Artificial sweeteners and risk of incident cardiovascular disease and mortality: evidence from UK Biobank.

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.

Modulation of the glycaemic index value of shortbread cookies by the use of erythritol and fruit pomace.

Fruit pomace, as a by-product of fruit and vegetable processing, is a cheap and easily accessible material for further processing that can replace selected recipe ingredients, most often flour. In addition, their advantage is their high health-promoting potential. The aim of this study was to evaluate the effect of the simultaneous use of erythritol (100% sucrose substitution) and the addition of varying amounts of blackcurrant, chokeberry and apple pomace (0%, 10%, 30% and 50% by weight of flour) on the glycaemic response after consumption of shortbread cookies in an in vivo study with humans (ISO 26642:2010). It was shown that an increase in the addition of each type of pomace reduced the glycaemic index value of the cookies. The pomace and sucrose-sweetened cookies were classified in the medium and low GI group. For each type of pomace, an increase in its share in the recipe of cookies was associated with a reduction in GI values (pomace: apple 49.1-37.2%, blackcurrant 56.4-41.0%, chokeberry 59.4-35.5%). Similar correlations were shown for the use of erythritol (pomace: apple 39.5-29.1%, blackcurrant 43.9-31.9%, chokeberry 34.6-20.7%). A significant effect of pomace addition on the GI values of shortbread cookies, was only observed for sucrose-sweetened products. The results obtained allow the conclusion that there is potential for the use of waste raw materials in the production of functional foods.

Artificial and Natural Sweeteners Biased T1R2/T1R3 Taste Receptors Transactivate Glycosylated Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition of Metastatic Phenotype.

Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing effects mediated by artificial and natural sweeteners, particularly in cancer and metastasis. Sweetener-taste GPCRs can be activated by several active states involving either biased agonism, functional selectivity, or ligand-directed signaling. However, there are increasing arrays of sweetener ligands with different degrees of allosteric biased modulation that can vary dramatically in binding- and signaling-specific manners. Here, emerging evidence proposes the involvement of taste GPCRs in a biased GPCR signaling crosstalk involving matrix metalloproteinase-9 (MMP-9) and neuraminidase-1 (Neu-1) activating glycosylated receptors by modifying sialic acids. The findings revealed that most natural and artificial sweeteners significantly activate Neu-1 sialidase in a dose-dependent fashion in RAW-Blue and PANC-1 cells. To confirm this biased GPCR signaling crosstalk, BIM-23127 (neuromedin B receptor inhibitor, MMP-9i (specific MMP-9 inhibitor), and oseltamivir phosphate (specific Neu-1 inhibitor) significantly block sweetener agonist-induced Neu-1 sialidase activity. To assess the effect of artificial and natural sweeteners on the key survival pathways critical for pancreatic cancer progression, we analyzed the expression of epithelial-mesenchymal markers, CD24, ADLH-1, E-cadherin, and N-cadherin in PANC-1 cells, and assess the cellular migration invasiveness in a scratch wound closure assay, and the tunneling nanotubes (TNTs) in staging the migratory intercellular communication. The artificial and natural sweeteners induced metastatic phenotype of PANC-1 pancreatic cancer cells to promote migratory intercellular communication and invasion. The sweeteners also induced the downstream NFκB activation using the secretory alkaline phosphatase (SEAP) assay. These findings elucidate a novel taste T1R2/T1R3 GPCR functional selectivity of a signaling platform in which sweeteners activate downstream signaling, contributing to tumorigenesis and metastasis via a proposed NFκB-induced epigenetic reprogramming modeling.

Research progress on biosynthesis of erythritol and multi-dimensional optimization of production strategies.

Erythritol, as a new type of natural sweetener, has been widely used in food, medical, cosmetics, pharmaceutical and other fields due to its unique physical and chemical properties and physiological functions. In recent years, with the continuous development of strategies such as synthetic biology, metabolic engineering, omics-based systems biology and high-throughput screening technology, people's understanding of the erythritol biosynthesis pathway has gradually deepened, and microbial cell factories with independent modification capabilities have been successfully constructed. In this review, the cheap feedstocks for erythritol synthesis are introduced in detail, the environmental factors affecting the synthesis of erythritol and its regulatory mechanism are described, and the tools and strategies of metabolic engineering involved in erythritol synthesis are summarized. In addition, the study of erythritol derivatives is helpful in expanding its application field. Finally, the challenges that hinder the effective production of erythritol are discussed, which lay a foundation for the green, efficient and sustainable production of erythritol in the future and breaking through the bottleneck of production.

Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome.

AIMS: Precocious puberty (PP) may lead to many adverse outcomes. Recent evidence suggests that PP is a gut-brain disease. On the other hand, the use of glycyrrhizin, a natural sweetener, has become popular in the past decade. Glycyrrhizin possesses various health benefits, but its impact on PP has yet to be investigated. We aimed to explore the protective effects of glycyrrhizin against PP in both humans (observational) and animals (interventional). MATERIALS AND METHODS: In the human cohort, we investigated the association between glycyrrhizin consumption and risk of PP. In the animal experiment, we observed puberty onset after feeding danazol-induced PP rats with glycyrrizin. Blood, fecal, and hypothalamic samples were harvested to evaluate potential mechanistic pathways. We also performed a fecal microbiota transplantation to confirm to causal relationship between glycyrrhizin and PP risk. KEY FINDINGS: Glycyrrhizin exhibited a protective effect against PP in children (OR 0.60, 95%CI: 0.39-0.89, p = 0.013), primarily driven by its significance in girls, while no significant effect was observed in boys. This effect was consistent with findings in rodents. These benefits were achieved through the modulation of the gut microbiome, which functionally suppressed the hypothalamic-pituitary-gonadal axis and prevented PP progression. A fecal microbiota transplantation indicated that the causal correlation between glycyrrhizin intake and PP is mediated by the gut microbiome alterations. SIGNIFICANCE: Our findings suggest that glycyrrhizin can protect against PP by altering the gut microbiome. Long term use of glycyrrhizin is safe and tolerable. Therefore, glycyrrhizin can serve as a safe and affordable complementary therapy for PP.

Analysis of physicochemical properties of nut-based milk and sweetened condensed milk alternatives.

This study analyzed the physicochemical properties of nut-based milk and sweetened condensed milk (SCM) alternatives. Four types of nuts (almonds, cashews, hazelnuts, and walnuts) were roasted at 140 °C for 15 min, followed by the preparation and analysis of milk and SCM alternatives. During the production of SCM by heating with adding sugar, the pH, moisture, and L* decreased, while the carbohydrates, viscosity, and browning index increased significantly (p < 0.05). Oleic acid, linoleic acid, and linolenic acid contents were comparable among all samples (p > 0.05). Volatile compounds were analyzed using HS-SPME-GC-MS to determine changes due to roasting and heating, and a total of 54 volatile compounds were identified. These findings to show the importance of the physicochemical characteristics of milk and SCM alternatives, provide practical information for the development of improved-quality dairy alternatives.

Xylitol is prothrombotic and associated with cardiovascular risk.

BACKGROUND AND AIMS: The pathways and metabolites that contribute to residual cardiovascular disease risks are unclear. Low-calorie sweeteners are widely used sugar substitutes in processed foods with presumed health benefits. Many low-calorie sweeteners are sugar alcohols that also are produced endogenously, albeit at levels over 1000-fold lower than observed following consumption as a sugar substitute. METHODS: Untargeted metabolomics studies were performed on overnight fasting plasma samples in a discovery cohort (n = 1157) of sequential stable subjects undergoing elective diagnostic cardiac evaluations; subsequent stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses were performed on an independent, non-overlapping validation cohort (n = 2149). Complementary isolated human platelet, platelet-rich plasma, whole blood, and animal model studies examined the effect of xylitol on platelet responsiveness and thrombus formation in vivo. Finally, an intervention study was performed to assess the effects of xylitol consumption on platelet function in healthy volunteers (n = 10). RESULTS: In initial untargeted metabolomics studies (discovery cohort), circulating levels of a polyol tentatively assigned as xylitol were associated with incident (3-year) major adverse cardiovascular event (MACE) risk. Subsequent stable isotope dilution LC-MS/MS analyses (validation cohort) specific for xylitol (and not its structural isomers) confirmed its association with incident MACE risk [third vs. first tertile adjusted hazard ratio (95% confidence interval), 1.57 (1.12-2.21), P < .01]. Complementary mechanistic studies showed xylitol-enhanced multiple indices of platelet reactivity and in vivo thrombosis formation at levels observed in fasting plasma. In interventional studies, consumption of a xylitol-sweetened drink markedly raised plasma levels and enhanced multiple functional measures of platelet responsiveness in all subjects. CONCLUSIONS: Xylitol is associated with incident MACE risk. Moreover, xylitol both enhanced platelet reactivity and thrombosis potential in vivo. Further studies examining the cardiovascular safety of xylitol are warranted.

Risks and benefits of nonsugar sweeteners: conflicting evidence between observational studies and randomized controlled trials.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: For more evidence-based recommendations for practice and policy, scientifically sound studies with long follow-up are required.

Aspartame, as an artificial sweetener, does not affect renal function and antioxidative states in mice.

BACKGROUND AND OBJECTIVE: Aspartame (L-aspartyl L-phenylalanine methyl ester) is an artificial sweetener widely used as a sugar substitute. There are concerns regarding the effects of high aspartame doses on the kidney owing to oxidative stress; however, whether the maximum allowed dose of aspartame in humans affects the kidneys remains unknown. Therefore, in this study, we investigated whether the maximum allowed dose of aspartame in humans affects the kidneys. METHODS: In this study, animals were fed a folate-deficient diet to mimic human aspartame metabolism. Eight-week-old ICR mice were divided into control (CTL), 40 mg/kg/day of aspartame-administered (ASP), folate-deficient diet (FD), and 40 mg/kg/day of aspartame-administered with a folate-deficient diet (FD + ASP) groups. Aspartame was administered orally for eight weeks. Thereafter, we evaluated aspartame's effect on kidneys via histological analysis. RESULTS: There were no differences in serum creatinine and blood urea nitrogen levels between the CTL and ASP groups or between the FD and FD + ASP groups. There was no histological change in the kidneys in any group. The expression of superoxide dismutase and 4-hydroxy-2-nonenal in the kidney did not differ between the CTL and ASP groups or the FD and FD + ASP groups. CONCLUSION: Our findings indicate that the allowed doses of aspartame in humans may not affect kidney function or oxidative states.

The effect of mango aroma in low-sugar beverage: A sensory study on odor induced sweetness enhancement.

Excessive intake of sugar has become a public concern. However, it is challenging for food industries to decrease sugar level without sacrificing safety and sensory profile. Odor-induced sweetness enhancement (OISE) is believed to be a novel and promising strategy for sugar reduction. In order to investigate the OISE effect of mango aroma and evaluate its degree of sugar reduction in low-sugar beverages, a mathematical model was constructed through sensory evaluation in this study. The results showed that the maximum liking of low-sugar model beverages was 4.28 % sucrose and 0.57 % mango flavor. The most synergistic of OISE was at the concentration level of 2.24 % sucrose + 0.25 % mango flavor, which was equivalent to 2.96 % pure sucrose solution. With 32.14 % sugar reduction, the mango aroma was suggested to generate the OISE effect. However, the same level of garlic aroma was not able to enhance sweetness perception, suggesting that the congruency of aroma and taste is a prerequisite for the OISE effect to occur. This study demonstrated that the cross-modal interaction of mango aroma on sweetness enhancement in low-sugar model beverages could provide practical guidance for developing sugar-reduced beverages without applying sweeteners.

Activation and inhibition of the sweet taste receptor TAS1R2-TAS1R3 differentially affect glucose tolerance in humans.

The sweet taste receptor, TAS1R2-TAS1R3, is expressed in taste bud cells, where it conveys sweetness, and also in intestinal enteroendocrine cells, where it may facilitate glucose absorption and assimilation. In the present study, our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism bidirectionally via hyperactivation with 5 mM sucralose (n = 12) and inhibition with 2 mM sodium lactisole (n = 10) in mixture with 75 g glucose loads during oral glucose tolerance tests (OGTTs) in healthy humans. Plasma glucose, insulin, and glucagon were measured before, during, and after OGTTs up to 120 minutes post-prandially. We also assessed individual participants' sweet taste responses to sucralose and their sensitivities to lactisole sweetness inhibition. The addition of sucralose to glucose elevated plasma insulin responses to the OGTT (F(1, 11) = 4.55, p = 0.056). Sucralose sweetness ratings were correlated with early increases in plasma glucose (R2 = 0.41, p<0.05), as well as increases in plasma insulin (R2 = 0.38, p<0.05) when sucralose was added to the OGTT (15 minute AUC). Sensitivity to lactisole sweetness inhibition was correlated with decreased plasma glucose (R2 = 0.84, p<0.01) when lactisole was added to the OGTT over the whole test (120 minute AUC). In summary, stimulation and inhibition of the TAS1R2-TAS1R3 receptor demonstrates that TAS1R2-TAS1R3 helps regulate glucose metabolism in humans and may have translational implications for metabolic disease risk.

Sugar substitutes on caries prevention in permanent teeth among children and adolescents: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to systematically review the effect of sugar substitute consumption on caries prevention in permanent teeth among children and adolescents. DATA: Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing the clinical effect of sugar substitutes (both high- and low-intensity sweeteners) in preventing caries in permanent teeth among children and adolescents aged 6-19 were included. SOURCES: A systematic search was conducted in three databases (PubMed, Web of Science and Embase) without any restrictions on publication year. STUDY SELECTION: The initial search found 1,859 items, and finally, 15 studies (11 RCTs and 4 CCTs) with a total of 6325 participants (age: 6-18 years) were included. The Cochrane risk-of-bias assessment tools were used for quality assessment. Most (80%, 12/15) were graded as having a 'moderate' or 'high' risk of bias. All trials investigated sugar alcohol, which is a low-intensity sweetener. Xylitol was the most commonly investigated (73.3%, 11/15), followed by sorbitol (46.7%, 7/15), and erythritol (13.3%, 2/15). Results of the meta-analysis showed that both xylitol (standardized mean difference [SMD]: -0.50, 95% confidence interval [CI] -0.85 to -0.16, P = 0.005) and sorbitol (SMD: -0.10, 95% CI: -0.19 to -0.01, P = 0.03) had a significant effect in preventing dental caries compared to no treatment/placebo. No clinical trials on high-intensity sweeteners such as aspartame and saccharin were found. CONCLUSION: The consumption of xylitol or sorbitol is potentially effective in preventing caries in permanent teeth among children and adolescents. No clinical evidence is available regarding the role of high-intensity sweeteners in caries prevention. CLINICAL SIGNIFICANCE: The use of xylitol or sorbitol as sugar substitutes has a beneficial effect in preventing dental caries among children and adolescents.

Do chewing gums and sweets containing xylitol prevent caries in children?

DATA SOURCES: Three electronic databases (Pubmed, Embase and the Cochrane Library) were searched in December 2022, and again for additional literature on 3-5th January 2023. Reference lists of relevant systematic reviews were hand searched for other eligible studies for inclusion. STUDY SELECTION: Randomised controlled clinical trials and controlled clinical trials conducted on children (aged ≤ 18 years), conducted between 1974-2022 and available in English, were eligible for inclusion. Studies were excluded if caries was not an outcome, the control group was not sufficient, they were lab-based studies or studies where xylitol delivery was not a sweet or chewing gum and where the xylitol product contained a component such as fluoride which may influence the outcomes. DATA EXTRACTION AND SYNTHESIS: Four calibrated reviewers independently screened titles and abstracts, and disagreements were resolved via group discussion. Preventative effect was determined by comparing the mean caries increment in the control and intervention groups, producing a preventative fraction. A total of 617 titles were initially screened for relevance. After duplicate removal, 268 abstracts were screened and 16 full text articles reviewed, with one more study then excluded. 10 studies investigated xylitol-containing chewing gum, and six looked at xylitol candy (one did both). Eight included studies were randomised controlled trials. Data extraction was undertaken by two reviewers. RESULTS: 3466 participants were included in the 10 studies that investigated xylitol chewing gum, and all 10 studies reported a statistically significant preventive effect compared to a no chewing gum or placebo control. In 9 studies, the preventive fraction was clinically significant. The six studies investigating xylitol candies contained a total of 1023 participants, and only one study demonstrated a significant preventative effect. CONCLUSIONS: There is some evidence that incorporating xylitol chewing gum daily has a caries-reducing effect in those with a moderate-to-high baseline caries level. This effect was not present for xylitol sweets.

Aspartame-induced cognitive dysfunction: Unveiling role of microglia-mediated neuroinflammation and molecular remediation.

Aspartame, an artificial sweetener, is consumed by millions of people globally. There are multiple reports of aspartame and its metabolites affecting cognitive functions in animal models and humans, which include learning problems, headaches, seizures, migraines, irritable moods, anxiety, depression, and insomnia. These cognitive deficits and associated symptoms are partly attributed to dysregulated excitatory and inhibitory neurotransmitter balance due to aspartate released from aspartame, resulting in an excitotoxic effect in neurons, leading to neuronal damage. However, microglia, a central immunocompetent cell type in brain tissue and a significant player in inflammation can contribute to the impact. Microglia rapidly respond to changes in CNS homeostasis. Aspartame consumption might affect the microglia phenotype directly via methanol-induced toxic effects and indirectly via aspartic acid-mediated excitotoxicity, exacerbating symptoms of cognitive decline. Long-term oral consumption of aspartame thus might change microglia's phenotype from ramified to activated, resulting in chronic or sustained activation, releasing excess pro-inflammatory molecules. This pro-inflammatory surge might lead to the degeneration of healthy neurons and other glial cells, impairing cognition. This review will deliberate on possible links and research gaps that need to be explored concerning aspartame consumption, ecotoxicity and microglia-mediated inflammatory cognitive impairment. The study covers a comprehensive analysis of the impact of aspartame consumption on cognitive function, considering both direct and indirect effects, including the involvement of microglia-mediated neuroinflammation. We also propose a novel intervention strategy involving tryptophan supplementation to mitigate cognitive decline symptoms in individuals with prolonged aspartame consumption, providing a potential solution to address the adverse effects of aspartame on cognitive function.

Properties, extraction and purification technologies of Stevia rebaudiana steviol glycosides: A review.

For health and safety reasons, the search for green, healthy, and low-calorie sweeteners with good taste has become the demand of many consumers. Furthermore, the need for sugar substitutes of natural origin has increased dramatically. In this review, we briefly discussed the safety and health benefits of stevia sweeteners and enumerated some examples of physiological functions of steviol glycosides (SGs), such as anti-inflammatory, anti-obesity, antihypertensive, anti-diabetes, and anticaries, citing various evidence related to their application in the food industry. The latest advances in emerging technologies for extracting and purifying SGs and the process variables and operational strategies were discussed. The impact of the extraction methods and their comparison against the conventional techniques have also been demonstrated. These technologies use minimal energy solvents and simplify subsequent purification stages, making viable alternatives suitable for a possible industrial application. Furthermore, we also elucidated the potential for advancing and applying the natural sweeteners SGs.

Glucose appetition in C57BL/6J mice: Influence of nonnutritive sweetener experience, food deprivation state and sex differences.

In addition to its sweet taste, glucose has potent and rapid postoral actions (appetition) that enhance its reward value. This has been demonstrated by the experience-induced preference for glucose over initially preferred nonnutritive sweetener solutions in 24-h choice tests. However, some sweetener solutions (e.g., 0.8% sucralose) have inhibitory postoral actions that may exaggerate glucose appetition whereas others (e.g., 0.1% sucralose + 0.1% saccharin, S+S) do not. Experiment 1 revealed that food-restricted (FR) male C57BL/6J mice displayed similar rapid glucose appetition effects (stimulation of glucose licking within minutes) and conditioned flavor preferences following 1-h experience with flavored 0.8% sucralose or 0.1% S+S and 8% glucose solutions. Thus, the inhibitory effects of 0.8% sucralose observed in 24-h tests were not apparent in 1-h tests. Experiment 2 evaluated the effects of food deprivation state and sweetener concentration on glucose appetition in female mice. Unlike FR mice tested with 0.1% S+S and 8% glucose, ad libitum (AL) fed mice displayed no stimulation of 8% glucose licking in the 1-h tests. A second ad libitum group (AL) tested with 0.2% S+S and 16% glucose solutions displayed stimulation of 16% glucose licking by the third 1-h test. Both AL groups, like the FR group, developed a preference for the glucose-paired flavor over the S+S paired flavor. Thus, food restriction promotes increased glucose licking but is not required for a conditioned preference. The FR male mice (Exp. 1) and FR female mice (Exp. 2) showed similar appetition responses (licking stimulation and flavor preference) to 8% glucose.

A Pharmacological perspective on the temporal properties of sweeteners.

Several non-caloric sweeteners exhibit a delay in sweetness onset and a sweetness linger after sampling. These temporal properties are thought to be the result of non-specific interactions with cell membranes and proteins in the oral cavity. Data and analysis presented in this report also support the potential involvement of receptor affinity and binding kinetics to this phenomenon. In general, affected sweeteners exhibit distinctly higher binding affinity compared to carbohydrate sweeteners, which do not have temporal issues. In addition, binding kinetic simulations illustrate much slower receptor binding association and dissociation kinetics for a set of non-caloric sweeteners presenting temporal issues, in comparison to carbohydrate sweeteners. So, the higher affinity of some non-caloric sweeteners, dictating lower use levels, and affecting binding kinetics, could contribute to their delay and linger in sweetness perception. Simple pharmacology principles could explain, at least in part, some of the temporal issues of sweeteners.

Neural responses to oral administration of erythritol vs. sucrose and sucralose explain differences in subjective liking ratings.

INTRODUCTION: High sugar intake is associated with many chronic diseases. However, non-caloric sweeteners (NCSs) might fail to successfully replace sucrose due to the mismatch between their rewarding sweet taste and lack of caloric content. The natural NCS erythritol has been proposed as a sugar substitute due to its satiating properties despite being non-caloric. We aimed to compare brain responses to erythritol vs. sucrose and the artificial NCS sucralose in a priori taste, homeostatic, and reward brain regions of interest (ROIs). METHODS: We performed a within-subject, single-blind, counterbalanced fMRI study in 30 healthy men (mean ± SEM age:24.3 ± 0.8 years, BMI:22.3 ± 0.3 kg/m2). Before scanning, we individually matched the concentrations of both NCSs to the perceived sweetness intensity of a 10% sucrose solution. During scanning, participants received 1 mL sips of the individually titrated equisweet solutions of sucrose, erythritol, and sucralose, as well as water. After each sip, they rated subjective sweetness liking. RESULTS: Liking ratings were significantly higher for sucrose and sucralose vs. erythritol (both pHolm = 0.0037); water ratings were neutral. General Linear Model (GLM) analyses of brain blood oxygen level-depended (BOLD) responses at qFDR<0.05 showed no differences between any of the sweeteners in a priori ROIs, but distinct differences were found between the individual sweeteners and water. These results were confirmed by Bayesian GLM and machine learning-based models. However, several brain response patterns mediating the differences in liking ratings between the sweeteners were found in whole-brain multivariate mediation analyses. Both subjective and neural responses showed large inter-subject variability. CONCLUSION: We found lower liking ratings in response to oral administration of erythritol vs. sucrose and sucralose, but no differences in neural responses between any of the sweeteners in a priori ROIs. However, differences in liking ratings between erythritol vs. sucrose or sucralose are mediated by multiple whole-brain response patterns.