UNASSIGNED: Although artificial and non-nutritive sweeteners are widely used and generally recognized as safe by the US and European Union regulatory agencies, there have been no clinical trials to assess either long-term cardiovascular disease risks or short-term cardiovascular disease-relevant phenotypes. Recent studies report that fasting plasma levels of erythritol, a commonly used sweetener, are clinically associated with heightened incident cardiovascular disease risks and enhance thrombosis potential in vitro and in animal models. Effects of dietary erythritol on thrombosis phenotypes in humans have not been examined.
UNASSIGNED: Using a prospective interventional study design, we tested the impact of erythritol or glucose consumption on multiple indices of stimulus-dependent platelet responsiveness in healthy volunteers (n=10 per group). Erythritol plasma levels were quantified with liquid chromatography tandem mass spectrometry. Platelet function at baseline and following erythritol or glucose ingestion was assessed via both aggregometry and analysis of granule markers released.
UNASSIGNED: Dietary erythritol (30 g), but not glucose (30 g), lead to a >1000-fold increase in erythritol plasma concentration (6480 [5930-7300] versus 3.75 [3.35-3.87] μmol/L; P<0.0001) and exhibited acute enhancement of stimulus-dependent aggregation responses in all subjects, agonists, and doses examined. Erythritol ingestion also enhanced stimulus-dependent release of the platelet dense granule marker serotonin (P<0.0001 for TRAP6 [thrombin activator peptide 6] and P=0.004 for ADP) and the platelet α-granule marker CXCL4 (C-X-C motif ligand-4; P<0.0001 for TRAP6 and P=0.06 for ADP). In contrast, glucose ingestion triggered no significant increases in stimulus-dependent release of either serotonin or CXCL4.
UNASSIGNED: Ingestion of a typical quantity of the non-nutritive sweetener erythritol, but not glucose, enhances platelet reactivity in healthy volunteers, raising concerns that erythritol consumption may enhance thrombosis potential. Combined with recent large-scale clinical observational studies and mechanistic cell-based and animal model studies, the present findings suggest that discussion of whether erythritol should be reevaluated as a food additive with the Generally Recognized as Safe designation is warranted.
UNASSIGNED: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04731363.

BACKGROUND: Low-calorie sweetener (LCS) consumption is prevalent among lactating women, yet infants\' exposure to LCS in human milk is not well-characterized.
OBJECTIVE: Conduct a pharmacokinetic study of sucralose and ace-K in mothers\' milk and plasma over 72 hours, and in infants\' plasma.
METHODS: Following baseline blood and milk collection, mothers (n=40) consumed 20-ounces of diet cranberry juice, containing sucralose and ace-K. Blood samples were collected from the mother 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours after beverage ingestion, and milk was expressed at 1, 2, 3, 4, 6, 8, 12, and 24 hours post-ingestion. One blood sample was collected from each infant, the timing of which was determined using pharmacokinetics model-based simulation. Concentration-time profiles of LCS from mother\'s plasma and milk were analyzed using non-compartmental methods.
RESULTS: Ace-K rapidly entered human milk with the largest observed concentration of 373.0 (CV 69%) ng/ml first detected 4 hours following diet beverage ingestion. Sucralose appeared in human milk 1-2 hours after diet beverage ingestion with the largest observed concentration of 7.2 (CV 63%) ng/ml first detected 7 hours post-ingestion. The mean 24-hour milk to plasma ratio (MPR) of ace-K was 1.75 (SD 1.37) with a mean relative infant dose (RID) of 1.59% (SD 1.72%). ace-K was detected in all infants\' plasma with an average concentration of 9.2 (SD% 14.8) ng/ml approximately 6 hours after maternal beverage ingestion. The mean 24-hour MPR of sucralose was 0.15 (SD 0.06) with a mean RID of 0.04% (SD 0.02%). Sucralose was detected in only fifteen infants\' plasma, and the average concentration was 5.0 (SD% 7.1) ng/ml, approximately 5 hours after diet beverage ingestion.
CONCLUSIONS: Ace-K rapidly transfers from human milk into infants\' circulation whereas sucralose was detected at much lower concentrations and in some but not all infants. Future research should investigate effects of early life sucralose and ace-K exposure via human milk on infants\' health.
BACKGROUND: NCT05379270, https://classic.
RESULTS: gov/ct2/show/NCT05379270.

OBJECTIVE: Excessive consumption of added sugars has been linked to the rise in obesity and associated metabolic abnormalities. Non-nutritive sweeteners (NNSs) offer a potential solution to reduce sugar intake, yet their metabolic safety remains debated. This study aimed to systematically assess the long-term metabolic effects of commonly used NNSs under both normal and obesogenic conditions.
METHODS: To ensure consistent sweetness level and controlling for the acceptable daily intake (ADI), eight weeks old C57BL/6 male mice were administered with acesulfame K (ace K, 535.25 mg/L), aspartame (411.75 mg/L), sucralose (179.5 mg/L), saccharin (80 mg/L), or steviol glycoside (Reb M, 536.25 mg/L) in the drinking water, on the background of either regular or high-fat diets (in high fat diet 60% of calories from fat). Water or fructose-sweetened water (82.3.gr/L), were used as controls. Anthropometric and metabolic parameters, as well as microbiome composition, were analyzed following 20-weeks of exposure.
RESULTS: Under a regular chow diet, chronic NNS consumption did not significantly affect body weight, fat mass, or glucose metabolism as compared to water consumption, with aspartame demonstrating decreased glucose tolerance. In diet-induced obesity, NNS exposure did not increase body weight or alter food intake. Exposure to sucralose and Reb M led to improved insulin sensitivity and decreased weight gain. Reb M specifically was associated with increased prevalence of colonic Lachnospiracea bacteria.
CONCLUSIONS: Long-term consumption of commonly used NNSs does not induce adverse metabolic effects, with Reb M demonstrating a mild improvement in metabolic abnormalities. These findings provide valuable insights into the metabolic impact of different NNSs, aiding in the development of strategies to combat obesity and related metabolic disorders.

BACKGROUND: Artificial sweeteners are widely popular worldwide as substitutes for sugar or caloric sweeteners, but there are still several important unknowns and controversies regarding their associations with cardiovascular disease (CVD). We aimed to extensively assess the association and subgroup variability between artificial sweeteners and CVD and CVD mortality in the UK Biobank cohort, and further investigate the modification effects of genetic susceptibility and the mediation role of type 2 diabetes mellitus (T2DM).
METHODS: This study included 133,285 participants in the UK Biobank who were free of CVD and diabetes at recruitment. Artificial sweetener intake was obtained from repeated 24-hour diet recalls. Cox proportional hazard models were used to estimate HRs. Genetic predisposition was estimated using the polygenic risk score (PRS). Furthermore, time-dependent mediation was performed.
RESULTS: In our study, artificial sweetener intake (each teaspoon increase) was significantly associated with an increased risk of incident overall CVD (HR1.012, 95%CI: 1.008,1.017), coronary artery disease (CAD) (HR: 1.018, 95%CI: 1.001,1.035), peripheral arterial disease (PAD) (HR: 1.035, 95%CI: 1.010,1.061), and marginally significantly associated with heart failure (HF) risk (HR: 1.018, 95%CI: 0.999,1.038). In stratified analyses, non-whites were at greater risk of incident overall CVD from artificial sweetener. People with no obesity (BMI < 30 kg/m2) also tended to be at greater risk of incident CVD from artificial sweetener, although the obesity interaction is not significant. Meanwhile, the CVD risk associated with artificial sweeteners is independent of genetic susceptibility, and no significant interaction exists between genetic susceptibility and artificial sweeteners in terms of either additive or multiplicative effects. Furthermore, our study revealed that the relationship between artificial sweetener intake and overall CVD is significantly mediated, in large part, by prior T2DM (proportion of indirect effect: 70.0%). In specific CVD subtypes (CAD, PAD, and HF), the proportion of indirect effects ranges from 68.2 to 79.9%.
CONCLUSIONS: Our findings suggest significant or marginally significant associations between artificial sweeteners and CVD and its subtypes (CAD, PAD, and HF). The associations are independent of genetic predisposition and are mediated primarily by T2DM. Therefore, the large-scale application of artificial sweeteners should be prudent, and the responses of individuals with different characteristics to artificial sweeteners should be better characterized to guide consumers\' artificial sweeteners consumption behavior.

BACKGROUND: Insulin exerts a crucial impact on glucose control, cellular growing, function, and metabolism. It is partially modulated by nutrients, especially as a response to the intake of foods, including carbohydrates. Moreover, insulin can exert an anorexigenic effect when inserted into the hypothalamus of the brain, in which a complex network of an appetite/hunger control system occurs. The current literature review aims at thoroughly summarizing and scrutinizing whether insulin release in response to glucose exposure may be a better choice to control body weight gain and related diseases compared to the use of sucrose substitutes (SSs) in combination with a long-term, well-balanced diet.
METHODS: This is a comprehensive literature review, which was performed through searching in-depth for the most accurate scientific databases and applying effective and relevant keywords.
RESULTS: The insulin action can be inserted into the hypothalamic orexigenic/anorexigenic complex system, activating several anorexigenic peptides, increasing the hedonic aspect of food intake, and effectively controlling the human body weight. In contrast, SSs appear not to affect the orexigenic/anorexigenic complex system, resulting in more cases of uncontrolled body weight maintenance while also increasing the risk of developing related diseases.
CONCLUSIONS: Most evidence, mainly derived from in vitro and in vivo animal studies, has reinforced the insulin anorexigenic action in the hypothalamus of the brain. Simultaneously, most available clinical studies showed that SSs during a well-balanced diet either maintain or even increase body weight, which may indirectly be ascribed to the fact that they cannot cover the hedonic aspect of food intake. However, there is a strong demand for long-term longitudinal surveys to effectively specify the impact of SSs on human metabolic health.

OBJECTIVE: Recommendations on the use of nonsugar sweeteners are contradictory, even if they come from official sources. The aim is to review and discuss recent findings on the potential impact of nonsugar sweeteners on human health.
RESULTS: While randomized controlled trials (RCTs) with short duration and risk factors endpoints mostly show favourable effects on body weight and cardiometabolic parameters when nonsugar sweeteners are used to replaced sugar-sweetened products, observational studies mostly show a positive association between the consumption of nonsugar sweeteners and cardiometabolic diseases. The conflicting results may be explained by the heterogenous nature of nonsugar sweeteners but also likely is a consequence of serious weaknesses of available studies.
CONCLUSIONS: For more evidence-based recommendations for practice and policy, scientifically sound studies with long follow-up are required.

OBJECTIVE: It is unclear whether parental consumption of non-nutritive sweetener (NNS) can affect subsequent generations. The aim of this study was to determine whether chronic parental consumption of sucralose and stevia in mice affects body weight gain and liver and intestinal expression of histone deacetylase 3 (Hdac3) in these animals and in the subsequent first filial (F1) and second filial (F2) generations.
METHODS: Male and female mice (n = 47) were divided into three groups to receive water alone or supplemented with sucralose (0.1 mg/mL) or stevia (0.1 mg/mL) for 16 wk (parental [F0] generation). F0 mice were bred to produce the F1 generation; then, F1 mice were bred to produce the F2 generation. F1 and F2 animals did not receive NNSs. After euthanasia, hepatic and intestinal expression of Hdac3 was determined by quantitative reverse transcription polymerase chain reaction.
RESULTS: Body weight gain did not differ between the three groups in the F0 generation, but it was greater in the F1 sucralose and stevia groups than in the control group. Consumption of both NNSs in the F0 generation was associated with lower Hdac3 expression in the liver and higher in the intestine. Hepatic Hdac3 expression was normalized to the control values in the F1 and F2 animals of the sucralose and stevia groups. Intestinal expression was still higher in the F1 generations of the sucralose and stevia groups but was partially normalized in the F2 generation of these groups, compared with control.
CONCLUSIONS: NNS consumption differentially affects hepatic and intestinal Hdac3 expression. Changes in hepatic expression are not transmitted to the F1 and F2 generations whereas those in intestinal expression are enhanced in the F1 and attenuated in the F2 generations.

Recent studies suggest that some nonnutritive sweeteners (NNS) have deleterious effects on the human gut microbiome (HGM). The effect of steviol glycosides on the HGM has not been well studied.
We aimed to evaluate the effects of stevia- compared with sucrose-sweetened beverages on the HGM and fecal short-chain fatty acid (SCFA) profiles.
Using a randomized, double-blinded, parallel-design study, n = 59 healthy adults [female/male, n = 36/23, aged 31±9 y, body mass index (BMI): 22.6±1.7 kg/m2] consumed 16 oz of a beverage containing either 25% of the acceptable daily intake (ADI) of stevia or 30 g of sucrose daily for 4 weeks followed by a 4-week washout. At weeks 0 (baseline), 4, and 8, the HGM was characterized via shotgun sequencing, fecal SCFA concentrations were measured using ultra-high performance liquid chromatography-tandem mass spectrometry and anthropometric measurements, fasting serum glucose, insulin and lipids, blood pressure, pulse, and 3-d diet records were obtained.
There were no significant differences in the HGM or fecal SCFA between the stevia and sucrose groups at baseline (P > 0.05). At week 4 (after intervention), there were no significant differences in the HGM at the phylum, family, genus, or species level between the stevia and sucrose groups and no significant differences in fecal SCFA. At week 4, BMI had increased by 0.3 kg/m2 (P = 0.013) in sucrose compared with stevia, but all other anthropometric and cardiometabolic measures and food intake did not differ significantly (P > 0.05). At week 8 (after washout), there were no significant differences in the HGM, fecal SFCA, or any anthropometric or cardiometabolic measure between the stevia and sucrose groups (P > 0.05).
Daily consumption of a beverage sweetened with 25% of the ADI of stevia for 4 weeks had no significant effects on the HGM, fecal SCFA, or fasting cardiometabolic measures, compared with daily consumption of a beverage sweetened with 30 g of sucrose.
clinicaltrials.gov as NCT05264636.

BACKGROUND: Non-nutritive sweeteners (NNS) are commonly used in sweetened foods and beverages; however their role in metabolic regulation is still not clear. In this experiment, we used guinea pigs as an animal model to study the effect of NNS on body growth and intestinal health by modifying gut microbiota and hypothalamus-related proteins.
RESULTS: For a 28-day feeding experiment a total of 40 guinea pigs were randomly divided into four groups, one control (CN) group and three treatments, in which three NNS were added to the diet: rebaudioside A (RA, 330 mg kg-1), sodium saccharin (SS, 800 mg kg-1), and sucralose (TGS, 167 mg kg-1), respectively. The TGS group exhibited significantly reduced food consumption in comparison with the CN group (P < 0.05) whereas the RA group showed increased food consumption in comparison with the CN group (P < 0.05). Notably, Taste receptor type 1 subunit 2 (T1R2) expression in the hypothalamus was significantly higher in the RA group than in the CN group (P < 0.05). The mRNA expressions of appetite-stimulated genes arouti-related neuropeptide (AGRP), neuropeptide Y (NPY), and thyroid stimulating hormone (TSHB) were significantly higher than those in the CN group (P < 0.05) but mRNA expressions of appetite-suppressed genes tryptophan hydroxylase 2(THP2) were significantly lower in the TGS group (P < 0.05). Furthermore, NNS in the guinea pig diets (RA, SS, TGS) significantly increased the relative abundance of Muribaculaceae but decreased the relative abundance of Clostridia_vadin BB60 in comparison with the CN group (P < 0.05). We also found that dietary supplementation with RA also significantly altered the relative abundance of Lactobacillus.
CONCLUSIONS: Our finding confirmed that dietary supplementation with RA and TGS affected body growth and intestinal health by modulating hypothalamic RNA profiles and ileum microbiota, suggesting that NNS should be included in guinea-pig feeding. © 2024 Society of Chemical Industry.

The use of non-nutritive sweeteners (NNSs) as an alternative to caloric sugars has increased in recent years. Stevia is an NNS that has demonstrated beneficial effects on appetite and energy intake. However, the impact on the gut microbiota is not well understood. Therefore, we investigated how regular consumption of stevia, for up to 12 weeks, impacts the human gut microbiota. Healthy subjects with a normal body mass index participated in our study; the stevia group (n = 14) was asked to consume five drops of stevia twice daily, compared to control participants (n = 13). Faecal samples collected before and after treatment were analysed by 16S rRNA gene sequencing. Stevia did not cause significant changes in the alpha or beta diversity when compared to the control groups. When the relative abundances of taxa were investigated, no clear differences were detected. Conversely, a random forest analysis correctly associated the gut microbiome with the control and stevia groups with an average of 75% accuracy, suggesting that there are intrinsic patterns that could discriminate between control and stevia use. However, large-scale changes in the gut microbiota were not apparent in this study, and, therefore, our data suggest that stevia does not significantly impact the gut microbiota.