Sugar substitutes may have unexpected effects on the human body

Some non-caloric sweeteners may actually contribute to the changes in sugar metabolism that they are supposed to prevent. (Credit: iStock photo)


Non-caloric sweeteners, also known as sugar substitutes or artificial sweeteners, are supposed to provide all the sweetness of sugar without the calories. But a controlled study by researchers at the Weizmann Institute of Science, published today in the journal Cell, suggests that, contrary to preconceived notions, such sweeteners are not inert.

They really affect the human body. In fact, some of them can change consumer microbiomes — the trillions of microbes that live in our gut — in ways that can change a person’s blood sugar levels. And the effects that these sweeteners produce vary greatly from person to person.

In 2014, a Weizmann Institute study in mice showed that some non-caloric sweeteners may actually contribute to the changes in sugar metabolism that they are supposed to prevent. In the new trial, a team of researchers led by Professor Eran Elinav from Weizmann’s Department of Systemic Immunology tested nearly 1,400 potential participants, selecting 120 who strictly avoided any artificially sweetened foods or drinks.

The volunteers were then divided into six groups. Participants in four groups were given sachets of common non-caloric sweeteners below the daily allowance, one sweetener per group: saccharin, sucralose, aspartame, or stevia. The other two groups served as controls.

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The study was led by Dr. Jotam Suez, a former Elinawa graduate student and now principal investigator at the Johns Hopkins University School of Medicine, and Yotam Cohen, a graduate student in the Elinawa Laboratory; it was conducted in collaboration with Prof. Eran Segal from the Weizmann Departments of Computer Science, Applied Mathematics, and Molecular Cell Biology.

The researchers found that two weeks of eating all four sweeteners altered the composition and function of the microbiome and the small molecules that gut microbes release into people’s blood—each sweetener in a different way. They also found that two sweeteners, saccharin and sucralose, significantly altered glucose tolerance, that is, correct glucose metabolism, in the recipients. Such changes, in turn, may contribute to metabolic diseases. In contrast, no changes were found in either the microbiome or glucose tolerance in the two control groups.

Changes induced by sweeteners in gut microbes correlated closely with changes in glucose tolerance. “These results support the notion of the microbiome as a node that integrates signals from the human body’s own systems and from external factors such as the food we eat, the medications we take, our lifestyle and the physical environment,” says Elinav.

To test whether changes in the microbiome are indeed responsible for impaired glucose tolerance, the researchers transplanted gut microbes from more than 40 study participants into groups of sterile mice that had never consumed non-caloric sweeteners.

In each experimental group, grafts were collected from several “best responders” (trial participants with the greatest changes in glucose tolerance) and several “bottom responders” (participants with the least changes in glucose tolerance).

Changes in the composition and function of gut microbes were observed in all four groups of study participants who consumed non-caloric sweeteners. Each group consumed one of the following foods: saccharin, sucralose, stevia, or aspartame. The chart shows the increase in glucose levels in the saccharin and sucralose groups (left two graphs) compared to the stevia and aspartame groups (center) and two control groups (right). (CREDIT: Weizmann Institute of Science)

Strikingly, the recipient mice exhibited patterns of glucose tolerance that largely mirrored those of human donors. Mice that received microbiomes from “upper responders” had the most pronounced changes in glucose tolerance compared with mice that received microbiomes from “lower responders” and human controls.

In subsequent experiments, the researchers determined how different sweeteners affect the abundance of certain types of gut bacteria, their functions, and the small molecules they release into the bloodstream.

“Our study showed that non-caloric sweeteners can disrupt the glucose response by altering our microbiome, and they do so in a very personalized way, that is, affecting each person in a unique way,” says Elinav. “In fact, this variability is to be expected due to the unique composition of each individual’s microbiome.”

Elinav adds: “The implications of the changes that non-nutritive sweeteners can cause in humans remain to be determined and merit more long-term research. At the same time, it is important to emphasize that our results do not in any way imply that sugar consumption, which is detrimental to human health, is superior to non-caloric sweeteners in many studies.”

The study involved Dr. Rafael Valdez-Mas, Uria Mor, Dr. Malli Dori-Bachash, Dr. Sarah Federici, Dr. Niv Zmora, Dr. Avner Leshem, Dr. Melina Heinemann, Raquel Linewski, Maya Zur, Rotem Ben-Zeev. Brik, Aurelie Bookimer, Shimrit Eliyahu Miller, Alona Metz, Ruthie Fishbein, Olga Sharova, and Dr. Hagit Shapiro from the Elinava Laboratory; Dr. Sergey Malitsky and Maxim Itkin from the Weizmann Life Sciences Assets Department; Dr. Noah Stettner and Prof. Alon Harmelin from Weizmann Veterinary Resources; and Dr. Christoph C. Stein-Theringer, Department of Microbiome and Cancer, German Cancer Research Center (DKFZ).

To learn more about science and technology, visit our New Discoveries section at The bright side of the news.

Note. Materials provided above by the Weizmann Institute of Science. Content can be edited for style and length.

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