Low-calorie sweeteners (LCSs) and LCS-containing beverages have been proposed as appropriate substitutes for caloric sugars in recent years. In this Perspective, we highlight the recent findings from observational and interventional studies, focusing on obesity, gut microbiome, and cardiometabolic health. We provide public health actors and health care professionals with an insightful overview of recent evidence to bridge the gap between research and practice.

The prevalence of precocious puberty and the consumption of nonnutritive sweeteners (NNS) is rapidly growing worldwide. However, the effects of NNSs on precocious puberty remain unclear. We examined the impact of acesulfame potassium (AceK), one of the most widely used NNS, on central precocious puberty (CPP) development using ex vivo and in vitro studies. 884 girls aged 6-12 were enrolled with complete AceK consumption data and CPP outcome assessment in the Taiwan Pubertal Longitudinal Study from 2018 to 2022. After adjustment for confounders, compared with no AceK consumption, AceK consumption at more than the median dose was associated with higher CPP risk in girls (odds ratio = 1.88, 95% confidence interval = 1.16-3.06; p for trend = 0.003). In rats, AceK consumption from in-utero to post-weaning stages accelerated puberty onset, accompanied by increased brain gonadotropin-releasing hormone (GnRH) expression. Intracerebroventricular AceK injection also induced early puberty onset in rats. In N44 hypothalamic neuron cells, AceK treatment increased reactive oxygen species production, which led to protein kinase A (PKA) activation and increased GnRH expression. These findings suggest that prepubertal girls should consume soft drinks or food products containing AceK more cautiously.

UNASSIGNED: Chile\'s landmark food labeling and advertising policy led to major reductions in sugar purchases. However, it is unclear whether this led to increases in the purchases of nonnutritive sweeteners (NNS).
UNASSIGNED: The objective of this study was to assess the changes in NNS and caloric-sweetened (CS) products purchased after the law\'s first phase.
UNASSIGNED: Longitudinal data on food and beverage purchases from 2,381 households collected from January 1, 2015 to December 31, 2017, were linked to nutritional information and categorized into added sweetener groups (unsweetened, NNS-only, CS-only, or NNS with CS). Logistic random-effects models and fixed-effects models were used to compare the percentage of households purchasing products and the mean volume purchased by sweetener category to a counterfactual based on pre-regulation trends.
UNASSIGNED: Compared with the counterfactual, the percentage of households purchasing any NNS beverages (NNS-only or NNS with CS) increased by 4.2 percentage points (pp) (95% CI: 2.8, 5.7; P < 0.01). This increase was driven by households purchasing NNS-only beverages (12.1 pp, 95% CI: 10.0, 14.2; P < 0.01). The purchased volume of beverages with any NNS increased by 25.4 mL/person/d (95% CI: 20.1, 30.7; P < 0.01) or 26.5%. Relative to the counterfactual, there were declines of -5.9 pp in households purchasing CS-only beverages (95% CI: -7.0, -4.7; P < 0.01). Regarding the types of sweeteners purchased, we found significant increases in the amounts of sucralose, aspartame, acesulfame K, and steviol glycosides purchased from beverages. Among foods, differences were minimal.
UNASSIGNED: The first phase of Chile\'s law was associated with an increase in the purchases of beverages containing NNS and decreases in beverages containing CS, but virtually no changes in foods.

Aspartame (Asp) and acesulfame-K (Ace-K) are nonnutritive sweeteners (NNSs) commonly used in combination to replace added sugars in reduced- or low-calorie foods and beverages. Despite Asp/Ace-K blends having negligible calories, their effects on appetite have not been reviewed systematically. We therefore undertook a systematic review and meta-analysis of the metabolic effects of Asp/Ace-K blends on energy intake (EI), subjective appetite scores, blood glucose, and the incretin hormones glucose-dependent insulinotropic peptide and glucagon-like peptide. MEDLINE, Web of Science, and Cochrane CENTRAL databases (Embase, PubMed, and CINAHL) were searched (May 2021) for randomized controlled trials (RCTs). Human RCTs using Asp/Ace-K blends compared with sugar and water controls were included, whereas isolated cell and animal studies were excluded. An overall 4829 publications were identified and 8 studies, including 274 participants, were retrieved for review. The Asp/Ace-K group\'s EI was significantly reduced compared with sugar [mean difference (MD): -196.56 kcal/meal; 95% CI: -332.01, -61.11 kcal/meal; P = 0.004] and water (MD: -213.42 kcal/meal; 95% CI: -345.4, -81.44 kcal/meal; P = 0.002). Meta-analysis of subjective appetite scores and incretins could not be undertaken due to inconsistencies in data reporting and insufficient data, respectively, but of the 4 studies identified, no differences were observed between Asp/Ace-K blends and controls. The Asp/Ace-K group\'s blood glucose was nonsignificantly reduced compared with sugar (MD: -1.48 mmol/L; 95% CI: -3.26, 0.3 mmol/L; P = 0.1) and water (MD: -0.08 mmol/L; 95% CI: -0.62, 0.47 mmol/L; P = 0.78). Lower EI in participants who were predominantly healthy and assigned to Asp/Ace-K blends could not be reliably attributed to changes in subjective appetite scores. Blood glucose and incretins were also generally not affected by Asp/Ace-K blends when compared with controls. Additional short- and long-term RCTs using NNSs and sugars at dietarily relevant levels are needed. This trial was registered at the International Prospective Register of Systematic Reviews (PROSPERO: CRD42017061015).

The aim of this study was to determine the effects of regular exposure to certain low- or no-calorie sweeteners (LNCS) on glucose tolerance and glucagon-like peptide 1 (GLP-1) release in healthy individuals.
It was designed as a randomized, single-blinded, controlled study. Healthy and normoglycemic adults who did not have regular consumption of LNCS were recruited. Participants underwent a 75-g oral glucose tolerance test (OGTT) at baseline and were randomly assigned to consume 330 mL water sweetened with saccharine, sucralose, or aspartame + acesulfame-K (Asp+Ace-K), or plain water for the control group, daily for 4 wk. Fasting plasma glucose, insulin, GLP-1, and glycated hemoglobin A1c (HbA1c) levels and 1-h, 2-h, and 3-h plasma glucose and insulin levels during OGTT were obtained at baseline. The change in insulin sensitivity was assessed by both the Homeostatic Model Assessment Insulin Resistance (HOMA-IR) Index and the Matsuda Index. Anthropometric measurements and dietary intakes were determined at baseline. Baseline measurements were repeated at week 4.
Of the participants enrolled in the study, 42 (age, 21.24 ± 2.26 y; body mass index, 20.65 ± 2.88 kg/m2) completed the 4-wk intervention period. There were no differences for glucose, insulin, GLP-1, or HbA1c levels or HOMA-IR scores at baseline or at week 4 when compared with the control group. The area under the curve of mean glucose and insulin values during OGTT were also found to be similar between groups at baseline and week 4. There were also no effects of LNCS intake on body weight, body composition, and waist circumference.
These results suggest that regular consumption of LNCS-sweetened water similar to doses consumed in daily life over 4 wk had no significant effect on glycemic response, insulin sensitivity, GLP-1 release, and body weight in healthy individuals. This trial was registered at www.
gov as NCT04904133.

Government regulatory actions and public policies to reduce sugar consumption were recently implemented in Brazil. To evaluate their potential impact on the supply of products containing high-intensity sweeteners (HIS) and on dietary exposure to these substances, this study aimed to create a comprehensive database on HIS declared in Brazilian commercial products and estimate their intake through consumption of these products. The occurrence of HIS was evaluated through labeling information of 1869 commercial products available in the Brazilian market, collected between January 2021 and August 2021, and the daily intake was estimated for eight HIS (acesulfame K, advantame, aspartame, cyclamate, steviol glycosides, neotame, saccharin and sucralose) using a deterministic approach by multiplying the maximum permitted levels of HIS in foods and beverages by the consumption data of these products. The consumption data were obtained from the report of Household Budget Survey (POF/IBGE), conducted from 2017 to 2018 through a 24-hour dietary recall applied to 46,164 individuals aged 10 years and over, which included only average data (i.e. average consumption for the general population or subgroups). The most frequent HIS in the investigated products were sucralose (26.8 %; n = 938) and acesulfame K (21.7 %; n = 759), and although the combination of sweeteners is a common practice in the food industry, there was a predominance of only one substance in the investigated products (46.7 %; n = 873). The estimated intake of HIS for average consumers was below the Acceptable Daily Intake (ADI) and does not suggest a toxicological concern. A similar scenario was observed for high consumers, except for cyclamate and steviol glycosides, which corresponded to 144 % and 131 % of their respective ADIs in the general population. To our knowledge, this is the most comprehensive database on HIS in Brazil and the most recent exposure assessment performed nationally.

Aspartame (Asp) and acesulfame-K (Ace-K) are nonnutritive sweeteners (NNSs) commonly used in combination to replace added sugars in reduced- or low-calorie foods and beverages. Despite Asp/Ace-K blends having negligible calories, their effects on appetite have not been reviewed systematically. We therefore undertook a systematic review and meta-analysis of the metabolic effects of Asp/Ace-K blends on energy intake (EI), subjective appetite scores, blood glucose, and the incretin hormones glucose-dependent insulinotropic peptide and glucagon-like peptide. MEDLINE, Web of Science, and Cochrane CENTRAL databases (Embase, PubMed, and CINAHL) were searched (May 2021) for randomized controlled trials (RCTs). Human RCTs using Asp/Ace-K blends compared with sugar and water controls were included, whereas isolated cell and animal studies were excluded. An overall 4829 publications were identified and 8 studies, including 274 participants, were retrieved for review. The Asp/Ace-K group\'s EI was significantly reduced compared with sugar [mean difference (MD): -196.56 kcal/meal; 95% CI: -332.01, -61.11 kcal/meal; P = 0.004] and water (MD: -213.42 kcal/meal; 95% CI: -345.4, -81.44 kcal/meal; P = 0.002). Meta-analysis of subjective appetite scores and incretins could not be undertaken due to inconsistencies in data reporting and insufficient data, respectively, but of the 4 studies identified, no differences were observed between Asp/Ace-K blends and controls. The Asp/Ace-K group\'s blood glucose was nonsignificantly reduced compared with sugar (MD: -1.48 mmol/L; 95% CI: -3.26, 0.3 mmol/L; P = 0.1) and water (MD: -0.08 mmol/L; 95% CI: -0.62, 0.47 mmol/L; P = 0.78). Lower EI in participants who were predominantly healthy and assigned to Asp/Ace-K blends could not be reliably attributed to changes in subjective appetite scores. Blood glucose and incretins were also generally not affected by Asp/Ace-K blends when compared with controls. Additional short- and long-term RCTs using NNSs and sugars at dietarily relevant levels are needed. This trial was registered at the International Prospective Register of Systematic Reviews (PROSPERO: CRD42017061015).

The first phase of Chile\'s Law of Food Labelling and Advertising showed important declines in the sugar content of packaged foods, but it is unknown whether the law led to an increase in nonnutritive sweetener (NNS) intake, particularly among preschool children.
Estimate the changes in preschoolers\' NNS intake after the first phase of the Chilean law.
We used 24-h dietary recalls collected in 2016 (pre-law) and 2017 (post-law) from a cohort of preschoolers (n = 875). The primary caretaker was the respondent of the recalls. Information on NNS was obtained from nutrition facts panels collected annually and linked to dietary data. We used logistic regression to estimate the changes in the proportion of preschoolers who consume NNS and two-part models to estimate the changes in mean intake. We determined the percentage of children that surpassed the acceptable daily intake (ADI) of each NNS using the National Cancer Institute method.
The proportion of consumers of at least one NNS increased from 77.9% to 92.0% (p-value < 0.01). The mean intake increased for sucralose, aspartame, acesulfame-K and steviol glycosides (+20.3, +15.1, +6.1 and +3.3 mg/day, respectively). In addition, NNS dietary sources changed for sucralose and steviol glycosides, becoming industrialized juices and dairy beverages more relevant while tabletop NNS became less relevant. None of the children surpassed the ADI.
NNS intake increased in preschoolers after the first phase of a national policy that promoted sugar reformulation.

BACKGROUND: Against expert recommendations, sugar-sweetened beverages, especially fruit drinks, are consumed by young children. Misperceptions about drink ingredients and healthfulness can contribute to caregivers\' provision.
OBJECTIVE: To assess caregivers\' reasons for serving sweetened fruit-flavored drinks and unsweetened juices to their young children (1-5 y) and perceptions of product healthfulness and drink ingredients.
METHODS: A cross-sectional online survey assessed participants\' (n = 1614) perceptions of sweetened fruit-flavored drinks (fruit drinks and flavored water) and unsweetened juices (100% juice and water/juice blends) provided to their child in the past month, including product healthfulness, reasons for providing, and knowledge of product ingredients [added sugar, nonnutritive sweeteners (NNSs), percentage juice]. One-factor ANOVA compared perceived healthfulness of drink categories and types of sugar and NNSs, and differences between participants who could compared with those who could not accurately identify drink ingredients.
RESULTS: Participants\' top reasons for providing sweetened drinks included child liking it, being inexpensive, child asking for it, and being a special treat. Participants perceived 100% juice as healthiest, followed by juice/water blends, flavored waters, and, lastly, fruit drinks (P < 0.05). Many participants inaccurately believed the fruit drink or flavored water they served their child most often did not contain NNSs (59.0% and 64.9%) and/or added sugars (20.1% and 42.2%), when in fact they did, and 81.3-91.1% overestimated the percentage juice in the drink. Perceived healthfulness of fruit drinks was associated with caregivers\' belief that the drink contained added sugar (P < 0.05), but not with their belief that it contained NNS; increased accuracy was associated with decreased perceived healthfulness (P < 0.05).
CONCLUSIONS: Inaccurate understanding of added sugar, NNSs, and percentage juice in drinks served to young children was common and could contribute to sugary drink provision. Public health efforts should seek to improve labeling practices and revise nutrition education messages.

OBJECTIVE: Nonnutritive sweeteners (NNS) have been widely implemented as replacements for naturally occurring sugars in a wide array of foods, beverages, and non-consumables for the sake of reducing calories. The use of these products, whether naturally occurring or manufactured, have become commonplace and accepted as de facto beneficial. This point argues that rigorous analysis of the available data do not confirm benefit and indeed suggest harm.
METHODS: A literature review was conducted on all the available NNS supplements that are commonly used in all types of products. There was a focus on studies that evaluated the long-term as well as neurohormonal effects of NNS products. Key words used in the search included artificial sweeteners, nonnutritive sweeteners, saccharin, aspartame, acesulfame, sucralose, stevia, xylitol, and erythritol.
RESULTS: There was a consistent trend of no to minimal benefit when NNS were used instead of calorie-containing sweeteners particularly in persons with obesity or pre-diabetes risks. There was a consistent finding of detriment to the neurohormonal regulation of satiety, weight, and energy regulation. The only studies that were neutral to positive were biased studies funded by the large food and beverage corporations or done in healthy weight individuals without any underlying health concerns and for a very short time frame.
CONCLUSIONS: Although NNS usage has become ubiquitous, there has been very little in the way of rigorous review of the neurohormonal and physiologic effects. The arguments for NNS are purely thermodynamic in nature despite the overwhelming evidence that obesity and adiposity-related diseases are not that simplistic in their pathophysiology. Given that there are differences in how individuals process nutrition signals, very few studies focus on gender or disease predisposition differences and how they affect the outcomes when NNS are used. Studies that controlled these variables showed worsening outcomes when NNS products are used in the fight against adiposity-related diseases, such as hypertension, dyslipidemia, and diabetes. Alterations in the gut microbiome towards a more inflammatory pattern of gut microbiota is a disturbing finding in acute as well as chronic users of NNS regardless of baseline weight or disease. Most importantly, there were numerous studies that found long-term damage to the neurohormonal control of satiety in chronic users of NNS. In the fight against obesity and adiposity-related diseases, we cannot afford to blindly accept their usage based on a broken paradigm of thermodynamics and false assumptions that we are all created equal biologically.