Study: Artificial Sweeteners May be Contributing to Obesity; Findings Challenged by Industry

18 Sep 2014 --- Artificial sweeteners, promoted as aids to weight loss and diabetes prevention, could actually hasten the development of glucose intolerance and metabolic disease; and they do it in a surprising way: by changing the composition and function of the gut microbiota – the substantial population of bacteria residing in our intestines. These findings, the results of experiments in mice and humans, were published in Nature.

Among other things, says Dr. Eran Elinav of the Weizmann Institute's Immunology Department, who led this research together with Prof. Eran Segal of Computer Science and Applied Mathematics Department, the widespread use of artificial sweeteners in drinks and food may be contributing to the obesity and diabetes epidemic that is sweeping much of the world.

For years researchers have been puzzling over the fact that non-caloric artificial sweeteners do not seem to assist in weight loss, and some studies have suggested they may even have an opposite effect. Graduate student Jotham Suez in Elinav's lab, who led the study, collaborated with graduate students Tal Korem and David Zeevi in Segal's lab and Gili Zilberman-Shapira in Elinav's lab in discovering that artificial sweeteners, even though they do not contain sugar, nonetheless have a direct effect on the body's ability to utilize glucose. Glucose intolerance – generally thought to occur when the body cannot cope with large amounts of sugar in the diet – is the first step on the path to metabolic syndrome and adult-onset diabetes.

The scientists gave mice water laced with the three most commonly used artificial sweeteners – in the equivalent amounts to those permitted by the FDA. These mice developed glucose intolerance, as compared to mice that drank water, or even sugar water. Repeating the experiment with different types of mice and different doses of the sweeteners produced the same results – these substances were somehow inducing glucose intolerance.

Next, the researchers investigated a hypothesis that the gut microbiota are involved in this phenomenon. They thought the bacteria might do this by reacting to new substances like artificial sweeteners, which the body itself may not recognize as "food." Indeed, artificial sweeteners are not absorbed in the gastrointestinal tract, but in passing through they encounter trillions of the bacteria in the gut microbiota.

The researchers treated mice with antibiotics to eradicate many of their gut bacteria; this resulted in a full reversal of the artificial sweeteners' effects on glucose metabolism. Next, they transferred the microbiota from mice that consumed artificial sweeteners to 'germ-free' mice – resulting in a complete transmission of the glucose intolerance into the recipient mice. This, in itself, was conclusive proof that changes to the gut bacteria are directly responsible for the harmful effects to their host's metabolism. The group even found that incubating the microbiota outside the body, together with artificial sweeteners, was sufficient to induce glucose intolerance in the sterile mice. A detailed characterization of the microbiota in these mice revealed profound changes to their bacterial populations, including new microbial functions that are known to infer a propensity to obesity, diabetes and complications of these problems in both mice and humans.

Does the human microbiome function in the same way? Elinav and Segal had a means to test this as well. As a first step, they looked at data collected from their Personalized Nutrition Project, the largest human trial to date to look at the connection between nutrition and microbiota. Here, they uncovered a significant association between self-reported consumption of artificial sweeteners, personal configurations of gut bacteria and the propensity for glucose intolerance. They next conducted a controlled experiment, asking a group of volunteers who did not generally eat or drink artificially sweetened foods to consume them for a week and then undergo tests of their glucose levels as well as their gut microbiota compositions.

The findings showed that many – but not all – of the volunteers had begun to develop glucose intolerance after just one week of artificial sweetener consumption. The composition of their gut microbiota explained the difference: The researchers discovered two different populations of human gut bacteria – one that induced glucose intolerance when exposed to the sweeteners, the second that had no effect either way. Elinav believes that certain bacteria in the guts of those who developed glucose intolerance reacted to the chemical sweeteners by secreting substances that then provoked an inflammatory response similar to sugar overdose, promoting changes in the body's ability to utilize sugar.

Segal: "The results of our experiments highlight the importance of personalized medicine and nutrition to our overall health. We believe that an integrated analysis of individualized 'big data' from our genome, microbiome and dietary habits could transform our ability to understand how foods and nutritional supplements affect a person's health and risk of disease."

Elinav: "Our relationship with our own individual mix of gut bacteria is a huge factor in determining how the food we eat affects us. Especially intriguing is the link between use of artificial sweeteners – through the bacteria in our guts – to a tendency to develop the very disorders they were designed to prevent; this calls for reassessment of today's massive, unsupervised consumption of these substances."

According to the Calorie Control Council, the study findings are at odds with leading health organizations and many other peer-reviewed published studies. In contrast to the assertions made by the researchers of this study -- which claim the use of low calorie sweeteners increased diabetes and obesity risk -- the overall evidence from studies on low-calorie sweeteners, including numerous human studies, show that these sweeteners do not have adverse effects on blood glucose control nor lead to an increased risk of obesity.

"The study suffers from small sample sizes, unrealistic sweetener applications and doses, and a dependence largely on rodent research. Findings should be interpreted with caution," said Haley Curtis Stevens, Ph. D. and President of the Calorie Control Council.

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. 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 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.
•    Consumption Levels -- The study was conducted under circumstances not applicable to real life, with consumption levels at many times the typical intake.
•    Sample Size -- With its small sample size in both the mice and human research, the study findings may not be applicable to all populations.
•    Study Period -- The human trial was conducted over too short a period, with results inappropriately extrapolated and generalizations made despite the lack of confirmation from larger, longer studies with a more diverse population.
•    Lack of Evidence -- In the mice study, subjects in the low-calorie sweetener groups did not gain weight, yet researchers concluded that the observed changes in microbiota or blood glucose response were related to obesity.
•    Lack of a Control Group -- In the human study, there was no control group, which affects the generalizability of the results.

Aspartame supplier Ajinomoto responded that: “Allegations about foods and drinks with low calorie sweeteners published in a paper by Suez et al ignore the large body of science which demonstrates that low calorie alternatives help people to control their weight.”

“A thorough review and meta-analysis published by Miller & Perez earlier this year concludes that substituting "LCS (low calorie sweetened) options for the regular calorie versions results in modest weight loss and may be a useful dietary tool to improve compliance with weight-loss and weight management plans."

“Furthermore, an earlier meta-analysis undertaken by de la Hunty, Gibson & Ashwell showed that replacing one regular soft drink per day with a low calorie soft drink sweetened with aspartame will lead to a weight loss of about 11 pounds over the course of a year.”

“Comments throughout the paper by Suez et al suggest that the authors are unfamiliar with the science which supports the safety and benefits of low calorie sweeteners. They also seem to be unaware that different sweeteners are metabolised differently.”

“Aspartame in particular is digested completely to its component parts, all of which occur in much greater quantities in other everyday foods and drinks. Aspartame cannot, therefore, have the adverse effects that Suez et al allege.”

“At a time when overweight and obesity are major challenges to health and to the public purse, scaremongering about safe and beneficial ingredients, which can help people to manage their weight, is not without consequences. Providing publicity for these allegations, and ignoring major reviews of gold-standard randomly controlled trials, like those by Miller & Perez or de la Hunty, Gibson & Ashwell, does the public a disservice,” the statement concluded.

Nature 513, 290 (18 September 2014) doi:10.1038/513290a

Miller & Perez. Low-calorie sweeteners and body weight and composition: a meta-analysis of randomized controlled trials and prospective cohort studies. American Journal of Clinical Nutrition (2014)

de la Hunty, Gibson & Ashwell. A review of the effectiveness of aspartame in helping with weight control. Nutrition Bulletin (2006)