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Adverse Effects of Artificial Sweeteners on Gastrointestinal Microbiota

        Artificial sweeteners were first commonly used in America over a century ago (1). Saccharine was the first artificial sweetener to be introduced into the food supply in 1917 (2). Artificial sweeteners are man-made chemicals that are hundreds of times sweeter than natural sugar, which became popular in America due to their low-calorie qualities. Artificial sweeteners modify the glycemic response of the foods and beverages, which benefits diabetics, while limiting caloric intake for the general public. After products began incorporating artificial sweeteners and were added to many American beverages, several research groups found artificial sweeteners caused weight gain and glucose intolerance in select individuals (3). Researchers then began to look into possible mechanisms for these outcomes. One basis of how artificial sweeteners cause glucose intolerance and weight gain is because humans do not digest artificial sweeteners. Instead, artificial sweeteners directly affect the gastrointestinal (GI) microbiota (1). Intestinal microbiota are the microscopic organisms living in the large intestine of mammals.The interaction between the artificial sweeteners and GI microbiota cause changes in the types and colonies of microbiota that regulate physiological function, health-disease, and in the case of artificial sweeteners lead predominantly to adverse health effects.

        Animal research has found a connection between artificial sweetener use, microbiota modifications and glucose intolerance (1). Microbiota metabolize the nutrients that pass through the digestive system which have not been digested in the upper digestive tract (4). Like fibers, humans do not digest artificial sweeteners; instead artificial sweeteners pass through the digestive system and make direct contact with the GI microbiota (5). While fibers promote a favorable microbial environment, artificial sweeteners results in the opposite effect.A study looking at artificial sweetener consumption in mice, found that mice with artificially sweetened water developed glucose intolerance, while the mice with sucrose water maintained normal glucose tolerance (1). To determine the role of GI microbiota on the glucose intolerant mice, researches gave the mice broad spectrum, gram-negative antibiotics. Broad-spectrum antibiotics were given to wipe out GI microbiota. Wiping out microbiota eliminates the direct contact of the artificial sweetener and the microorganisms. The results showed no differences of antibiotic treated mouse glucose tolerance between the mice with artificially sweetened water and sucrose water. Mice lacking GI microbiota in the digestive tract, maintained normal glucose tolerance, even while consuming artificial sweeteners (1).

        Knowing that artificial sweeteners affected the gut microbiota of mice, researchers performed studies to test the impact of consuming artificial sweeteners on GI microbiota colonies in humans (5). The results found that there were non-responders who did not have side effects and responders to the artificial sweeteners who showed side effects. The responders showed major composition changes in their GI microbiota. The research showed that there were different organism groups that died off and other organisms groups that flourished with the consumption of artificial sweeteners (5). Adding artificial sweeteners in a diet kill off some microbiota, while allowing other groups of microbiota to take over (6). More importantly, consuming artificial sweeteners in the responders group showed an increased glucose intolerance. Not only did the responders develop glucose intolerance, there were also changes in physiological responses and metabolism: increase hip to waist ratio (related to an increase in visceral fat), higher fasting blood glucose, and higher HbA1c.

        Glucose intolerance from artificial sweeteners is not a direct consequence of consuming the chemicals themselves; rather it is a secondary consequence in response to the change in the GI microbiota. The change in microbiota and subsequent systemic metabolic and physiological consequences are what resulted in an increased glucose intolerance. A culture of the microbiota from mice who consumed artificial sweeteners was taken, incubated then transplanted into host mice (6). This transplant of microbiota alone allowed researchers to eliminate other factors in the artificial sweeteners that played a role in glucose tolerance, or intolerance. The results showed that the host mice also developed glucose intolerance. This same study was replicated in healthy, non-diabetic human volunteers. After artificial sweetener consumption, 4 of the 7 individuals showed evidence of poor glycemic responses due to changes in the microbiota. The microbiota of the 4 individuals was collected and transplanted into a host mice group. Following transplanted microbiota, the host mice group showed the same poor glycemic response as the human donors (6). The findings show the makeup of the gut microbiota play a key role in glucose intolerance in both mice and men.

        The mechanism of how a change in the make up of the gut microbiota can cause glucose intolerance has to do with the metabolites of the microorganisms involved. The types of microorganisms were studied in a low dose aspartame fed mice equivalent of a human drinking 2 to 3 cans of artificially sweetened beverages in a day. The aspartame fed mice gut microbiota showed an increase in Enterobaceriacae and Clostridium leptum microorganisms. The increase in Clostridium is responsible for the huge increase of the concentration of the metabolite, propionate. Propionate has been shown to be responsible for glucose intolerance, insulin resistance, gene expression, taste aversion, irritable bowel syndrome and mitochondrial dysfunction (7). The metabolite propionate is released from the Clostridium organisms which then enters the blood stream finding its way to the entero-hepatic circulation. Once propionate reaches the liver it goes through gluconeogenesis that increases the livers production of glucose, which contributes to glucose intolerance and insulin resistance (7).

        Overall, consuming artificial sweeteners can change the make up of one’s gut microbiota. Consuming artificial sweeteners will kill off healthy microorganisms, while allowing other unhealthy microorganisms to take over. This imbalance of microbiota is one factor involved in the development of glucose intolerance; through the metabolites produced by the microorganisms. Although artificial sweeteners allow for a low caloric option for sweetened beverages, their consequences may present more harmful consequences than their perceived benefits.

Written by Emily Hamocon with Eric Sternlicht, Ph.D., Chapman University, Orange CA.

Links Provided

1. Suez J., Korem T., Zeevi D., Zilberman-Schapira G., Thaiss CA., Maza O., Israeli D., Zmora N., Gilad S., Weinberger A., Kuperman Y, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. doi:10.1038/nature13793 & Spencer - J Neurogastr Motil.Artificial Sweeteners - Review & Primer for Gastroentrologists.2016

2. Hodgin, G. (n.d.). The History, Synthesis, The History, Synthesis, Metabolism and Uses of Artificial Sweeteners. Retrieved April 05, 2017, from .

3. Gardner, C., Wylie-Rosett, J., Gidding, S. S., Steffen, L. M., Johnson, R. K., Reader, D., & Lichtenstein, A. H. (2012). Nonnutritive Sweeteners: Current Use and Health Perspectives: A Scientific Statement from the American Heart Association and the American Diabetes Association. Diabetes Care, 35(8), 1798-1808. doi:10.2337/dc12-9002 .

4. Dahl , W., & Mai, V. (2016, August 08). Go With Your Gut: Understanding Microbiota and Prebiotics. Retrieved April 05, 2017, from 2009 & Harvard Health Letter.Can-gut-bacteria-improve-your-health

5. David, L. A., Maurice, C. F., Carmody, R. N., Gootenberg, D. B., Button, J. E., Wolfe, B. E., . . . Turnbaugh, P. J. (2013). Diet rapidly and reproducibly alters the human gut microbiome. Nature, 505(7484), 559-563. doi:10.1038/nature12820 .

6. Korem, T., Suez, J., Zilberman-Schapira, G., Segal, E., & Elinav, E. (2015, April 1). Non-caloric artificial sweeteners and the microbiome: Findings and challenges. Gut Microbes, 6(2), 149-155. doi:10.1080/19490976.2015.1017700 .

7. Palmnäs, M. S., Cowan, T. E., Bomhof, M. R., Su, J., Reimer, R. A., Vogel, H. J., . . . Shearer, J. (2014, October 14). Low-Dose Aspartame Consumption Differentially Affects Gut Microbiota-Host Metabolic Interactions in the Diet-Induced Obese Rat. Retrieved April 05, 2017, from Journal of Physiology, Reitelseder S. et al. .