Scientists have long suspected a link between artificial sweeteners and obesity in humans, but until now that connection had only been shown in lab mice. Now, in a first of its kind trial, scientists in Israel have tested these chemicals in humans. Their results show that artificial sweeteners not only disturb the microbes living in the guts of humans—which are critical for supplying essential nutrients, synthesizing vitamin K, and digesting dietary fibers among other things—but some may impact how quickly the body removes sugar from the blood after a meal. The longer glucose stays in the blood, the greater the risk of diabetes, cardiovascular disease, and chronic kidney disease.

“They are used with the hope of giving us the sweet taste without having to pay the caloric price,” says Eran Elinav an immunologist at Weizmann Institute of Science in Israel, who led the latest study. “But non-nutritive sweeteners are not inert in humans.”

Every human hosts a unique bouquet of microbes—bacteria, viruses, and fungi—that live naturally in and on our bodies; in the intestine, nose, mouth and on the skin and eye. The number of cells that make up this vast microbial community is approximately equal the number of cells in human body. This community, called microbiome, is seeded at birth, and not only helps digestion but also protects against pathogens and supports the immune system.

The disruption to the microbiome occurs because non-nutritional sweeteners, although zero or low calorie for humans, serve as nutrients for some microbes, which then proliferate. This causes an imbalance in microbial populations that can cause chronic intestinal inflammation or colon cancer.

“They’re designed to be calorie free for us, but not for our gut microbes, which can still thrive on them,” says Michael Goran, a professor of pediatrics and program director for Nutrition and Obesity at Children’s Hospital Los Angeles.

The Israeli study confirms that non-nutrition sweeteners can disrupt the gut microbiome within two weeks of exposure and suggest their effects on sugar metabolism can vary from person to person.

“It’s a convincing study to show how these sweeteners really are affecting the human body. And, also, they have similar effects, despite being different types of compounds,” Goran says.

David Katz, a nutrition specialist, and the founder of Yale University’s Yale-Griffin Prevention Research Center, agrees. “This is an elegant, elaborate, and powerful study which establishes decisively that non-nutritional sweeteners impair glucose metabolism by causing specific damage to the microbiome.”

Our innate taste for sweet edibles, and avoidance of bitter substances, is an evolutionary adaptation that drove us to high-energy foods at a time when nutritious foods were scarce. Natural sugars, such as glucose, fructose, cane, or milk sugars, are digested to produce energy—measured in calories—that helps our organs function. Non-nutritional sweeteners, which can be hundreds to thousands of times sweeter than cane sugar, are generally not metabolized by the human body, which is why they provide no or few calories.

Saccharin, the first commercialized non-nutritive sweetener, was discovered serendipitously in 1879 in coal-tar derivatives at Johns Hopkins University. Thanks to President Theodore Roosevelt, who thought that this artificial sugar was a guilt-free way to lose weight, saccharin dodged a ban by the nascent U.S. Food and Drug Administration. In 1977, when the FDA tried again to ban saccharin because of the suspected risk of causing cancer in rats, Americans fought back. They sent millions of letters to Congress, the FDA, and President Jimmy Carter protesting the proposed ban.

Ultimately, only a cancer warning label was required on products containing saccharin. But this was dropped too in 2000 when scientists found that humans metabolize saccharin differently from rats, and it didn’t pose a cancer risk for humans.

Low or zero calorie sugar substitutes are in thousands of beverages and foods worldwide and generated $21.3 billion in 2021. This number is expected to rise as demand for these sweeteners—particularly in low- and middle-income countries—continues to expand. In the United States, a 2017 nationwide nutritional survey found a quarter of children and 41.4 percent of adults consumed some low-calorie sweeteners once daily. Obese adults used low-calorie sweeteners more frequently.

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 personalized 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 metabolize 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.

“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 fecal 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.”

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 prioritized.”

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