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, with the hope of designing personalized medicine based on microbiomes.
In 2014, Elinav and her colleagues found that saccharin, sucralose, and aspartame raised the mice’s blood glucose to levels significantly higher than those of sugar-fed mice.
When gut microbes harvested 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 spiked as if they were consuming artificial sweeteners.
“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 altered gut microbes alter glucose metabolism?
Elinav’s team first evaluated 1,375 volunteers for any consumption of no-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 then monitored for a third week. The scientists compared their blood glucose responses with those of those who received no artificial sweeteners.
Within 14 days of starting any of the four artificial sweeteners tested, the scientists observed significant differences in gut bacteria populations 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 test glucose drink. Normally, blood glucose levels should peak in 15 to 30 minutes and then return to normal in two to three hours. If glucose levels remain elevated, it indicates that the body is not properly processing and storing excess glucose, a phenomenon known as glucose intolerant.
In the Israeli study, sucralose and saccharin pushed the body into glucose intolerance, which if maintained may cause weight gain and diabetes. Aspartame and stevia did not affect glucose tolerance at the ingested levels tested.
“The glycemic responses induced by saccharin and sucralose, possibly by the gut microbiome, may be more pronounced,” says Elinav.
To confirm that disturbance in 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 microbes from volunteers with elevated blood sugar levels also suppressed glucose control in the mice.
“Gut microbes and the molecules they secrete into our bloodstream are highly altered in all four non-nutritive sweetener consumers,” says Elinav. “Each of the groups responded in a unique way.”
Although the study did not follow volunteers long-term, it is the first to show that the human microbiome responds to non-nutritive sweeteners in a very individual way. 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 raises new questions, more than it answers,” says Dylan Mackay, a human nutrition specialist at the University of Manitoba in Canada and a diabetic. Since the volunteers were tested to have no prior exposure to non-nutritional sweeteners, it’s not clear if similar glucose dysregulation would be seen in people who habitually consume such sweeteners or if there might be some degree of adaptation, says Katz. 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 believe that changes in the gut microbiome after brief exposure to non-nutritional sweeteners are not enough to raise alarm. “It’s reasonable to consider the variety of non-nutritional sugars to have some sort of physiological impact,” says Karl Nadolsky, an endocrinologist at Michigan State University. “But projecting that onto clinical outcomes and concerns is a pretty big jump.”
“We still don’t know anything about the durability of these results,” says Mackay. “Could it be something that happens when you are first exposed to these non-nutritional 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 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 the 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 sugar consumption,” says Elinav. “But on the other hand, these impacts of sweeteners that we show mean that a healthy precaution should be advised.”
This study provides fairly compelling evidence for both short-term harmful effects and mechanisms that could cause the same long-term adverse effects, says Katz. “That does not mean that non-nutritional sweeteners should be replaced by sugar, but rather that alternative approaches to reduce sugar consumption should be prioritized.”
“We need better solutions for our sweet tooth,” says Elinav. “For me personally, drinking only water is the best.”
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