Calorie Control Council* comments on “Artificial sweeteners induce glucose intolerance by altering the gut microbiota”, Nature** 17 September 2014

Summary: The study suffers from small sample sizes, unrealistic sweetener applications, and a dependence largely on rodent research. Findings should be interpreted with caution.

Statements from leading health organizations and other peer-reviewed published studies are contrary to the study findings.
Leading health organizations, including the Academy of Nutrition and Dietetics (AND), the American Diabetes Association (ADA) and the American Heart Association (AHA), as well as numerous scientific studies agree that low-calorie sweeteners can be used as a safe tool to help manage calorie intake, which, in turn can be helpful for both weight management and diabetes management. In contrast to the assertions made by the researchers of this study, the overall evidence from studies on low-calorie sweeteners, including numerous human studies, show that these sweeteners are safe and do not have adverse effects on blood glucose control. Investigators of more than 40 studies in people, including a recent meta-analysis of clinical trials and other available evidence, have concluded that the use of low-calorie sweeteners does not lead to either an increased risk of obesity or diabetes. The safety of low-calorie sweeteners has been confirmed time and time again by scientists and regulatory agencies around the world, including the U.S. Food and Drug Administration (FDA), the European Food Safety Authority (EFSA) and Health Canada.

The study suffers from several significant limitations.
The study by Suez et al., which concluded that low-calorie sweeteners lead to glucose intolerance and disruption in gut microbiota which in turn may be associated with increased obesity and diabetes, suffers from several limitations that diminish the generalizability of the findings.

MICE EXPERIMENTS

1. Findings in mice may not be applicable to humans. The research was conducted mostly in mice, which have biological processes and microbiota that are different from humans, thus making it potentially difficult to translate the study findings to humans. Further, the mice in the high fat diet group received 60% of their calories from fat, which is twice as much as recommended for humans.
2. Limited testing. The study shows results of only a single glucose tolerance test – there is no baseline glucose test for comparison.
3. Testing results are inappropriately extrapolated. The researchers make generalizations largely based on one sweetener, about sweetener effects, on glucose control or tolerance. These assumptions were based on limited information and despite absence of confirmation from larger, longer studies, including clinical trials in people.
4. Too small a sample size to generalize. The different experiments conducted in the study included only a few mice in each experimental group. The small sample sizes used in these experiments further limit the applicability of the study results to humans.
5. Situations not reflective of real life. The experiments were also conducted in situations that are not applicable to real life. In some experiments, mice were fed low-calorie sweeteners in their pure form, which are not readily marketed to humans; in other experiments, mice were fed low-calorie sweeteners as available in the marketplace, but at a higher level than typically consumed. Some mice included in the study were also germ-free, an almost impossible scenario for humans with few exceptions unless in a restricted and controlled medical environment.
6. Consumption of low-calorie sweeteners was associated with decrease in food intake. Mice that were in the low-calorie sweetener groups had a dramatic increase in beverage consumption and an associated decrease in food intake. This change means that there was a significant change in the overall diet and nutrient consumption, even if the total calories remained the same. Therefore, less consumption of food and likely a reduced intake of fiber and protein rather than low-calorie sweetener consumption, and, may have led to the change in microbiota in those mice.
7. Mice in the low-calorie sweetener groups did not gain weight. The mice that were in the low-calorie sweetener group did not have any changes in weight. Therefore, it does not seem plausible for the researchers to conclude that the observed changes in microbiota or blood glucose response are related to obesity.

HUMAN EXPERIMENTS

The authors did examine humans. However, this research had some limitations that affect the ability to translate that study to the larger human population.

1. The observational study included a small sample size that may not be applicable to all populations. The observational study included 381 people, a relatively small sample size. There may be other confounders that may have influenced the outcome and it is not clear how the adjustments were made to address these confounding variables.
2. The methods of the observational study may introduce recall bias. This study introduces recall bias as consumers were asked to remember their past consumption of products containing low-calorie sweeteners. This potential bias may have affected the mean increase in HbA1C% that was reported, especially as there was no indication provided with regards to dose response and increase in HbA1C%.
3. The experimental study included too small a sample size to generalize. The study was conducted in only 7 individuals, an extremely small sample which makes it difficult to translate the results to the larger population.
4. Sample not representative. The participants in this study were nearly the same age (ages 28-36), which also makes it difficult to apply the study findings to the majority of the population.
5. Too short a time period. The experimental study was conducted over only one week. A longer trial with a larger, more diverse population would be more likely to generate findings that could be more statistically relevant and translatable to the human condition.
6. Lack of control group and unrealistic consumption levels. The experimental study did not include a control group and the amounts of low-calorie sweetener consumed by the participants were not levels that are typically consumed. These factors likely impact the generalizability of the study results.

“The study by Suez et al. contains several studies and experiments which have a number of limitations that are at odds with a large number of other peer-reviewed publications. Therefore, the results of the Suez et al. study warrant further research.

* The Calorie Control Council (the “Council”) is an international association of manufacturers of low-calorie, reduced-fat and “light” foods and beverages.  Companies that make and use low-calorie sweeteners are among the Council’s members.

**Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature, 2014; doi: 10.1038/nature13793.