When you choose a diet version of your favorite fizzy drink, you consume non-nutritive sweeteners, which taste sweet but — unlike sugar — contain no calories. But health organizations are starting to raise concerns about the potential long-term impacts of these sweeteners, suggesting they could interfere with energy metabolism and increase the eventual risk of diabetes or cardiovascular disease. Now a new study in mice indicates that the popular sweeteners sucralose and stevia have negative effects on the gut microbiome and gene expression, potentially compromising metabolic health, which can be transmitted between 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."
Sugar by any other name?
The scientists started by splitting 47 male and female mice into three groups, each of which received either plain water or water with a dose of sucralose or stevia, comparable to the amount a human might consume as part of a normal diet. These groups of mice were then bred for two consecutive generations, both of which received 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.
Each generation received a test for glucose oral tolerance, which tests insulin resistance — a warning sign for diabetes. The researchers also took fecal samples to look for changes in the gut microbiome and the concentration of short-chain fatty acids, which could signal epigenetic changes, transmissible from parents to children: sweeteners are thought to affect short-chain fatty acids by compromising the function of the gut microbiome, which can ultimately alter gene expression.
The scientists also looked at the expression of five genes involved with inflammation, gut barrier function, and metabolism in the liver and intestines. These were chosen to provide a snapshot of potential epigenetic influences on the gut, inflammatory, and metabolic factors which could be responsible for the negative health impacts of non-nutritive sweeteners.
A tale of two sweeteners
The scientists found that different sweeteners produced different effects, which changed over time. In the first generation, only the male offspring of sucralose-consuming mice showed signs of impaired glucose tolerance, but by the second generation, elevated fasting blood sugar was detected in male descendants of sucralose-consuming mice and female descendants of stevia-consuming mice.
Both groups of mice that ate sweeteners had more diverse fecal microbiomes but lower concentrations of short-chain fatty acids, suggesting the bacteria were producing fewer beneficial metabolites; both succeeding generations also had lower concentrations of short-chain fatty acids. Sucralose-consuming mice were more seriously and more persistently affected by changes to the fecal microbiome, with more pathogenic species and fewer beneficial species of bacteria in their feces.
Similarly, sucralose appears to kick-start the expression of genes linked to inflammation and dampen the expression of genes linked to metabolism for two generations after consumption. Stevia also impacts gene expression, but its effects are smaller and are not passed on for more than 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."
But the team emphasizes that while this research identifies associations between different health status changes, it doesn't establish causation. Additionally, the impact of non-nutritive sweeteners on mice will not exactly reflect their impact on 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."
