泛的血清和粪便代谢组学分析将揭示影响葡萄糖代谢的肠道-宿主介质。* * * * * *的影响。这项拨款将探索人工甜味剂诱导代谢紊乱的机制基础。研究结果有可能改变人们目前对阿斯巴甜是一种无害食品添加剂的看法，并可能对食品工业、农业（人工甜味剂通常被添加到动物饲料中，以鼓励食物消费和体重增加）、医疗专业人员和立法者等产生深远影响。

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.