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Little is known about possible effects of maternal non-nutritive sweetener (NNS) consumption on the metabolic health of a child. Animal models of maternal NNS consumption during pregnancy or weaning have yielded widely varying results, and there appears to be no clear consensus on the consequences for offspring body weight, glycaemic control or sweet preference choices. Moreover, heterogeneity in study design has hampered a clear focus for future research relevant to human health. In an effort to bring clarity, we have conducted a systematic review and meta-analysis (protocol no: CRD42018109509) in animal models (rat or mouse) of maternal NNS feeding (compared to water or basal diet) during pre-gestation, pregnancy or lactation. Four databases were searched from inception to 15th September 2018: PubMed, EMBASE, SCOPUS and Web of Science. We present maternal and offspring data from 24 included studies, which have been quantitatively analysed after study quality assessment, to identify relationships between maternal diet and offspring body weight (BW), feeding behaviour and glycaemic control. In 11 data sets, exposure to NNS reduced maternal BW during pregnancy, with no effect on litter outcomes. Meta-analyses on offspring BW during weaning (1123 offspring) and adulthood (646 offspring) identified small decreases in BW for both sexes. Subgroup analyses revealed reductions in BW of rat, but not mouse models. High dosage appears to be a potential factor for reduced palatability that could influence BW results; however, a lack of reported data limited our ability to confirm. Despite this, and the fact many papers were predisposed to bias, the balance of evidence suggests a maternal NNS diet during pregnancy or lactation did not increase the body weight in offspring., (Copyright © 2019 Elsevier Inc. All rights reserved.)

For more than a decade, pioneering animal studies conducted by investigators at Purdue University have provided evidence to support a central thesis: that the uncoupling of sweet taste and caloric intake by low-calorie sweeteners (LCS) can disrupt an animal's ability to predict the metabolic consequences of sweet taste, and thereby impair the animal's ability to respond appropriately to sweet-tasting foods. These investigators' work has been replicated and extended internationally. There now exists a body of evidence, from a number of investigators, that animals chronically exposed to any of a range of LCSs - including saccharin, sucralose, acesulfame potassium, aspartame, or the combination of erythritol+aspartame - have exhibited one or more of the following conditions: increased food consumption, lower post-prandial thermogenesis, increased weight gain, greater percent body fat, decreased GLP-1 release during glucose tolerance testing, and significantly greater fasting glucose, glucose area under the curve during glucose tolerance testing, and hyperinsulinemia, compared with animals exposed to plain water or - in many cases - even to calorically-sweetened foods or liquids. Adverse impacts of LCS have appeared diminished in animals on dietary restriction, but were pronounced among males, animals genetically predisposed to obesity, and animals with diet-induced obesity. Impacts have been especially striking in animals on high-energy diets: diets high in fats and sugars, and diets which resemble a highly-processed 'Western' diet, including trans-fatty acids and monosodium glutamate. These studies have offered both support for, and biologically plausible mechanisms to explain, the results from a series of large-scale, long-term prospective observational studies conducted in humans, in which longitudinal increases in weight, abdominal adiposity, and incidence of overweight and obesity have been observed among study participants who reported using diet sodas and other LCS-sweetened beverages daily or more often at baseline. Furthermore, frequent use of diet beverages has been associated prospectively with increased long-term risk and/or hazard of a number of cardiometabolic conditions usually considered to be among the sequelae of obesity: hypertension, metabolic syndrome, diabetes, depression, kidney dysfunction, heart attack, stroke, and even cardiovascular and total mortality. Reverse causality does not appear to explain fully the increased risk observed across all of these studies, the majority of which have included key potential confounders as covariates. These have included body mass index or waist circumference at baseline; total caloric intake and specific macronutrient intake; physical activity; smoking; demographic and other relevant risk factors; and/or family history of disease. Whether non-LCS ingredients in diet beverages might have independently increased the weight gain and/or cardiometabolic risk observed among frequent consumers of LCS-sweetened beverages deserves further exploration. In the meantime, however, there is a striking congruence between results from animal research and a number of large-scale, long-term observational studies in humans, in finding significantly increased weight gain, adiposity, incidence of obesity, cardiometabolic risk, and even total mortality among individuals with chronic, daily exposure to low-calorie sweeteners - and these results are troubling., (Copyright © 2016 Elsevier Inc. All rights reserved.)

For thirty years there has been a debate about whether low calorie sweeteners (LCS) provide a benefit for body weight management. Early studies showed that when consumed alone in a beverage appetite and food intake were increased. Some, observational longitudinal cohort studies reported an association between LCS usage and increasing BMI, suggesting that LCS may actually promote weight gain. In the ensuing decades numerous additional observational and experimental trials have been conducted with the experimental trials nearly uniformly showing a benefit for LCS, either in weight loss or weight gain prevention. The observational trials have been more inconsistent with two recent meta-analyses indicating either a small positive association between LCS usage and BMI (weighted group mean correlation, p=0.03) or an inverse association with body weight change (-1.35 kg, p=.004). Numerous potential mechanisms have been explored, mostly in animal models, in an attempt to explain this association but none have yet been proven in humans. It is also possible that the association between LCS and BMI increase in the observational studies may be due to reverse causality or residual confounding. Randomized controlled trials are consistent in showing a benefit of LCS which suggests that simple behavioral engagement by individuals attempting to control their weight is a sufficiently strong signal to overcome any potential mechanism that might act to promote energy intake and weight gain. Based on existing evidence, LCS can be a useful tool for people actively engaged in managing their body weight for weight loss and maintenance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Low calorie sweeteners are some of the most thoroughly tested and evaluated of all food additives. Products including aspartame and saccharin, have undergone several rounds of risk assessment by the United States Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA), in relation to a number of potential safety concerns, including carcinogenicity and more recently, effects on body weight gain, glycemic control and effects on the gut microbiome. The majority of the modern day sweeteners; acesulfame K, advantame, aspartame, neotame and sucralose have been approved in the United States through the food additive process, whereas the most recent sweetener approvals for steviol glycosides and lo han guo have occurred through the Generally Recognized as Safe (GRAS) system, based on scientific procedures. While the regulatory process and review time of these two types of sweetener evaluations by the FDA differ, the same level of scientific evidence is required to support safety, so as to ensure a reasonable certainty of no harm., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Low-calorie sweeteners (LCSs) are used globally to increase the palatability of foods and beverages, without the calories of sugar. Recently, however, there have been claims that LCSs promote obesity. Here, I review the literature linking LCS consumption to elevated body weight in rodents. A recent systematic review found when the LCSs were presented in water or chow, only a minority of the studies reported elevated weight gain. In contrast, when the LCSs were presented in yogurt, the majority of the studies reported elevated weight gain. This review focuses on this latter subset of studies, and asks why the combination of LCSs and yogurt promoted weight gain. First, LCSs have been hypothesized to induce metabolic derangement because they uncouple sweet taste and calories. However, the available evidence indicates that the LCS-treated yogurts did not actually taste sweet to rats in the published studies. Without a sweet taste, the concerns about uncoupling sweet taste and calories would not be relevant. Second, in several studies, the LCS-treated yogurt increased weight gain without increasing caloric intake. This indicates that caloric intake alone cannot explain the elevated weight gain. Third, there is evidence that LCSs and yogurt can each alter the gut microbiota of rodents. Given recent work indicating that changes in gut microbiota can modulate body weight, it is possible that the combination of LCS and yogurt alters the gut microbiota in ways that promote weight gain. While this hypothesis remains speculative, it is consistent with the observed rodent data. In human studies, LCSs are usually presented in beverages. Based on the rodent work, it might be worthwhile to evaluate the impact of LCS-treated yogurt in humans., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Disruption in the gut microbiota is now recognized as an active contributor towards the development of obesity and insulin resistance. This review considers one class of dietary additives known to influence the gut microbiota that may predispose susceptible individuals to insulin resistance - the regular, long-term consumption of low-dose, low calorie sweeteners. While the data are controversial, mounting evidence suggests that low calorie sweeteners should not be dismissed as inert in the gut environment. Sucralose, aspartame and saccharin, all widely used to reduce energy content in foods and beverages to promote satiety and encourage weight loss, have been shown to disrupt the balance and diversity of gut microbiota. Fecal transplant experiments, wherein microbiota from low calorie sweetener consuming hosts are transferred into germ-free mice, show that this disruption is transferable and results in impaired glucose tolerance, a well-known risk factor towards the development of a number of metabolic disease states. As our understanding of the importance of the gut microbiota in metabolic health continues to grow, it will be increasingly important to consider the impact of all dietary components, including low calorie sweeteners, on gut microbiota and metabolic health., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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 throughout the digestive system that play a role in glucose absorption and trigger insulin secretion. In addition, recent findings from our laboratory showing an association between individual taste sensitivity to detect sucralose and sucralose's acute effects on metabolic response to an oral glucose load are reported. Taken as a whole, data support the notion that NNSs have metabolic effects. More research is needed to elucidate the mechanisms by which NNSs may drive metabolic dysregulation and better understand potential effects of these commonly used food additives., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Evidence linking sugar-sweetened beverage (SSB) consumption to weight gain and other negative health outcomes has prompted many individuals to resort to artificial, non-nutritive sweetener (NNS) substitutes as a means of reducing SSB intake. However, there is a great deal of controversy regarding the biological consequences of NNS use, with accumulating evidence suggesting that NNS consumption may influence feeding and metabolism via a variety of peripheral and central mechanisms. Here we argue that NNSs are not physiologically inert compounds and consider the potential biological mechanisms by which NNS consumption may impact energy balance and metabolic function, including actions on oral and extra-oral sweet taste receptors, and effects on metabolic hormone secretion, cognitive processes (e.g. reward learning, memory, and taste perception), and gut microbiota., (Copyright © 2015 Elsevier Inc. All rights reserved.)