Insight into the interaction and binding mechanism of a natural nonnutritive sweetener mogroside V with soybean protein isolates based on multi-spectroscopic techniques and computational simulations.

As a natural low-calorie sweetener, Mogroside V (Mog-V) has gradually become one of the alternatives to sucrose with superior health attributes. However, Mog-V will bring unpleasant aftertastes when exceeding a threshold concentration. To investigate the possibility of soy protein isolates (SPIs), namely ß-conglycinin (7S), and glycinin (11S) as flavor-improving agents of Mog-V, the binding mechanism between Mog-V and SPIs was explored through multi-spectroscopy, particle size, zeta potential, and computational simulation. The results of the multi-spectroscopic experiments indicated that Mog-V enhanced the fluorescence of 7S/11S protein in a static mode. The binding affinity of 7S-Mog-V was greater compared with 11S-Mog-V. Particle size and zeta potential analysis revealed that the interaction could promote aggregation of 7S/11S protein with different stability. Furthermore, computational simulations further confirmed that Mog-V could interact with the 7S/11S protein in different ways. This research provides a theoretical foundation for the development and application of SPI to improve the flavor of Mog-V, opening a new avenue for further expanding the market demand for Mog-V.

Exploring Bitter and Sweet: The Application of Large Language Models in Molecular Taste Prediction.

The perception of bitter and sweet tastes is a crucial aspect of human sensory experience. Concerns over the long-term use of aspartame, a widely used sweetener suspected of carcinogenic risks, highlight the importance of developing new taste modifiers. This study utilizes Large Language Models (LLMs) such as GPT-3.5 and GPT-4 for predicting molecular taste characteristics, with a focus on the bitter-sweet dichotomy. Employing random and scaffold data splitting strategies, GPT-4 demonstrated superior performance, achieving an impressive 86% accuracy under scaffold partitioning. Additionally, ChatGPT was employed to extract specific molecular features associated with bitter and sweet tastes. Utilizing these insights, novel molecular compounds with distinct taste profiles were successfully generated. These compounds were validated for their bitter and sweet properties through molecular docking and molecular dynamics simulation, and their practicality was further confirmed by ADMET toxicity testing and DeepSA synthesis feasibility. This research highlights the potential of LLMs in predicting molecular properties and their implications in health and chemical science.

Stevioside Ameliorates Palmitic Acid-Induced Abnormal Glucose Uptake via the PDK4/AMPK/TBC1D1 Pathway in C2C12 Myotubes.

BACKGROUND: Stevioside (SV) with minimal calories is widely used as a natural sweetener in beverages due to its high sweetness and safety. However, the effects of SV on glucose uptake and the pyruvate dehydrogenase kinase isoenzyme (PDK4) as an important protein in the regulation of glucose metabolism, remain largely unexplored. In this study, we used C2C12 skeletal muscle cells that was induced by palmitic acid (PA) to assess the effects and mechanisms of SV on glucose uptake and PDK4. METHODS: The glucose uptake of C2C12 cells was determined by 2-NBDG; expression of the Pdk4 gene was measured by quantitative real-time PCR; and expression of the proteins PDK4, p-AMPK, TBC1D1 and GLUT4 was assessed by Western blotting. RESULTS: In PA-induced C2C12 myotubes, SV could significantly promote cellular glucose uptake by decreasing PDK4 levels and increasing p-AMPK and TBC1D1 levels. SV could promote the translocation of GLUT4 from the cytoplasm to the cell membrane in cells. Moreover, in Pdk4-overexpressing C2C12 myotubes, SV decreased the level of PDK4 and increased the levels of p-AMPK and TBC1D1. CONCLUSION: SV was found to ameliorate PA-induced abnormal glucose uptake via the PDK4/AMPK/TBC1D1 pathway in C2C12 myotubes. Although these results warranted further investigation for validation, they may provide some evidence of SV as a safe natural sweetener for its use in sugar-free beverages to prevent and control T2DM.

Recent advancements in mogrosides: A review on biological activities, synthetic biology, and applications in the food industry.

Mogrosides are low-calorie, biologically active sweeteners that face high production costs due to strict cultivation requirements and the low yield of monk fruit. The rapid advancement in synthetic biology holds the potential to overcome this challenge. This review presents mogrosides exhibiting antioxidant, anti-inflammatory, anti-cancer, anti-diabetic, and liver protective activities, with their efficacy in diabetes treatment surpassing that of Xiaoke pills (a Chinese diabetes medication). It also discusses the latest elucidated biosynthesis pathways of mogrosides, highlighting the challenges and research gaps in this field. The critical and most challenging step in this pathway is the transformation of mogrol into a variety of mogrosides by different UDP-glucosyltransferases (UGTs), primarily hindered by the poor substrate selectivity, product specificity, and low catalytic efficiency of current UGTs. Finally, the applications of mogrosides in the current food industry and the challenges they face are discussed.

Development of a tamarind-based functional beverage with partially-hydrolyzed agave syrup and the health effects of its consumption in C57BL/6 mice.

Excess consumption of sweetened beverages is associated with a global rise in metabolic diseases. Tamarind and partially-hydrolyzed agave syrup have potential for developing healthier beverages. Our objective was to develop a functional beverage using these ingredients (PH-AS-B). We also evaluate shelf-life stability (physicochemical, microbiological, and antioxidant properties) and health effects in C57BL/6 mice compared with tamarind beverages sweetened with glucose or fructose. Optimal tamarind extraction conditions were a 1:10 ratio (g pulp/mL water) and boiling for 30 min, and the resulting beverage had a shelf life of two months at 4 °C. Non-volatile metabolites were identified using HPLC/MS. PH-AS-B was associated with decreased blood cholesterol (5%) and triglyceride (20-35%) concentrations in healthy mice as well as lower lipid (82%) concentrations and evidence of protein oxidation (42%) in the liver, compared with glucose- and fructose-sweetened tamarind beverages. In conclusion, PH-AS-B was stable and associated with beneficial metabolic properties in healthy mice.

Effects of common artificial sweeteners at environmentally relevant concentrations on soil springtails and their gut microbiota.

Artificial sweeteners (AS) are extensively utilized as sugar substitutes and have been recognized as emerging environmental contaminants. While the effect of AS on aquatic organisms has garnered recent attention, their effects on soil invertebrates and gut microbial communities remain unclear. To address this knowledge gap, we exposed springtails (Folsomia candida) to both single and combined treatments of four typical AS (sucralose [SUC], saccharin [SAC], cyclamate [CYC], and acesulfame [ACE]) at environmentally relevant concentrations of 0.01, 0.1 and 1 mg kg-1 in soil. Following the first-generational exposure, the reproduction of juveniles showed a significant increase under all the AS treatments of 0.1 mg kg-1. The transcriptomic analysis revealed significant enrichment of several Kyoto Encyclopedia of Gene and Genome pathways (e.g., glycolysis/gluconeogenesis, pentose and glucuronate interconversions, amino sugar, and nucleotide sugar metabolism, ribosome, and lysosome) in springtails under all AS treatments. Analysis of gut bacterial microbiota indicated that three AS (SUC, CYC, and ACE) significantly decreased alpha diversity, and all AS treatments increased the abundance of the genus Achromobacter. After the sixth-generational exposure to CYC, weight increased, but reproduction was inhibited. The pathways that changed significantly (e.g., extracellular matrix-receptor interaction, amino sugar and nucleotide sugar metabolism, lysosome) were generally similar to those altered in first-generational exposure, but with opposite regulation directions. Furthermore, the effect on the alpha diversity of gut microbiota was contrary to that after first-generational exposure, and more noticeable disturbances in microbiota composition were observed. These findings underscore the ecological risk of AS in soils and improve our understanding of the toxicity effects of AS on living organisms.

Computational simulations on the taste mechanism of steviol glycosides based on their interactions with receptor proteins.

Steviol glycoside (SG) is a potential natural sugar substitute. The taste of various SG structures differ significantly, while their mechanism has not been thoroughly investigated. To investigate the taste mechanism, molecular docking simulations of SGs with sweet taste receptor TAS1R2 and bitter taste receptor TAS2R4 were conducted. The result suggested that four flexible coils (regions) in TAS1R2 constructed a geometry open pocket in space responsible for the binding of sweeteners. Amino acids that form hydrogen bonds with sweeteners are located in different receptor regions. In bitterness simulation, fewer hydrogen bonds were formed with the increased size of SG molecules. Particularly, there was no interaction between RM and TAS2R4 due to its size, which explains the non-bitterness of RM. Molecular dynamics simulations further indicated that the number of hydrogen bonds between SGs and TAS1R2 was maintained during a simulation time of 50 ns, while sucrose was gradually released from the binding site, leading to the break of interaction. Conclusively, the high sweetness intensity of SG can be attributed to its durative concurrent interaction with the receptor's binding site, and such behavior was determined by the structure feature of SG.

Adrenomedullin Enhances Mouse Gustatory Nerve Responses to Sugars via T1R-Independent Sweet Taste Pathway.

On the tongue, the T1R-independent pathway (comprising glucose transporters, including sodium-glucose cotransporter (SGLT1) and the KATP channel) detects only sugars, whereas the T1R-dependent (T1R2/T1R3) pathway can broadly sense various sweeteners. Cephalic-phase insulin release, a rapid release of insulin induced by sensory signals in the head after food-related stimuli, reportedly depends on the T1R-independent pathway, and the competitive sweet taste modulators leptin and endocannabinoids may function on these two different sweet taste pathways independently, suggesting independent roles of two oral sugar-detecting pathways in food intake. Here, we examined the effect of adrenomedullin (ADM), a multifunctional regulatory peptide, on sugar sensing in mice since it affects the expression of SGLT1 in rat enterocytes. We found that ADM receptor components were expressed in T1R3-positive taste cells. Analyses of chorda tympani (CT) nerve responses revealed that ADM enhanced responses to sugars but not to artificial sweeteners and other tastants. Moreover, ADM increased the apical uptake of a fluorescent D-glucose derivative into taste cells and SGLT1 mRNA expression in taste buds. These results suggest that the T1R-independent sweet taste pathway in mouse taste cells is a peripheral target of ADM, and the specific enhancement of gustatory nerve responses to sugars by ADM may contribute to caloric sensing and food intake.

Nano-stevia interaction: Past, present, and future.

Nanotechnology has recently been emerged as a transformative technology that offers efficient and sustainable options for nano-bio interface. There has been a considerable interest in exploring the factors affecting elicitation mechanism and nanomaterials have been emerged as strong elicitors in medicinal plants. Stevia rebaudiana is well-known bio-sweetener and the presence of zero calorie, steviol glycosides (SGs) in the leaves of S. rebaudiana have made it a desirable crop to be cultivated on large scale to obtain its higher yield and maximal content of high quality natural sweeteners. Besides, phenolics, flavonoids, and antioxidants are abundant in stevia which contribute to its medicinal importance. Currently, scientists are trying to increase the market value of stevia by the enhancement in production of its bioactive compounds. As such, various in vitro and cell culture strategies have been adopted. In stevia agronanotechnology, nanoparticles behave as elicitors for the triggering of its secondary metabolites, specifically rebaudioside A. This review article discusses the importance of S. rebaudiana and SGs, conventional approaches that have failed to increase the desired yield and quality of stevia, modern approaches that are currently being applied to obtain utmost benefits of SGs, and future needs of advanced technologies for further exploitation of this wonder of nature.

Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays.

The purpose of this study was to determine the toxicological and pharmacokinetic properties of sucralose-6-acetate, a structural analog of the artificial sweetener sucralose. Sucralose-6-acetate is an intermediate and impurity in the manufacture of sucralose, and recent commercial sucralose samples were found to contain up to 0.67% sucralose-6-acetate. Studies in a rodent model found that sucralose-6-acetate is also present in fecal samples with levels up to 10% relative to sucralose which suggest that sucralose is also acetylated in the intestines. A MultiFlow® assay, a high-throughput genotoxicity screening tool, and a micronucleus (MN) test that detects cytogenetic damage both indicated that sucralose-6-acetate is genotoxic. The mechanism of action was classified as clastogenic (produces DNA strand breaks) using the MultiFlow® assay. The amount of sucralose-6-acetate in a single daily sucralose-sweetened drink might far exceed the threshold of toxicological concern for genotoxicity (TTCgenotox) of 0.15 µg/person/day. The RepliGut® System was employed to expose human intestinal epithelium to sucralose-6-acetate and sucralose, and an RNA-seq analysis was performed to determine gene expression induced by these exposures. Sucralose-6-acetate significantly increased the expression of genes associated with inflammation, oxidative stress, and cancer with greatest expression for the metallothionein 1 G gene (MT1G). Measurements of transepithelial electrical resistance (TEER) and permeability in human transverse colon epithelium indicated that sucralose-6-acetate and sucralose both impaired intestinal barrier integrity. Sucralose-6-acetate also inhibited two members of the cytochrome P450 family (CYP1A2 and CYP2C19). Overall, the toxicological and pharmacokinetic findings for sucralose-6-acetate raise significant health concerns regarding the safety and regulatory status of sucralose itself.

The effect of alginate as an elicitor on transcription of steviol glycosides biosynthesis pathway related key genes and sweeteners content in in vitro cultured Stevia rebaudiana.

BACKGROUND: Stevia rebaudiana is a medicinal herb that accumulates non-caloric sweeteners called steviol glycosides (SGs) which are approximately 300 times sweeter than sucrose. This study used alginate (ALG) as an elicitor to increase steviol glycosides accumulation and elucidate gene transcription in the steviol glycosides biosynthesis pathway. METHODS AND RESULTS: To minimize the grassy taste associated with stevia sweeteners, plantlets were grown in complete darkness. ALG was applied to stevia plants grown in suspension culture with a Murashige and Skoog (MS) medium to determine its effect on SGs' content and the transcription profile of SG-related genes using the HPLC and RT-qPCR methods, respectively. Treatment with alginate did not significantly affect plantlet growth parameters such as shoot number, dry and fresh weight. Rebaudioside A (Reb A) content increased approximately sixfold in the presence of 1g L-1 alginate and KS, KAH, and UGT74G1 genes showed significant up-regulation. When the concentration was increased to 2g L-1, the transcription of KO and UGT76G1, responsible for the conversion of stevioside to Reb A, was increased about twofold. CONCLUSIONS: The current study proposes that adding alginate to the MS suspension medium can increase Reb A levels by altering the SG biosynthesize pathway's transcription profile. The present experiment provides new insights into the biochemical and transcriptional response mechanisms of suspension-cultured stevia plants to alginate.

Natural and low-caloric rebaudioside A as a substitute for dietary sugars: A comprehensive review.

For health and safety concerns, traditional high-calorie sweeteners and artificial sweeteners are gradually replaced in food industries by natural and low-calorie sweeteners. As a natural and high-quality sugar substitute, steviol glycosides (SvGls) are continually scrutinized regarding their safety and application. Recently, the cultivation of organic stevia has been increasing in many parts of Europe and Asia, and it is obvious that there is a vast market for sugar substitutes in the future. Rebaudioside A, the main component of SvGls, is gradually accepted by consumers due to its safe, zero calories, clear, and sweet taste with no significant undesirable characteristics. Hence, it can be used in various foods or dietary supplements as a sweetener. In addition, rebaudioside A has been demonstrated to have many physiological functions, such as antihypertension, anti-diabetes, and anticaries. But so far, there are few comprehensive reviews of rebaudioside A. In this review article, we discuss the physicochemical properties, metabolic process, safety, regulatory, health benefits, and biosynthetic pathway of rebaudioside A and summarize the modification methods and state-of-the-art production and purification techniques of rebaudioside A. Furthermore, the current problems hindering the future production and application of rebaudioside A are analyzed, and suggestions are provided.

Boosting the Heterologous Expression of d-Allulose 3-Epimerase in Bacillus subtilis through Protein Engineering and Catabolite-Responsive Element Box Engineering.

As a natural sweetener with low calories and various physiological activities, d-allulose has drawn worldwide attention. Currently, d-allulose 3-epimerase (DAEase) is mainly used to catalyze the epimerization of d-fructose to d-allulose. Therefore, it is quite necessary to enhance the food-grade expression of DAEase to meet the surging market demand for d-allulose. In this study, initially, the promising variant H207L/D281G/C289R of Clostridium cellulolyticum H10 DAEase (CcDAEase) was generated by protein engineering, the specific activity and the T1/2 of which were 2.24-fold and 13.45-fold those of the CcDAEase wild type at 60 °C, respectively. After that, PamyE was determined as the optimal promoter for the recombinant expression of CcDAEase in Bacillus subtilis, and catabolite-responsive element (CRE) box engineering was further performed to eliminate the carbon catabolite repression (CCR) effect. Lastly, high-density fermentation was carried out and the final activity peaked at 4971.5 U mL-1, which is the highest expression level and could effectively promote the industrial production of DAEase. This research provides a theoretical basis and technical support for the molecular modification of DAEase and its efficient fermentation preparation.

The genomes of chicory, endive, great burdock and yacon provide insights into Asteraceae palaeo-polyploidization history and plant inulin production.

Inulin is an important reserve polysaccharide in Asteraceae plants, and is also widely used as a sweetener, a source of dietary fibre and prebiotic. Nevertheless, a lack of genomic resources for inulin-producing plants has hindered extensive studies on inulin metabolism and regulation. Here, we present chromosome-level reference genomes for four inulin-producing plants: chicory (Cichorium intybus), endive (Cichorium endivia), great burdock (Arctium lappa) and yacon (Smallanthus sonchifolius), with assembled genome sizes of 1.28, 0.89, 1.73 and 2.72 Gb, respectively. We found that the chicory, endive and great burdock genomes were shaped by whole genome triplication (WGT-1), and the yacon genome was shaped by WGT-1 and two subsequent whole genome duplications (WGD-2 and WGD-3). A yacon unique whole genome duplication (WGD-3) occurred 5.6-5.8 million years ago. Our results also showed the genome size difference between chicory and endive is largely due to LTR retrotransposons, and rejected a previous hypothesis that chicory is an ancestor of endive. Furthermore, we identified fructan-active-enzyme and transcription-factor genes, and found there is one copy in chicory, endive and great burdock but two copies in yacon for most of these genes, except for the 1-FEH II gene which is significantly expanded in chicory. Interestingly, inulin synthesis genes 1-SST and 1-FFT are located close to each other, as are the degradation genes 1-FEH I and 1-FEH II. Finally, we predicted protein structures for 1-FFT genes to explore the mechanism determining inulin chain length.

Expression of a triple mutational des-pGlu brazzein in transgenic mouse milk.

Brazzein has excellent potential for use as a sweetener because of its high level of sweetening potency and stability against extreme temperature and pH. It is extracted from the tropical and difficult-to-cultivate African plant Pentadiplandra brazzeana, which hampers its commercial viability. Here we report the mammary-specific expression of wildtype or triple mutational (H31R/E36D/E41A) des-pGlu brazzeins in the milk of transgenic mice. Using enzyme-linked immunoassay (ELISA), western blot, and sweetness intensity testing, we confirmed that the triple mutation made the des-pGlu brazzein molecule 10,000 times sweeter than sucrose in a weight base, even after 10 min of incubation at 100 °C; in addition, the triple mutant was also significantly sweeter than the wildtype des-pGlu brazzein. This study provides new insights for producing brazzein or brazzein-sweetened milk from animals for use in food and healthcare applications.

Acute exposure to environmentally relevant concentrations of sucralose disrupts embryonic development and leads to an oxidative stress response in Danio rerio.

Sucralose (SUC) is the most consumed artificial sweetener worldwide, not metabolized by the human body, and barely eliminated from water in wastewater treatment plants. Although different studies have reported high concentrations of this sweetener in aquatic environments, limited to no information is known about the toxic effects this drug may produce over water organisms. Moreover, most of the current studies have used non-environmentally relevant concentrations of SUC for these effects. Herein, we aimed to evaluate the harmful effects that environmentally relevant concentrations of SUC may induce in the early life stages of Danio rerio. According to our results, SUC altered the embryonic development of D. rerio, producing several malformations that led to their death. The major malformations were scoliosis, pericardial edema, yolk deformation, and tail malformation. However, embryos also got craniofacial malformations, eye absence, fin absence, dwarfism, delay of the hatching process, and hypopigmentation. SUC also generated an oxidative stress response in the embryos characterized by an increase in the levels of lipid peroxidation, hydroperoxides, and carbonyl proteins. To overcome this oxidative stress response, we observed a significant increase in the levels of antioxidant enzymes superoxide dismutase and catalase. Moreover, a significant boost in the expression of antioxidant defense-related genes, Nuclear respiratory factor 1a (Nrf1a) and Nuclear respiratory factor 2a (Nrf2a), was also observed at all concentrations. Concerning apoptosis-related genes, we observed the expression of Caspase 3 (CASP3) and Caspase 9 (CASP9) was increased in a concentration-dependent manner. Overall, we conclude environmentally relevant concentrations of SUC are harmful to the early life stages of fish as they produce malformations, oxidative stress, and increased gene expression of apoptosis-related genes on embryos.

Associations of maternal non-nutritive sweetener intake during pregnancy with offspring body mass index and body fat from birth to adolescence.

BACKGROUND/OBJECTIVE: The evidence that maternal non-nutritive sweetener (NNS) intake during pregnancy increases childhood obesity risk is conflicting. A potential reason for this is that all prior studies examined childhood body mass index (BMI) at only one timepoint and at different ages. We examined the extent to which NNS intake during pregnancy is associated with offspring BMI z-score and body fat longitudinally from birth to 18 years. SUBJECTS: A total of 1683 children from Project Viva, a prospective pre-birth cohort, were recruited from 1999 to 2002 in Massachusetts. METHODS: We assessed maternal NNS intake in the first and second trimesters of pregnancy using a semiquantitative food frequency questionnaire. Our outcomes were offspring BMI z-score, (at birth, infancy (median 6.3 months), early childhood (3.2 years), mid-childhood (7.7 years), and early adolescence (12.9 years)), sum of skinfolds (SS), fat mass index (FMI) measured by dual x-ray absorptiometry, and BMI z-score trajectory from birth to 18 years. We adjusted models for maternal pre-pregnancy BMI, age, race/ethnicity, education, parity, pre-pregnancy physical activity, smoking, and paternal BMI and education. RESULTS: A total of 70% of mothers were white and pre-pregnancy BMI was 24.6 ± 5.2 kg/m2. The highest quartile of NNS intake (Q4: 0.98 ± 0.91 servings/day) was associated with higher BMI z-score in infancy (ß 0.20 units; 95% CI 0.02, 0.38), early childhood (0.21; 0.05, 0.37), mid-childhood (0.21; 0.02, 0.40), and early adolescence (0.14; -0.07, 0.35) compared with Q1 intake (Q1: 0.00 ± 0.00 servings/day). Q4 was also associated with higher SS in early childhood (1.17 mm; 0.47, 1.88), mid-childhood (2.33 mm; 0.80, 3.87), and early adolescence (2.27 mm; -0.06, 4.60) and higher FMI in mid-childhood (0.26 kg/m2; -0.07, 0.59). Associations of maternal NNS intake with offspring BMI z-score became stronger with increasing age from 3 to 18 years (Pinteraction < 0.0001). CONCLUSIONS: Maternal NNS intake during pregnancy is associated with increased childhood BMI z-score and body fat from birth to teenage years. This is relevant given the escalating obesity epidemic, and popularity of NNS.

Catalytic flexibility of rice glycosyltransferase OsUGT91C1 for the production of palatable steviol glycosides.

Steviol glycosides are the intensely sweet components of extracts from Stevia rebaudiana. These molecules comprise an invariant steviol aglycone decorated with variable glycans and could widely serve as a low-calorie sweetener. However, the most desirable steviol glycosides Reb D and Reb M, devoid of unpleasant aftertaste, are naturally produced only in trace amounts due to low levels of specific ß (1-2) glucosylation in Stevia. Here, we report the biochemical and structural characterization of OsUGT91C1, a glycosyltransferase from Oryza sativa, which is efficient at catalyzing ß (1-2) glucosylation. The enzyme's ability to bind steviol glycoside substrate in three modes underlies its flexibility to catalyze ß (1-2) glucosylation in two distinct orientations as well as ß (1-6) glucosylation. Guided by the structural insights, we engineer this enzyme to enhance the desirable ß (1-2) glucosylation, eliminate ß (1-6) glucosylation, and obtain a promising catalyst for the industrial production of naturally rare but palatable steviol glycosides.

The complex relationship between metabolic syndrome and sweeteners.

Metabolic syndrome is a multifactorial disorder originating from central obesity through a high caloric intake and a sedentary lifestyle. Metabolic syndrome increases the risk of type 2 diabetes (T2D) disease, converting it to one of the costliest chronic diseases, which reduces life quality. A strategy proposed by the food industry to reduce this problem is the generation of low-caloric products using sweeteners, which are compounds that can substitute sucrose, given their sweet taste. For many years, it was assumed that sweeteners did not have a relevant interaction in metabolism. However, recent studies have demonstrated that sweeteners interact either with metabolism or with gut microbiota, in which sweet-taste receptors play an essential role. This review presents an overview of the industrial application of most commonly consumed sweeteners. In addition, the interaction of sweeteners within the body, including their absorption, distribution, metabolism, gut microbiota metabolism, and excretion is also reviewed. Furthermore, the complex relationship between metabolic syndrome and sweeteners is also discussed, presenting results from in vivo and clinical trials. Findings from this review indicate that, in order to formulate sugar-free or noncaloric food products for the metabolic syndrome market, several factors need to be considered, including the dose, proportions, human metabolism, and interaction of sweeteners with gut microbiota and sweet-taste receptors. More clinical studies, including the metabolic syndrome, are needed to better understand the interaction of sweeteners with the human body, as well as their possible effect on the generation of dysbiosis.