Low-calorie sweeteners may 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 discovering the links between nutrition, gut microbes and the risk of developing common diseases, such as obesity and diabetes, in the hope of developing personalized medicine based on in the microbiome.

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

When gut microbes collected from mice fed artificial sweeteners were given to mice that had no gut bacteria of their own and had never received 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 detected and affect gut microbes, which have an amazing ability to metabolize many of these compounds,” says Elinav. He decided to test whether the same was true in humans: could altering gut microbes disrupt glucose metabolism?

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

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

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

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

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

To confirm that disrupting microbial populations altered blood glucose levels, the scientists administered fecal microbes from the feces of human participants to germ-free mice. The study found that the microbes in the volunteers with high blood sugar levels also suppressed glucose control in the mice.

“Gut microbes and the molecules they secrete into our bloodstream are greatly altered in all four consumers of non-nutritive sweeteners,” says Elinav. “Each group responded in a unique way.”

Although the study did not 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 alter 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,” says Goran.

“But this study creates new questions, more than it answered,” says Dylan Mackay, a human nutrition specialist at the University of Manitoba in Canada and a diabetic. Since the volunteers were found to have no prior exposure to nonnutritive sweeteners, it’s unclear whether a similar dysregulation of glucose would be seen in people who regularly consume these sweeteners, or whether there might be some degree of adaptation, Katz says. It is also unclear whether the observed differences between 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 brief exposure to non-nutritive sweeteners are not enough to cause alarm. “It’s reasonable to consider the variety of non-nutritive sugars that have some sort of physiological impact,” says Karl Nadolsky, an endocrinologist at Michigan State University. “But projecting that to clinical outcomes and concerns is a very big leap.”

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

The study authors themselves caution that long-term exposure to different artificial sweeteners may need to be studied 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-nutritive sweeteners.

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

This study provides fairly conclusive evidence of both the short-term harmful effects and the mechanisms that can cause the same long-term adverse effects, Katz says. “This does not mean that non-nutritive sweeteners should be substituted for sugar, but that alternative approaches to reducing sugar intake should be prioritized.”

“We need better solutions to our craving for sweets,” says Elinav. “For me personally, drinking only water is the best.”

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