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

You know the feeling. You drink diet soda, enjoying the sweet taste and no guilt. But a new study suggests that these artificial sweeteners may not be as harmless as once thought; they may even increase the risk of diabetes or weight gain.

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. Non-nutritional sweeteners are nutrients that some microbes need to grow. 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 confirmed that non-nutrition sugar sweeteners can disrupt the microbiome of the gut within two weeks. It also suggests that their effects on sugar metabolism may vary from person to person.

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

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.”

Bitter history of artificial sweeteners

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 80 percent of children and more than half of adults consumed low-calorie sweeteners once daily. Low-calorie sweeteners were more commonly used by obese adults.

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 mice were given artificial sweeteners and their gut microbes were collected, their blood glucose levels rose to the point that they were eating artificial sweeteners.

“Some of these non-nutritive sweeteners can be sensed in mice and have an impact on the gut microbes. They have an incredible capacity to metabolize many compounds,” Elinav says. Elinav decided to see if the same could be said for humans. Could altered gut microbes affect 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 followed for a third week. Scientists compared the blood-glucose responses of the volunteers to those who were not given artificial sweetness.

Within 14 days after beginning any of the four tested artificial sweeteners, scientists observed significant differences in the populations of gut bacteria among volunteers. Elinav states that scientists found very distinct changes in gut microbes’ composition and function, as well as the blood molecules they secrete. This suggests that artificial sweeteners can quickly be absorbed by gut microbes.

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. The glucose tolerance was not affected by stevia and aspartame at the tested ingested levels.

” The glycemic reactions that are induced in the gut by saccharin or sucralose may be more severe,” Elinav states.

To confirm that disturbances in microbial populations disrupted glucose levels, scientists gave fecal microbes taken from the stool of human participants to germ free mice. The study showed that microbes from volunteers with high blood sugar levels suppressed glucose control in mice.

” The gut microbes and the molecules that they secrete into our bloodstream are altered in all four nonnutritive sweetener users, Elinav states. “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 cause a disruption in sugar metabolism in some consumers, if not all, depending on the sweeteners they eat and their microbes. Goran states that the study is comprehensive in terms of the microbiome.

“But, this study raises new questions, more so than it answers,” says Dylan Mackay (a Canadian human nutrition specialist at the University of Manitoba and a diabetic). Katz states that the screening of volunteers revealed that they had not been exposed to non-nutritional sweeteners before. This makes it unclear if similar glucose dysregulation could be seen in people who regularly consume these sweeteners. Or if there might be some adaptation. It is not clear if differences observed among individuals could be due 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. Karl Nadolsky, an Endocrinologist at Michigan State University, says that it is reasonable to assume that non-nutritional sweeteners have some physiological impact. “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 you experience when you first start to use these non-nutritional 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. However, the scientists caution that these results should not be taken as a recommendation to consume more sugar in place of non-nutritional sweeteners.

“Sugar consumption is still a serious and well-documented health risk for obesity and diabetes. Our findings do not support or encourage sugar consumption. “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 be