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Satiation signals begin to occur after a sufficient amount of food has been consumed, and satiation signals are what tells us to bring a meal to an end. Satiety starts at the end of a meal and results in the delay of the next meal, until the return of hunger signals. While satiation is primarily driven by the volume of food in the stomach, satiety is also driven by other factors, including the body’s ability to sense the nutrient content of food in the intestine. The brain detects chemical signals from a variety of gut hormones and neural signals from the intestine that regulate how full one feels or how hungry one feels. These signals are also impacted by a host of factors, like stomach fullness, rate of stomach content flow to the intestine, the concentration of glucose in the bloodstream, etc. The potential for low-calorie sweeteners to adversely affect satiety, however, is not supported by the scientific literature. While there have been a few studies suggesting effects based on results from cellular studies, it is important to know that cellular studies do not include, by their nature, the full regulatory control pathways for satiation and hunger that include the interplay of various and multiple signals.

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Alexandra R. Lobach, Ashley Roberts, Ian R. Rowland. Assessing the in vivo data on low/no-calorie sweeteners and the gut microbiota. Food and Chemical Toxicology. 2019; 124 (2019): 385–399.

It has recently been hypothesized that low/no-calorie sweeteners (LNCS) may adversely affect the gut microbiome function in health.  A new comprehensive review, conducted by experts in both gut microbiome and food ingredient safety research, has found that this hypothesis is not supported by the available research.  Indeed, the experts found that there is no credible evidence for LNCSs to adversely affect health through an effect on the gut microbiome.  The experts based their findings on a systematic review, which was specifically designed to find any published studies with gut microbiome measures in either animal or human subjects that were exposed to LNCSs.  It was also based on the results of studies that investigated the general nature of the gut microbiome.  The investigation found “clear evidence that changes in the diet unrelated to LNCS consumption (emphasis added) are likely the major determinants of change in gut microbiota numbers and phyla.”   Moreover, without regard to LNCSs, the number and type of microbiome organisms are likely changing on a daily basis, in response to normal dietary changes.  This means that it is virtually impossible to predict the clinical meaningfulness of the types of changes reported in the gut microbiome LNCS research studies to date.  Moreover, of the extremely limited clinical trials reported (three total; two by one research group – Suez et al. [2014]), all were short term and the authors noted that none were designed to avoid the confounding effects of normal diet practices.  In particular, the experts noted serious deficiencies with the microbiome research reported by Suez et al. (2014), and concluded that no adverse effect of LNCSs, including any possible effect on blood glucose levels, could be determined on the basis of that research.  In all, the review found no general trends in the types of changes reported following exposure to LNCSs, in either humans and/or laboratory animal species, whether considering LNCSs as a class or on an individual basis.  Further, the review noted that, while distal gut microbiota in mice is comprised of the same bacterial phyla as in humans, “most of the bacterial genera and species present in mice do not exist in the human gut.”  Thus, research in rodent species requires specific considerations when designing studies for extrapolation to humans.  Additionally, numerous of the animal studies reported utilized extremely high LNCS doses – doses that could never be expected to result from human consumption, and this was noted as a further difficulty for interpreting laboratory animal findings.  Finally, the experts found no evidence of a likely mechanism by which any of the LNCSs reviewed could meaningfully impact the gut microbiome with human use, by reviewing metabolism studies and studies specifically designed to evaluate safety.  In contrast, studies designed specifically to elicit possible adverse effects were deemed as reliable evidence that LNCSs have no clinically meaningful effect on gut health or function.  In concluding statements, the reviewers emphasized that any new studies need to be carefully designed and evaluated for reliable data interpretation and that “the available data confirm[s] the viewpoint supported by all the major international food safety and health regulatory authorities LNCS are safe at currently approved levels.”

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C. Bryant, J. Mclaughlin, Low calorie sweeteners: Evidence remains lacking for effects on human gut function, Physiol Behav (2016).

Recently several studies have suggested an effect of LCS on human health via the activation of gut taste receptors and/or the release of gut hormones involved in nutrient signaling and appetite regulation. This recent paper review, by researchers at the Gastrointestinal Centre, Institute of Inflammation and Repair, of the University of Manchester, UK, reviews the relevant data in light of this hypothesis. This review covers cellular, animal and clinical studies and puts the results into context with the gut-brain axis and its regulation of food intake. It also provides a summary of the signals arising from the gastrointestinal tract that allow for efficient digestion and absorption of nutrients and details the role of carbohydrates, including sugars, in this signaling allowing a comparison of the effects of LCS to sugars. The authors determined that research supports an interaction of LCS with gut taste receptors and noted that these are the same interactions that occur with nutritive (calorie-containing) sweeteners (sugars). The authors point out that nutritive sugars and other digestible carbohydrates are well known to have a role in food intake with their effects on gut hormones, like GLP-1 and GIP, or by influencing blood glucose and/or insulin levels. In contrast, the authors conclude that human studies do not support a clinically meaningful effect of ingested LCS on the hormones involved in gut signaling. While noting that to date the human studies are limited, they state scientific literature currently shows that “Sucralose, aspartame and ace-K [acesulfame-K] had no greater effect than water on secretion of GLP-1, insulin, PYY, or ghrelin, nor any impact on appetitive responses.” Based on currently available research, the authors stated: “The data do not support the concept that acute consumption of low calorie sweeteners can impinge on food intake via modulation of gastrointestinal homeostatic mechanisms.” Lastly, the authors encourage continued research, but conclude that “human studies to date have very consistently failed to show that activation of the [gut] sweet taste receptor by LCS”…replicate the effects of caloric sugars “on gastric motility, gut hormones or appetitive responses.” Overall this review concludes that “evidence remains lacking for effects [of LCS] on human gut function.”

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Antenucci, R. G., & Hayes, J. E. (2014). Nonnutritive sweeteners are not supernormal stimuli. International Journal of Obesity.

This study aimed to investigate the perceived sweetness intensity of a variety of nutritive sweeteners and non-nutritive sweeteners (NNS) in a large cohort of untrained participants using contemporary psychophysical methods. It is alleged that NNS have a supernormal stimuli with regard to perceived sweetness intensity and therefore can lead to sweet cravings and/or overeating of sweets. The study, supported by the National Institutes for Health, evaluated the perceived sweetness intensity of various low calorie sweeteners and other sugar substitutes when compared to sugar. Researchers at Penn State University recruited 401 participants for four separate test groups. The age range of participants ranged from 18-64. The results showed that participants perceived the sweetness of sugar substitutes at lower concentrations than real sugar, but the intensity of these sensations was not sweeter than sugar. The researchers concluded that NNS are not supernormal stimuli with regard to perceived sweetness intensity and therefore the data do not support the claim that NNS overstimulate sweet taste receptors to produce hyper-intense sweet sensations.

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Ma J, Bellon M, Wishart JM, et al. Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects. Am J Physiol Gastrointest Liver Physiol. 2009;296(4): G735-739.

Study abstract: "The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in glucose homeostasis in both health and diabetes. In mice, sucralose, an artificial sweetener, stimulates GLP-1 release via sweet taste receptors on enteroendocrine cells. We studied blood glucose, plasma levels of insulin, GLP-1, and GIP, and gastric emptying (by a breath test) in 7 healthy humans after intragastric infusions of 1) 50 g sucrose in water to a total volume of 500 ml (approximately 290 mosmol/l), 2) 80 mg sucralose in 500 ml normal saline (approximately 300 mosmol/l, 0.4 mM sucralose), 3) 800 mg sucralose in 500 ml normal saline (approximately 300 mosmol/l, 4 mM sucralose), and 4) 500 ml normal saline (approximately 300 mosmol/l), all labeled with 150 mg 13C-acetate. Blood glucose increased only in response to sucrose (P<0.05). GLP-1, GIP, and insulin also increased after sucrose (P=0.0001) but not after either load of sucralose or saline. Gastric emptying of sucrose was slower than that of saline (t50: 87.4+/-4.1 min vs. 74.7+/-3.2 min, P<0.005), whereas there were no differences in t50 between sucralose 0.4 mM (73.7+/-3.1 min) or 4 mM (76.7+/-3.1 min) and saline. We conclude that sucralose, delivered by intragastric infusion, does not stimulate insulin, GLP-1, or GIP release or slow gastric emptying in healthy humans."

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Ma J, Chang J, Checklin HL, et al. Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects. Br J Nutr. 2010;104(6): 803-806.

Study abstract: "It has been reported that the artificial sweetener, sucralose, stimulates glucose absorption in rodents by enhancing apical availability of the transporter GLUT2. We evaluated whether exposure of the proximal small intestine to sucralose affects glucose absorption and/or the glycaemic response to an intraduodenal (ID) glucose infusion in healthy human subjects. Ten healthy subjects were studied on two separate occasions in a single-blind, randomised order. Each subject received an ID infusion of sucralose (4 mM in 0.9% saline) or control (0.9% saline) at 4 ml/min for 150 min (T = - 30 to 120 min). After 30 min (T = 0), glucose (25%) and its non-metabolised analogue, 3-O-methylglucose (3-OMG; 2.5%), were co-infused intraduodenally (T = 0-120 min; 4.2 kJ/min (1 kcal/min)). Blood was sampled at frequent intervals. Blood glucose, plasma glucagon-like peptide-1 (GLP-1) and serum 3-OMG concentrations increased during ID glucose/3-OMG infusion (P < 0.005 for each). However, there were no differences in blood glucose, plasma GLP-1 or serum 3-OMG concentrations between sucralose and control infusions. In conclusion, sucralose does not appear to modify the rate of glucose absorption or the glycaemic or incretin response to ID glucose infusion when given acutely in healthy human subjects."

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Ford HE, Peters V, Martin NM, et al. Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects. Eur J Clin Nutr. 2011;65(4):508-513.

This is a randomized, single-blind, crossover study in healthy subjects to investigate whether oral ingestion of sucralose could stimulate enteroendocrine L-cell release of the hormones GLP-1 and peptide YY (PYY), including measurement of appetite ratings and energy intake with a meal. The authors concluded that oral ingestion of sucralose at the dose tested (50 ml of sucralose in water [0.083% w/v] or about 5 times the sucralose concentration in a diet soft drink) "does not increase plasma GLP-1 or PYY concentrations and hence, does not reduce appetite in healthy subjects." They further concluded that "oral stimulation with sucralose had no effect on GLP-1, insulin or appetite."

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Renwick AG, Molinary SV. Sweet-taste receptors, low-energy sweeteners, glucose absorption and insulin release. Br J Nutr. 2010;104(10):1415-1420.

Study abstract: "The present review explores the interactions between sweeteners and enteroendocrine cells, and consequences for glucose absorption and insulin release. A combination of in vitro, in situ, molecular biology and clinical studies has formed the basis of our knowledge about the taste receptor proteins in the glucose-sensing enteroendocrine cells and the secretion of incretins by these cells. Low-energy (intense) sweeteners have been used as tools to define the role of intestinal sweet-taste receptors in glucose absorption. Recent studies using animal and human cell lines and knockout mice have shown that low-energy sweeteners can stimulate intestinal enteroendocrine cells to release glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. These studies have given rise to major speculations that the ingestion of food and beverages containing low-energy sweeteners may act via these intestinal mechanisms to increase obesity and the metabolic syndrome due to a loss of equilibrium between taste receptor activation, nutrient assimilation and appetite. However, data from numerous publications on the effects of low-energy sweeteners on appetite, insulin and glucose levels, food intake and body weight have shown that there is no consistent evidence that low-energy sweeteners increase appetite or subsequent food intake, cause insulin release or affect blood pressure in normal subjects. Thus, the data from extensive in vivo studies in human subjects show that low-energy sweeteners do not have any of the adverse effects predicted by in vitro, in situ or knockout studies in animals."

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Mattes RD, Popkin BM. Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. Am J Clin Nutr. 2009;89(1):1-14.

Mattes and Popkin reported their findings following a review of available literature on low-calorie sweetener use and utility in weight management strategies. Their review describes recent trends in the use of non-nutritive sweeteners and current knowledge of their effects on short-term appetite and food intake as well as longer-term energy balance and body weight. The authors report that the evidence suggests that, when non-nutritive sweeteners are used as substitutes for higher energy yielding sweeteners, they have the potential to aid in weight management. They also report that, with respect to energy intake, there is no substantive evidence of inherent liking for sweetness or non-nutritive sweetener- activation of reward systems is problematic.

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Ren X, Ferreira JG, Zhou L, Shammah-Lagnado SJ, Yeckel CW, de Araujo IE. Nutrient selection in the absence of taste receptor signaling. J Neurosci. 2010;30:8012–8023.

Taste quality, particularly sweet taste, seems to be an important driver of food preference by stimulating dopamine (DA) release, which is a marker of "pleasure" sensation. The authors report on a series of experiments, using "sweet knock-out" mice that are unable to taste sweetness to test this concept. The researchers showed mice preferred glucose over the sweet-tasting amino acid, L-serine (which has the same caloric value as glucose but cannot be converted to glucose). The preference for, and higher intake of glucose was associated with a higher glucose oxidation rate. In a related experiment, normal (wild-type) mice were found to have robust DA release in response to glucose infusion that bypasses interaction with taste receptors. The results suggest that signals related to glucose oxidation drive preference selections for sweets, not sweet taste alone. This further implies that beverages and foods with lower glucose oxidation potential (e.g., a diet drink) would be comparatively less likely to cause increased cravings for sweets than beverages and foods with higher glucose oxidation potential (e.g., a full-calorie soda).

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A selection of recent publications supporting the use of LNCS

More Studies


A Summary of the latest peer - reviewed research