Choosing the diet version of a favorite soda often means consuming non-nutritive sweeteners. These additives provide sweetness without the calories found in sugar. However, some health organizations have begun to raise questions about their possible long-term effects, including whether they may alter energy metabolism and eventually contribute to an increased risk of diabetes or cardiovascular disease.
New research in mice adds to those concerns. The study suggests that sucralose and stevia, two widely used sweeteners, may alter the gut microbiome and gene activity in ways that may affect metabolic health. Some of these biological changes were also observed in later generations.
“We found it intriguing that despite the increasing consumption of these additives, the prevalence of obesity and metabolic disorders such as insulin resistance has not decreased,” said Dr. Francisca Concha Celume of the University of Chile, lead author of the paper in Frontiers in nutrition. “This doesn’t mean that sweeteners are responsible for these trends, but it does raise the question of whether they influence metabolism in ways we don’t yet fully understand.”
Testing Sucralose and Stevia Between Generations
The researchers began by dividing 47 male and female mice into three groups. One group received plain water, while the other two received water containing sucralose or stevia. The doses were designed to resemble amounts a person could reasonably consume as part of a normal diet.
The mice were then bred for two successive generations. Unlike the original animals, both subsequent generations were given only running water.
“Animal models allow us to control environmental conditions very precisely and isolate the effect of a specific factor, such as a dietary compound, and at the same time follow several generations in a relatively short time,” explains Concha.
Tracking blood sugar, gut bacteria, and gene activity
The researchers assessed each generation’s oral glucose tolerance, a measure used to assess how well the body handles glucose and identify signs of insulin resistance, which is an important warning sign for diabetes.
They also collected fecal samples to examine changes in the gut microbiome and measure concentrations of short-chain fatty acids. These compounds are produced by intestinal bacteria and can influence biological processes related to genetic regulation. Therefore, changes in their levels could indicate epigenetic effects that can be transmitted from parents to children.
Scientists believe that sweeteners may alter the production of short-chain fatty acids by disrupting the normal function of the gut microbiome. These alterations could ultimately influence gene expression.
The team also measured the activity of five genes in the liver and intestines. Genes are involved in inflammation, intestinal barrier integrity, and metabolism. By examining them, the researchers hoped to identify possible epigenetic changes related to gut function, inflammation and metabolic health that could help explain some of the supposed negative effects of non-nutritive sweeteners.
Sucralose and stevia produced different effects
The two sweeteners did not affect the mice in exactly the same way, and their effects also changed between generations.
Among first-generation offspring, signs of glucose intolerance appeared only in males descended from mice that consumed sucralose. In the second generation, the researchers found elevated fasting blood sugar levels in male offspring of the sucralose group and female offspring of the stevia group.
Mice that consumed either sweetener also developed more diverse fecal microbiomes, but had lower levels of short-chain fatty acids. That pattern suggests that their gut bacteria were producing fewer beneficial metabolites. Reduced concentrations of short-chain fatty acids were also found in the two subsequent generations.
The effects associated with sucralose were stronger and more persistent. Mice exposed to sucralose showed greater changes in the composition of their fecal microbiomes, including greater numbers of potentially pathogenic bacteria and fewer beneficial species.
Sucralose changes persisted longer
Sucralose also appeared to increase the activity of genes related to inflammation while reducing the activity of genes associated with metabolism. Those effects were still detectable two generations after the original exposure.
Stevia also altered gene expression, but the changes were weaker and did not persist beyond one generation.
“When we compared generations, these effects were generally stronger in the first generation and tended to decrease in the second generation,” Concha said. “Overall, the effects related to sucralose were more consistent and persistent across generations.”
“The changes we observed in glucose tolerance and gene expression could be interpreted as early biological signals related to metabolic or inflammatory processes,” says Concha. “For example, the animals did not develop diabetes. Instead, what we observed were subtle changes in the way the body regulates glucose and in the activity of genes associated with inflammation and metabolic regulation. It is possible that such changes could increase susceptibility to metabolic alterations under certain conditions, such as a high-fat diet.”
What the mouse study shows and what it doesn’t show
The researchers caution that the findings show associations between exposure to sweeteners and changes in metabolic health, but do not prove that sweeteners directly caused all of the observed effects.
The results also come from mice, meaning that the biological response to non-nutritive sweeteners may differ in humans.
“The objective of this investigation is not to create alarm, but to highlight the need to continue investigating,” said Concha. “It may be reasonable to consider moderation in the consumption of these additives and continue studying their long-term biological effects.”