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 raising questions about their possible long-term effects, including whether they may disrupt energy metabolism and eventually contribute to a higher 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, can 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 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 began by dividing 47 male and female mice into three groups. One group received plain water, while the other two received water containing either sucralose or stevia. The doses were designed to resemble amounts that a person might reasonably consume as part of a normal diet.
The mice were then bred for two successive generations. Unlike the original animals, both later generations were given 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,” explained Concha.
Tracking Blood Sugar, Gut Bacteria, and Gene Activity
Researchers tested each generation for oral glucose tolerance, a measure used to evaluate how effectively 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 gut bacteria and can influence biological processes related to gene regulation. Changes in their levels could therefore point to epigenetic effects that may be transmitted from parents to offspring.
Scientists think sweeteners may alter short-chain fatty acid production by disrupting normal gut microbiome function. Those disruptions could ultimately influence gene expression.
The team also measured the activity of five genes in the liver and intestines. The genes are involved in inflammation, the integrity of the gut barrier, and metabolism. By examining them, researchers hoped to identify possible epigenetic changes connected with gut function, inflammation, and metabolic health that could help explain some of the suspected 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 shifted between generations.
Among first-generation offspring, signs of impaired glucose tolerance appeared only in males descended from mice that consumed sucralose. By the second generation, researchers found elevated fasting blood sugar in male descendants of the sucralose group and female descendants of the stevia group.
Mice that consumed either sweetener also developed more diverse fecal microbiomes, but they had lower levels of short-chain fatty acids. That pattern suggests their gut bacteria were producing fewer beneficial metabolites. Reduced short-chain fatty acid concentrations were also found in both subsequent generations.
The effects associated with sucralose were stronger and more persistent. Mice exposed to sucralose showed larger 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 linked 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 strongest in the first generation and tended to decrease in the second generation,” said Concha. “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,” said Concha. “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 caution that the findings show associations between sweetener exposure and changes in metabolic health, but they do not prove that the sweeteners directly caused all of the observed effects.
The results also come from mice, meaning the biological response to non-nutritive sweeteners may differ in humans.
“The goal of this research is not to create alarm, but to highlight the need for further investigation,” said Concha. “It may be reasonable to consider moderation in the consumption of these additives and to continue studying their long-term biological effects.”
