The scientific evidence behind the effects of Artificial Sweeteners on human metabolism

By Laurentia Campbell, Nutritionist and Neuroscientist (mental health, polyphenols, diabetes/obesity, gut microbiota) academic, content writer, food waste warrior & science/healthtech/food/fmcg NPD(ideation-scale)

Artificial sweeteners (AS) are low-calorie or calorie-free chemical substances used to sweeten and improve the palatability of foods and beverages as alternatives to added sugars and fats. They’re found in thousands of widely-available products, from sugar and fat-free or low-sugar and fat yoghurts to sugar-free beverages including flavoured waters, desserts, ready meals, “natural health foods,” breakfast bars, bread, medicines, chewing gums and even toothpaste. Although they were developed to help reduce diseases associated with metabolism, such as obesity and many have been shown to help reduce metabolic disorders such as type two diabetes, metanalysis data from randomised controlled trials in both animal and human models suggest that some artificial sweeteners (AS), especially Aspartame and Sucralose, appear to alter metabolism by changing the host microbiome, increasing appetite gut hormones, changing tastebuds and our desire for sweet things, altering glucose homeostasis and could be associated with impaired insulin sensitivity, increased caloric consumption and weight gain.

Sweeteners are sugar alternatives that are either nutritive, (NS) or non-nutritive (NNS), depending on if they contain calories and energy in the form of carbohydrates or not. The nutritive sweeteners include monosaccharide polyols (e.g., xylitol, mannitol, and sorbitol) and disaccharide polyols (e.g., lactitol and maltitol). The non-nutritive sweeteners (NNSs) include artificial sweeteners such as saccharin, aspartame, stevia, sucralose and acesulfame K. The most used sweeteners are aspartame, acesulfame k, saccharin, sucralose, polyols (such as xylitol, erythritol, sorbitol, and isomalt), and steviol glycosides (Carocho et al.,2017). China is the highest consumer of sugar and sweeteners per capita, followed by India and the United States.

Figure 1: types of sweetener- Toews, I., Lohner, S., de Gaudry, D. K., Sommer, H., & Meerpohl, J. J. (2019). Association between intake of non-sugar sweeteners and health outcomes: systematic review and meta-analyses of randomised and non-randomised controlled trials and observational studies. bmj, 364.

What does the scientific evidence say?

Human metabolism is a hugely complicated process, with many different factors from age to immune status to dietary fibre intake influencing an individual's metabolism. Metabolism is all the chemical reactions in the body, needed to maintain homeostasis. Every reaction needs energy and our metabolic rate is how efficiently we can break down fats, proteins and carbohydrates from food and beverages into energy to fuel all living processes. Each person will have a unique response to a food based upon their own personal biology, and therefore it is hard, with so many influencing factors involved, to draw any confirmative conclusions on human metabolism. In this report, I have tried to summarise the available scientific evidence, with the knowledge of the limitations to current metabolic research.

When analysing AS research it is also hard to draw accurate conclusions. This is because there is much potential for design flaws and errors in the current studies, which weaken the reliability of the data. Many studies on artificial sweeteners (AS) are undertaken in rats not humans, and as what happens in a rat may not necessarily happen in a human, many AS metabolic studies may not represent the effects on metabolism in a human population. Additionally, despite many studies doing just this, we cannot class all artificial sweeteners as the same as there is huge variability in the chemical structure and adsorption, distribution, metabolism and excretion (ADME) of each sweetener and these differences may affect the sweeteners' effect on human metabolism. Therefore, extrapolation of the metabolic effects of a single artificial sweetener to all artificial sweeteners is not appropriate. Some AS also break down into natural metabolites which makes it hard to determine if an observed effect is caused by an AS or another part of the diet.

Further potential for study design flaws lies in the fact that many AS are consumed in foods such as yoghurts or as part of a meal. Therefore, there is vast potential for confounding factors to influence results and it is unsure if it is an AS or another food source or part of a meal causing metabolism effects, eg: Aspartame metabolised into natural metabolites including aspartic acid, phenylalanine, and methanol, all of which found naturally in the diet. Furthermore, many AS are combined in foods, for example, Sucralose with Aspartame, making it hard to determine how each sweetener is independently affecting metabolism. Studies also do not take into consideration the degree of food processing, and the way food is prepared or cooked and the confounding impact this may have on how it is metabolised in the human body. They also do not take into consideration other parts of the study participants’ diet (such as fat, protein and fibre content) and how these, independent from the AS, may affect participants’ metabolism, appetite, glucose control and insulin sensitivity and gut microbiota.

Additionally, many AS human trials contain conclusions drawn from very small cohorts (eg: 45 non-regular users of AS in Greenhill study in 2020 which found when Sucralose is consumed with carbohydrates, insulin sensitivity is impaired and there is impaired metabolic dysfunction and reduced central sensitivity to sweet taste) or are very short in duration and so we can not be certain of long-term effects on metabolism. Also, as sweeteners are in so many unsuspected sources, even tightly regulated controlled studies involving dietary recall may be subject to measurement error, with some people consuming additional undetected dosages of AS in things such as toothpaste multivitamin tablets and supplements, without recording this and tracing its effect on metabolism.

Further potential for error lies in the fact that many human studies are undertaken in those overweight, or who already consume a diet rich in AS, and these individuals may have different metabolisms and gut microbiotas to that of non-AS, lean individuals. As each human has an individual metabolic rate, based on their own health status and body, the effects of sweeteners on the metabolism of one person in human trials, may also not reflect that of the population. Many trials did not take into consideration other potential confounding factors which may affect the basal metabolic rate (BMR) of participants and impact dietary metabolism, for example, how much the study participants exercise, their age, lifestyle, sleep, their iodine levels and thyroid function and other factors such as their dietary B vitamins concentrations and omega3:6 ratios, and how these affect human metabolism and may be impacting results. The meta-analysis systematic review by Towes et al which was published in the British Medical Journal, reviewed over 13941 randomised and non-randomised controlled trials and observational studies records and highlighted the lack of credibility of many of the studies undertaken on AS.

Despite this, due to their widespread use and the huge need to reduce the health burden of metabolic syndromes such as obesity, there is a desperate need for research into AS. The systemic review and Metanalysis on the health effects of the use of non-sugar sweeteners for WHO, 2022, by Magali Rios-Leyvraz and Jason Montez found that increased long-term AS use was associated with increased body weight, type 2 diabetes and cardiovascular disease. A total of 283 studies were included in the review which focused on randomized controlled trials, prospective cohort studies and case–control studies, and certainty in results was assessed via GRADE (Grading of Recommendations Assessment, Development and Evaluation) and Cochrane methodology looking at RCTs. They found that replacing sugars with NSS in the short term results in reductions in body weight, with little impact on other cardiometabolic risk factors, but is associated with increased risk of type 2 diabetes, cardiovascular diseases and mortality in the longer term.

The study by Rogers and Appleton in 2021 on “The effects of low-calorie sweeteners on energy intake and body weight: a systematic review and meta-analyses of sustained intervention studies” in the International journal of obesity, found that AS had a positive result on human metabolism and weight management. This study, adhered to the PROSPERO and PRISMA statement guidelines for critical analysis of research, selecting for studies as per Cochrane collaboration randomisation. However, it can be unsure whether the improvements in body mass, are because of the displacement of sugar intake or the direct benefits of AS on metabolism.

It was found in numerous trials, as summarised in metanalysis based on RCT by Pang et al, 2020, that AS may induce gut microbiota dysbiosis, or imbalance, by altering the gut microbiota composition and function. The gut microbiota is the layer of commensal bacteria that colonise the walls of the digestive tract. It has been reported in numerous peer-reviewed, reputable metanalysis studies to have benefits on human metabolism, linked to their production of small-chain fatty acids (SCFA) such as Butyrate. The microbiota has been claimed to provide an alternative energy source for metabolism, affect GLP-1 (inducing satiety), reduce gluconeogenesis (glucose production from carbon non-carbohydrate sources), increase lipid metabolism (reducing circulating LDL levels), improve insulin sensitivity and reduce metabolic glucose requirements and glycaemic control.

The gut microbiota has been reported to also encourage hypermetabolic vitamin synthesis, increase vitamin and mineral absorption, increase adipose tissue browning and increase bile acid metabolism. The review in 2017 by Pearlman et al found that AS impacts gut microbiota and found that this adversely affected appetite, energy consumption and glucose and lipid metabolism. Studies report that this dysbiosis is not caused by all AS, highlighting that each sweetener has a specific structure and individual effect on human metabolism. Multiple studies concur on the specific microbiota-disrupting effects of Aspartame and Acesulfame k. The systemic review in 2021 by Gomez- Fernandez et al found the affect of AS depends on the type of sweetener. Some cause dysbiosis/decrease insulin sensitivity (negatively affecting metabolism), whilst some are prebiotic and reduce type 2 diabetes. It mentioned the Suez et al 2014, Kuk & Brown, 2016 and Frankenfeld et al, 2015, studies which found that Aspartame and acesulfame k may cause an imbalance in carbohydrate metabolism and gut microbiota dysbiosis. On the other hand, it found that other studies such as Gostner et al, 2006 and Chukwuma & Islam, 2017, have reported that sweeteners such as Isomalt, xylitol and stevioside, have beneficial health effects as prebiotics, increasing the diversity of beneficial gut microbiota and thus representing a new option for the prevention and cotreatment of diseases related to metabolic syndromes, such as T2D.

Figure 2: Mora, M. R., & Dando, R. (2021). The sensory properties and metabolic impact of natural and synthetic sweeteners. Comprehensive Reviews in Food Science and Food Safety, 20(2), 1554–1583.

It appears, that aside from affecting the role of the microbiota in metabolism and glucose control, some AS may themselves decrease insulin sensitivity in healthy subjects. Insulin sensitivity is a measure of how quickly your body responds to insulin, which lowers blood sugar and affects metabolism. Obesity and T2D metabolic disorders are often linked to insulin resistance. Many RCTs, including the Romo-Romo et al study of 2018, found that certain AS, such as Sucralose, reduce insulin sensitivity and impede human metabolism. There has also been a reported link with Leptin, the satiety signal, resistance, and with some sweeteners up to 300–500x sweeter than sugar, it has been suggested that AS may increase dietary taste bud palate preference for sweet things, causing dietary and metabolic calorific compensation and increased body mass, obesity and T2D. Some suggest this may be linked to the effects of AS in stimulating Dopamine, the neurotransmitter linked to reward and pleasure which is activated by sugar and fat. It is believed that the brain responds to excessive Dopamine by down-regulating the Dopamine brain receptors, and therefore it has been hypothesized in studies, that some AS, that are 300x sweeter than sugar may blunted the sugar Dopamine response, resulting 300x increased desire for sugar and an increased glucose appetite.

The systematic review and meta-analysis of RCT by Nichol et al 2018 found that the sensory pathway for AS involves two G-protein receptors (T1R2 and T1R3) that form the sweet taste receptor in the oropharynx. The ingestion of sugar or AS activates the sweet taste receptor and sends signals to the hypothalamus and the amygdala which is associated with reward and satisfaction. The post-ingestion pathway is influenced by the energy content of the food or beverage being consumed. When AS are ingested instead of sugar, the sweet taste receptors are activated; however, the rise in blood glucose and insulin secretion does not occur at the same degree. As artificial sweeteners either have no energy content or are not metabolized, the post-ingestion pathway is significantly altered. AS activate the oral taste receptors but only partially activate the food reward pathway and do not activate the post-ingestion pathway because of the lack of caloric energy. Changes in these pathways ultimately lead to increased appetite, increased food cravings, and greater caloric consumption. AS may interfere with learned responses that normally contribute to glucose and energy homeostasis, resulting in the counterintuitive effect of inducing metabolic derangements.

The effects on sweet taste receptors and gut hormones of AS have also been widely documented, with AS effects on taste receptors (such as T1R1 and T1R2) linked to raised PYY, GLP-1 (satiation factor) and other gut hormones. As GLP-1 stimulates Insulin secretion in a glucose-dependent manner, it is unclear if AS are aiding metabolic syndromes by increasing insulin, or increasing obesity and T2D by increasing the symptoms of insulin resistance. Liauchonak et al, 2019 showed, it seems to differ dependent on the sweetener itself, and the specific metabolic disorder and the study participant's medical history.

Studies by Mace et al, 2009 and Margolskee et al, 2007, found that low-calorie AS such as Sucralose trigger the sweet taste receptors T1R3 and T1R2, which led to more sugar transporters GLUT2 and SLGT1 along the walls of the gut, leading to increased glucose absorption from food and increased insulin secretion and decreased insulin sensitivity, increasing type 2 diabetes risk. It increases the glycaemic load of a meal and the post-prandial (post-meal) insulin-induced blood glucose low, and therefore may increase appetite (as Ghrelin the appetite hormone is increased by low blood sugar). It may also contribute to more carbohydrates and fat being stored in fat cells instead of in the muscle and liver, contributing to weight gain and obesity. This is supported by a RCT by Romo-Romo et al, 2018, which found that Sucralose decreased insulin sensitivity in healthy individuals.

There are many more reasons why AS may affect human metabolism, from the potential laxative effects of some sweeteners to their role in impacting other dietary vitamin and mineral micronutrient absorption to their effect on many metabolic and digestive enzymes, which have yet to be explored fully. What is clear is that the effect of AS depends on the individual AS, and so we cannot class them all as one and that the effect on human metabolism depends upon the individual human, and so we must look towards personalised nutrition and medicine. There is considerably more research needed on AS before we can conclusively determine whether they are adverse or beneficial. In the meantime, we must go on the research evidence we have available at a time, which suggests some AS are beneficial and some are not, and tailor our AS use to those which support a health-promoting human metabolism, such as steviol glycoside which is 10–15x sweeter than sucrose without negative effects on gut microbiota and taste buds and dopamine.

References

• Ali, A., More, T. A., & Shaikh, Z. (2021). Artificial sweeteners and their health implications: A review. Biosciences Biotechnology Research Asia, 18(2), 227–237.
• Appleton KM, Blundell JE. Habitual high and low consumers of artificially-sweetened beverages: effects of sweet taste and energy on short-term appetite. Physiol Behav. 2007;92:479–86. doi: 10.1016/j.physbeh.2007.04.027.
• Appleton KM, Conner MT. Body weight, body-weight concerns and eating styles in habitual heavy users and non-users of artificially sweetened beverages. Appetite. 2001;37:225– 30. doi: 10.1006/appe.2001.0435.
• Azad MB, Abou-Setta AM, Chauhan BF, Rabbani R, Lys J, Copstein L, et al. Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. Can Med Assoc J. 2017;189:E929–39. doi: 10.1503/cmaj.161390.
• Bueno-Hernández N, Esquivel-Velázquez M, Alcántara-Suárez R, Gómez-Arauz AY, Espinosa-Flores AJ, de León-Barrera KL, et al. Chronic sucralose consumption induces elevation of serum insulin in young healthy adults: a randomized, double blind, controlled trial. Nutr J. 2020;19:32. doi: 10.1186/s12937–020–00549–5.
• Chappel, C. I. (1992). A review and biological risk assessement of sodium saccharin. Regulatory toxicology and Pharmacology, 15(3), 253–270.
• Dalenberg JR, Patel BP, Denis R, Veldhuizen MG, Nakamura Y, Vinke PC, et al. Shortterm consumption of sucralose with, but not without, carbohydrate impairs neural and metabolic sensitivity to sugar in humans. Cell Metab. 2020;31:493–502.e7. doi: 10.1016/j. cmet.2020.01.014.
• de Ruyter JC, Katan MB, Kuijper LDJ, Liem DG, Olthof MR. The effect of sugar-free versus sugar-sweetened beverages on satiety, liking and wanting: an 18 month randomized double-blind trial in children. PloS One. 2013;8:e78039. doi: 10.1371/journal. pone.0078039
• Fernstrom J. D. (2015). Non-nutritive sweeteners and obesity. Annual review of food science and technology, 6, 119–136. https://doi.org/10.1146/annurev-food-022814-015635
• Gómez‐Fernández, A. R., Santacruz, A., & Jacobo‐Velázquez, D. A. (2021). The complex relationship between metabolic syndrome and sweeteners. Journal of Food Science, 86(5), 1511–1531.
• Grotz, V. L., & Munro, I. C. (2009). An overview of the safety of sucralose. Regulatory toxicology and pharmacology, 55(1), 1–5.
• Koyuncu BU, Balci MK. Metabolic effects of dissolved aspartame in the mouth before meals in prediabetic patients: a randomized controlled cross-over study. J Endocrinol Diabetes Obes.2014; 2:1–6.
• Nichol AD, Holle MJ, An R. Glycemic impact of non-nutritive sweeteners: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2018;72:796– 804. doi: 10.1038/s41430–018–0170–6
• Pang, M. D., Goossens, G. H., & Blaak, E. E. (2021). The impact of artificial sweeteners on body weight control and glucose homeostasis. Frontiers in nutrition, 7, 598340.
• Pearlman, M., Obert, J., & Casey, L. (2017). The association between artificial sweeteners and obesity. Current gastroenterology reports, 19(12), 1–8.
• Raben A, Moller B, Flint A, Vasilaras T, Moller A, Holst J, et al. Increased postprandial glycaemia, insulinemia, and lipidemia after 10 weeks’ sucrose-rich diet compared to an artificially sweetened diet: a randomised controlled trial. Food Nutr Res. 2011;55.
• Ragi, M. E. E., El-Haber, R., El-Masri, F., & Obeid, O. A. (2022). The effect of aspartame and sucralose intake on body weight measures and blood metabolites: Role of their form (solid and/or liquid) of ingestion. British Journal of Nutrition, 128(2), 352–360.
• Rios-Leyvraz, M., Montez, J., & World Health Organization. (2022). Health effects of the use of non-sugar sweeteners: a systematic review and meta-analysis.
• Mace, O. J., Affleck, J., Patel, N., & Kellett, G. L. (2007). Sweet taste receptors in rat small intestine stimulate glucose absorption through apical GLUT2. J Physiol, 582(Pt 1), 379–392. https://doi.org/10.1113/jphysiol.2007.130906
• Margolskee, R. F., Dyer, J., Kokrashvili, Z., Salmon, K. S., Ilegems, E., Daly, K., Maillet, E. L., Ninomiya, Y., Mosinger, B., & Shirazi-Beechey, S. P. (2007). T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proc Natl Acad Sci U S A, 104(38), 15075–15080. https://doi.org/10.1073/pnas.0706678104
• Sclafani, A. (2007). Sweet taste signaling in the gut. Proc Natl Acad Sci U S A, 104(38), 14887–14888. https://doi.org/10.1073/pnas.0707410104
• Rogers, P. J., & Appleton, K. M. (2021). The effects of low-calorie sweeteners on energy intake and body weight: a systematic review and meta-analyses of sustained intervention studies. International journal of obesity, 45(3), 464–478.
• Romo-Romo, A., Aguilar-Salinas, C. A., Brito-Córdova, G. X., Gómez-Díaz, R. A., & Almeda-Valdes, P. (2018). Sucralose decreases insulin sensitivity in healthy subjects: a randomized controlled trial. The American journal of clinical nutrition, 108(3), 485–491
• Stamataki NS, Crooks B, Ahmed A, McLaughlin JT. Effects of the daily consumption of stevia on glucose homeostasis, body weight, and energy intake: a randomised open-label 12-week trial in healthy adults. Nutrients. 2020;12:3049. doi: 10.3390/nu12103049.
• Toews, I., Lohner, S., de Gaudry, D. K., Sommer, H., & Meerpohl, J. J. (2019). Association between intake of non-sugar sweeteners and health outcomes: systematic review and meta-analyses of randomised and non-randomised controlled trials and observational studies. bmj, 364.
• Vázquez-Durán M, Orea-Tejeda A, Castillo-Martínez L, Cano-García Á, Téllez-Olvera L, Keirns-Davis C. A randomized control trial for reduction of caloric and non-caloric sweetened beverages in young adults: effects in weight, body composition and blood pressure. Nutr Hosp. 2016;33:1372–8. doi: 10.20960/nh.797.
• Whitehouse, C. R., Boullata, J., & McCauley, L. A. (2008). The potential toxicity of artificial sweeteners. Aaohn Journal, 56(6), 251–261.