Artificial sweeteners may lead to diabetes too, study
Particular gut bacteria may induce metabolic changes that contribute to obesity and diabetes following exposure to artificial sweeteners, according to a new study from the Weizmann Institute in Israel.
The research, published on 17 September 2014 in the journal Nature, found that artificial sweeteners, which have been promoted as aids to weight loss and diabetes prevention, could actually hasten the development of glucose intolerance and metabolic disease. According to the researchers, experiments in mice and humans showed artificial sweeteners do this by changing the composition and function of the gut microbiota – the substantial population of bacteria residing in our intestines.
Dr Eran Elinav of the Weizmann Institute’s Immunology Department, who led this research together with Professor Eran Segal of Computer Science and Applied Mathematics Department, said, among other things, 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.
Confusion around non-caloric artificial sweeteners
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 Dr Elinav’s lab, who led the study, collaborated with graduate students Tal Korem and David Zeevi in Professor Segal’s lab and Gili Zilberman-Shapira in Dr 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 utilise 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. The researchers said this, in itself, was conclusive proof that changes to the gut bacteria were directly responsible for the harmful effects to their host’s metabolism.
The research group also found that incubating the microbiota outside the body, together with artificial sweeteners, was sufficient to induce glucose intolerance in the sterile mice. A detailed characterisation 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.
Study in humans
Dr Elinav and Professor Segal also tested whether the human microbiome functioned in the same way.
As a first step, they looked at data collected from their Personalized Nutrition Project (www.personalnutrition.org), 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.
Next, they 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.
Dr Elinav said she believed 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 utilise sugar.
“Our relationship with our own individual mix of gut bacteria is a huge factor in determining how the food we eat affects us,” Dr Elinav said. “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,” she said.
Professor Segal said the results of the experiment highlighted the importance of “personalised medicine and nutrition” for a person’s 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,” Professor Segal said.
Also participating in this research were Christoph A. Thaiss, Ori Maza, and Dr. Hagit Shapiro of Elinav’s group; Dr. Adina Weinberger of Segal’s group; Dr. Ilana Kolodkin-Gal of the Molecular Genetics Department; Prof. Alon Harmelin and Dr. Yael Kuperman of the Veterinary Resources Department; Dr. Shlomit Gilad of the Nancy and Stephen Grand Israel National Center for Personalized Medicine; Prof. Zamir Halperin and Dr. Niv Zmora of Tel Aviv Sourasky Medical Center and Tel Aviv University; and Dr. David Israeli of Kfar Shaul Hospital Jerusalem Center for Mental Health.
Dr Elinav is the Incumbent of the Rina Gudinski Career Development Chair. Dr Eran Elinav’s research is supported by the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Benoziyo Endowment Fund for the Advancement of Science; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; Yael and Rami Ungar, Israel; the Crown Endowment Fund for Immunological Research; John L. and Vera Schwartz, Pacific Palisades, CA; the Rising Tide Foundation; Alan Markovitz, Canada; Cynthia Adelson, Canada; the estate of Jack Gitlitz; the estate of Lydia Hershkovich; the European Research Council; the CNRS – Centre National de la Recherche Scientifique; the estate of Samuel and Alwyn J. Weber; and Mr. and Mrs. Donald L. Schwarz, Sherman Oaks, CA.
Professor Eran Segal’s research is supported by the Kahn Family Research Center for Systems Biology of the Human Cell; the Carolito Stiftung; the Cecil and Hilda Lewis Charitable Trust; the European Research Council; and Mr. and Mrs. Donald L. Schwarz, Sherman Oaks, CA.
Experts say study results should be “viewed cautiously”
The results of the study — particularly the human study — have been met with mixed reactions from experts.
Professor Sir Stephen O’Rahilly FRS, Professor of Clinical Biochemistry and Medicine at the University of Cambridge, said the evidence that the intake of sugared beverages contributes to recent increases in obesity is strong and growing.
“Recent randomised controlled trials in children have shown that substituting artificially sweetened fizzy drinks for sugared drinks reduces the risks of becoming overweight,” Professor O’Rahilly said. “This is the background against which the current study needs to be viewed,” he said.
Professor O’Rahilly said that while the study of mice was an “invaluable part of medical research” it was always difficult to know if the same disease mechanisms were at play in humans.
“The part of this report which reports effects in humans is not compelling as it is seriously underpowered,” Professor O’Rahilly said. “The authors report an association between artificially sweetened beverages and markers of diabetes in 381 people; however, a recent study involving more than a third of a million people showed no association between consumption of artificially sweetened drinks and the development of diabetes,” he said.
Professor O’Rahilly said the results must be viewed “very cautiously”.
Dr Nita Forouhi, Programme Leader at the MRC Epidemiology Unit, University of Cambridge, said that the findings in humans suggested that non-caloric sweeteners were not a “magic bullet” to help with obesity and diabetes, but that the results in humans were currently inconclusive.
“The findings point to the importance and relevance of investing in future better designed specific research in humans, but until then we are not ready to adopt a change in current advice,” Dr Forouhi said.