Choosing diet drinks or low-calorie foods often means turning to sucralose and stevia. These non-nutritive sweeteners deliver sweetness without sugar’s calories. Some health authorities, including the U.S. Food and Drug Administration, have raised questions about their long-term impacts, including whether they may affect energy metabolism and, over time, raise the risk of diabetes or cardiovascular disease.
New research in mice adds to those concerns. The study indicates that sucralose and stevia can shift the gut microbiome and gene activity in ways that may influence metabolic health. Several of these biological changes appeared in subsequent generations as well.
“We found it intriguing that despite the growing consumption of these additives, the prevalence of obesity and metabolic disorders such as insulin resistance has not declined,” said Dr. Francisca Concha Celume of the Universidad de Chile, lead author of the article in Frontiers in Nutrition. “This does not mean that sweeteners are responsible for these trends, but it raises the question of whether they influence metabolism in ways we do not yet fully understand.”
Testing sucralose and stevia across generations
Researchers divided 47 male and female mice into three groups. One group received plain water, while the others received water containing either sucralose or stevia. The doses were selected to mirror amounts a person might reasonably consume in a typical diet.
The animals were then bred for two successive generations. Unlike the original mice, both later generations received only plain water.
“Animal models allow us to control environmental conditions very precisely and to isolate the effect of a specific factor, such as a dietary compound, while also following several generations within a relatively short time,” Concha said.
Tracking blood sugar, gut bacteria, and gene activity
Each generation underwent oral glucose tolerance testing to assess how effectively the body processes glucose and to look for signs of insulin resistance, a key early indicator of diabetes risk.
Researchers collected fecal samples to analyze changes in the gut microbiome and to measure concentrations of short-chain fatty acids. These bacterial metabolites can affect biological processes tied to gene regulation. Shifts in their levels may signal epigenetic effects that can be passed from parents to offspring.
Scientists hypothesize that sweeteners may disrupt normal microbiome function, altering short-chain fatty acid production and, in turn, gene expression.
The team also measured activity for five genes in the liver and intestines that are involved in inflammation, gut barrier integrity, and metabolism. The goal was to identify possible epigenetic changes related to gut function, inflammation, and metabolic health that could help explain suspected adverse effects of non-nutritive sweeteners.
Sucralose and stevia produced different effects
The two sweeteners did not affect the mice in identical ways, and the effects varied across generations.
In the first generation of offspring, impaired glucose tolerance appeared only in males descended from mice that consumed sucralose. By the second generation, researchers observed elevated fasting blood sugar in male descendants of the sucralose group and in female descendants of the stevia group.
Mice exposed to either sweetener developed more diverse fecal microbiomes but showed lower levels of short-chain fatty acids, suggesting reduced production of beneficial metabolites. Reduced short-chain fatty acid levels also appeared in both subsequent generations.
Associations linked to sucralose were stronger and more persistent. Mice exposed to sucralose showed larger shifts in fecal microbiome composition, including more potentially pathogenic bacteria and fewer beneficial species. These findings echo broader evidence that common medications can alter the gut microbiome for years.
Sucralose changes persisted longer
Sucralose exposure appeared to increase the activity of genes tied to inflammation while decreasing activity of genes involved in metabolism. These signals were still detectable two generations after the initial exposure.
Stevia also influenced gene expression, but the changes were weaker and did not continue beyond one generation.
“When we compared generations, these effects were generally strongest in the first generation and tended to decrease in the second generation,” Concha said. “Overall, the effects linked 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,” Concha added. “For example, the animals did not develop diabetes. Instead, what we observed were subtle changes in how 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 disturbances under certain conditions, such as a high-fat diet.”
What the mouse study does and does not show
The researchers cautioned that the findings show associations between sweetener exposure and shifts in metabolic health markers, but they do not prove the sweeteners directly caused all observed effects.
The results derive from mice, which means human biological responses to non-nutritive sweeteners may differ.
“The goal of this research is not to create alarm, but to highlight the need for further investigation,” Concha said. “It may be reasonable to consider moderation in the consumption of these additives and to continue studying their long-term biological effects.” For current guidance, readers can consult dietary recommendations from the World Health Organization.