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Concept: Aspartame

213

Artificial sweeteners have been widely used in the modern diet, and their observed effects on human health have been inconsistent, with both beneficial and adverse outcomes reported. Obesity and type 2 diabetes have dramatically increased in the U.S. and other countries over the last two decades. Numerous studies have indicated an important role of the gut microbiome in body weight control and glucose metabolism and regulation. Interestingly, the artificial sweetener saccharin could alter gut microbiota and induce glucose intolerance, raising questions about the contribution of artificial sweeteners to the global epidemic of obesity and diabetes. Acesulfame-potassium (Ace-K), a FDA-approved artificial sweetener, is commonly used, but its toxicity data reported to date are considered inadequate. In particular, the functional impact of Ace-K on the gut microbiome is largely unknown. In this study, we explored the effects of Ace-K on the gut microbiome and the changes in fecal metabolic profiles using 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics. We found that Ace-K consumption perturbed the gut microbiome of CD-1 mice after a 4-week treatment. The observed body weight gain, shifts in the gut bacterial community composition, enrichment of functional bacterial genes related to energy metabolism, and fecal metabolomic changes were highly gender-specific, with differential effects observed for males and females. In particular, ace-K increased body weight gain of male but not female mice. Collectively, our results may provide a novel understanding of the interaction between artificial sweeteners and the gut microbiome, as well as the potential role of this interaction in the development of obesity and the associated chronic inflammation.

Concepts: Gut flora, Metabolism, Nutrition, Insulin, Obesity, Aspartame, Sweeteners, Sucralose

50

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

Concepts: Allele, Amino acid, Enzyme, Phenylketonuria, Phenylalanine, Tyrosine, Aspartame, Phenylalanine hydroxylase

40

It has been suggested that the use of nonnutritive sweeteners (NNSs) can lead to weight gain, but evidence regarding their real effect in body weight and satiety is still inconclusive. Using a rat model, the present study compares the effect of saccharin and aspartame to sucrose in body weight gain and in caloric intake. Twenty-nine male Wistar rats received plain yogurt sweetened with 20% sucrose, 0.3% sodium saccharin or 0.4% aspartame, in addition to chow and water ad libitum, while physical activity was restrained. Measurements of cumulative body weight gain, total caloric intake, caloric intake of chow and caloric intake of sweetened yogurt were performed weekly for 12weeks. Results showed that addition of either saccharin or aspartame to yogurt resulted in increased weight gain compared to addition of sucrose, however total caloric intake was similar among groups. In conclusion, greater weight gain was promoted by the use of saccharin or aspartame, compared with sucrose, and this weight gain was unrelated to caloric intake. We speculate that a decrease in energy expenditure or increase in fluid retention might be involved.

Concepts: Real number, E number, Aspartame, Sweeteners, Ad libitum, Sucralose, Saccharin, Equal

34

Despite safety reports of the artificial sweetener aspartame, health-related concerns remain.

Concepts: Aspartame, Sweeteners

27

Artificial sweeteners are gaining acceptance as tracers of human wastewater in the environment. The 3 artificial sweeteners analyzed in this study were detected in leachate or leachate-impacted groundwater at levels comparable to those of untreated wastewater at 14 of 15 municipal landfill sites tested, including several closed for >50 years. Saccharin was the dominant sweetener in old (pre-1990) landfills, while newer landfills were dominated by saccharin and acesulfame (introduced 2 decades ago; dominant in wastewater). Cyclamate was also detected, but less frequently. A case study at one site illustrates the use of artificial sweeteners to identify a landfill-impacted groundwater plume discharging to a stream. The study results suggest that artificial sweeteners can be useful tracers for current and legacy landfill contamination, with relative abundances of the sweeteners potentially providing diagnostic ability to distinguish different landfills or landfill cells, including crude age-dating, and to distinguish landfill and wastewater sources.

Concepts: Groundwater, Anaerobic digestion, Leachate, Landfill, Land reclamation, Aspartame, Sweeteners, Sucralose

8

Despite its widespread use, the artificial sweetener aspartame remains one of the most controversial food additives, due to mixed evidence on its neurobehavioral effects. Healthy adults who consumed a study-prepared high-aspartame diet (25 mg/kg body weight/day) for 8 days and a low-aspartame diet (10 mg/kg body weight/day) for 8 days, with a 2-week washout between the diets, were examined for within-subject differences in cognition, depression, mood, and headache. Measures included weight of foods consumed containing aspartame, mood and depression scales, and cognitive tests for working memory and spatial orientation. When consuming high-aspartame diets, participants had more irritable mood, exhibited more depression, and performed worse on spatial orientation tests. Aspartame consumption did not influence working memory. Given that the higher intake level tested here was well below the maximum acceptable daily intake level of 40-50 mg/kg body weight/day, careful consideration is warranted when consuming food products that may affect neurobehavioral health. © 2014 Wiley Periodicals, Inc.

Concepts: Psychology, Nutrition, Cognitive psychology, Food, Vinegar, Food additive, Aspartame, Sweetener

6

Phenylketonuria (PKU) is an inborn error of metabolism associated with high blood levels of phenylalanine (Phe). A Phe-restricted diet supplemented with L-amino acids is the main treatment strategy for this disease; if started early, most neurological abnormalities can be prevented. The healthy human gut contains trillions of commensal bacteria, often referred to as the gut microbiota. The composition of the gut microbiota is known to be modulated by environmental factors, including diet. In this study, we compared the gut microbiota of 8 PKU patients on Phe-restricted dietary treatment with that of 10 healthy individuals. The microbiota were characterized by 16S rRNA sequencing using the Ion Torrent™ platform. The most dominant phyla detected in both groups were Bacteroidetes and Firmicutes. PKU patients showed reduced abundance of the Clostridiaceae, Erysipelotrichaceae, and Lachnospiraceae families, Clostridiales class, Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus and Veillonella genera, and enrichment of Prevotella, Akkermansia, and Peptostreptococcaceae. Microbial function prediction suggested significant differences in starch/glucose and amino acid metabolism between PKU patients and controls. Together, our results suggest the presence of distinct taxonomic groups within the gut microbiome of PKU patients, which may be modulated by their plasma Phe concentration. Whether our findings represent an effect of the disease itself, or a consequence of the modified diet is unclear.

Concepts: Bacteria, Gut flora, Amino acid, Nutrition, Phenylketonuria, Phenylalanine, Aspartame, Clostridia

6

Nonnutritive sweeteners (NNS), including saccharin, sucralose, aspartame, and acesulfame-potassium, are commonly consumed in the general population, and all except for saccharin are considered safe for use during pregnancy and lactation. Sucralose (Splenda) currently holds the majority of the NNS market share and is often combined with acesulfame-potassium in a wide variety of foods and beverages. To date, saccharin is the only NNS reported to be found in human breast milk after maternal consumption, while there is no apparent information on the other NNS. Breast milk samples were collected from 20 lactating volunteers, irrespective of their habitual NNS intake. Saccharin, sucralose, and acesulfame-potassium were present in 65% of participants' milk samples, whereas aspartame was not detected. These data indicate that NNS are frequently ingested by nursing infants, and thus prospective clinical studies are necessary to determine whether early NNS exposure via breast milk may have clinical implications.

Concepts: Milk, Breastfeeding, Lactation, Breast, Breast milk, Aspartame, Sweeteners, Sucralose

4

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.

Concepts: Scientific method, Nutrition, Obesity, Adipose tissue, Body mass index, Metabolic syndrome, Aspartame, Sucralose

3

The current review examined published data on the intake of all major low-/no-calorie sweeteners-aspartame, acesulfame-K, saccharin, sucralose, cyclamate, thaumatin and steviol glycosides-globally over the last decade. The most detailed and complex exposure assessments were conducted in Europe, following a standardized approach. Japan and Korea similarly had up-to-date and regular intake data available. The data for other Asian countries, Latin America, Australia/New Zealand and global estimates, evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), while available, were shown to be more limited in terms of design. Overall, the studies conducted since 2008 raised no concerns with respect to exceedance of individual sweetener acceptable daily intake (ADIs) among the general population globally. The data identified do not suggest a shift in exposure over time, with several studies indicating a reduction in intake. However, some data suggest there may have been an increase in the numbers of consumers of low-/no-calorie-sweetened products. Future research should consider a more standardized approach to allow the monitoring of potential changes in exposure based upon events such as sugar reduction recommendations, to ensure there is no shift in intake, particularly for high-risk individuals, including diabetics and children with specific dietary requirements, and to ensure risk management decisions are based on quality intake analyses.

Concepts: Nutrition, Food additive, Aspartame, Sweeteners, Sugar substitute, Sucralose, Acceptable daily intake, Sweetener