Low-calorie sweeteners might not be as good for us as we thought

Artificial sweeteners, from mice to humans

For more than a decade, Elinav has been interested in uncovering the links between nutrition, gut microbes, and the risk of developing common diseases, such as obesity and diabetes, with the hope of devising microbiome-based personalised medicine.

In 2014, Elinav and colleagues found that saccharin, sucralose, and aspartame each raised blood glucose of mice to levels that were significantly higher than those of mice that were fed sugar.

When gut microbes collected from mice fed with artificial sweeteners were administered to mice that had no gut bacteria of their own and had never been given artificial sweeteners, their blood-glucose levels shot-up as if they were consuming artificial sweeteners themselves.

“In mice, some of these non-nutritive sweeteners are sensed, and they impact the gut microbes, which have an amazing capacity to metabolise many of these compounds,” Elinav says. He decided to test whether the same held true in humans: Could altered gut microbes disturb the glucose metabolism?

Elinav’s team first screened 1,375 volunteers for any consumption of zero-calorie sweeteners in their daily lives. They identified 120 adults not previously exposed and gave them one of the four commonly used sweeteners—saccharin, sucralose, aspartame, and stevia for two weeks. The volunteers were then monitored for a third week. Scientists compared their blood-glucose responses against those who were not given artificial sweeteners.

Within 14 days after beginning any of the four tested artificial sweeteners, scientists observed significant differences in the populations of gut bacteria among volunteers. “We identified very distinct changes in the composition and function of gut microbes, and the molecules they secret in blood,” Elinav says. This suggests that gut microbes rapidly respond to artificial sweeteners.

To test how artificial sweeteners affect the body’s ability to control the surges in blood sugar after consuming sugar as part of meals, volunteers were monitored for blood glucose levels after a test glucose drink. Normally, blood glucose levels should peak in 15 to 30 minutes and then return to normal within two to three hours. If the glucose levels remain elevated, it signals that the body isn’t processing and storing excess glucose properly, a phenomenon known as glucose intolerance.

In the Israeli study, sucralose and saccharin pushed the body towards glucose intolerance, which if sustained can cause weight gain and diabetes. Aspartame and stevia did not affect the glucose tolerance at the tested ingested levels.

“The glycemic responses that are induced by saccharin and sucralose, possibly by the gut microbiome, may be more pronounced,” Elinav says.

To confirm that disturbance in microbial populations disrupted blood glucose levels, scientists administered faecal microbes from stool of human participants to germ-free mice. The study found that microbes from the volunteers with elevated blood sugar levels also suppressed glucose control in the mice.

“The gut microbes, and the molecules they secrete into our bloodstream, are very altered in all four non-nutritive sweetener consumers,” Elinav says. “Each of the groups responded in a unique way.”

Although, the study didn’t follow the volunteers long term, the study is the first to show that the human microbiome responds to non-nutritive sweeteners in a highly individual manner. This can disrupt sugar metabolism in some, if not all consumers, depending on their microbes and the sweeteners they consume. “This study is very comprehensive in terms of the microbiome,” Goran says.

“But this study creates new questions, more than it answered,” says Dylan Mackay, a human nutrition specialist at University of Manitoba in Canada and a diabetic. Since volunteers were screened to be free of prior exposure to non-nutritional sweeteners, it is unclear whether similar glucose dysregulation would be seen in people who routinely consume such sweeteners or whether there might be some degree of adaptation, Katz says. It is also unclear whether differences observed among individuals could be due to genetic, epigenetic, or lifestyle factors.

Should we switch to eating more sugar?

Some scientists think that changes in the gut microbiome after a short exposure to non-nutritional sweeteners are not sufficient to cause alarm. “It is reasonable to consider the variety of non-nutritional sugars of having some sort of impact physiologically,” says Karl Nadolsky, an endocrinologist at Michigan State University. “But projecting that to clinical outcomes and concerns is a very big jump.”

“We don’t know anything about the durability of these results yet,” says Mackay. “Could this be something that happens when you are first exposed to these non-nutritiional sweeteners? Does it continue forever?”

The study authors themselves caution that studying long term exposure to different artificial sweeteners might be required to fully assess the potential health effects due to altered microbiomes. But the scientists also stress that their results should not be interpreted as a call to consume more sugar as an alternative to non-nutritional sweeteners.

“On one hand, sugar consumption still constitutes a very bad and well-proven health risk for obesity, diabetes, and other health implications, and our findings do not support or promote the consumption of sugar,” Elinav says. “But on the other hand, these impacts from sweeteners that we show means a healthy caution should be advised.”

This study provides fairly decisive evidence of both short-term harmful effects and of mechanisms that might cause the same adverse effects in the long term, Katz says. “That does not mean non-nutritional sweeteners should be replaced with sugar, but rather that alternative approaches to reducing sugar intake should be prioritised.”

“We need better solutions to our sweet-tooth craving,” Elinav says. “To me personally, drinking only water is the best.”

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