Artificial Sweeteners Leave a Multigenerational Mark on the Gut and Genes

A high-sugar diet can resemble a rollercoaster ride, marked by spikes in metabolic stress and inflammation alongside dips in beneficial short chain fatty acids (SCFAs). Although non-nutritive sweeteners (NNSs) were developed as sugar substitutes, it remains unclear whether they replicate sugar’s effects or pose their own risks.

“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 Francisca Concha Celume, a biological anthropologist from the University of Chile, in a statement.

In particular, she and her colleagues wanted to know whether there are generational consequences to an artificially sweet treat. To do so, the team compared the effect of parental sucralose and stevia consumption in mice.

Their findings, published in Frontiers in Nutrition, demonstrated that the two sweeteners increased expression of genes linked to metabolism and inflammation as well as lowered SCFA concentrations in both parents and offspring.¹ However, sucralose’s effects were more persistent across generations. “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,” said Concha Celume.

First, the researchers divided mice into three groups, each of which received either plain water or water with a dose of sucralose or stevia for 16 weeks. The dose was comparable to the amount a human would consume as part of a normal diet. The parental F0 mice were then bred to produce the F1 generation, and the F1 mice were bred to produce the F2 generation. The F1 and F2 animals did not receive either NNS.

Across the three generations, the team assessed changes in blood glucose, gene expression related to gut inflammation and metabolism, microbiome composition, and SCFA concentration. They observed different effects between the two sweeteners which also shifted over time.

Within the F0 generation, the animals did not exhibit significant changes to overall oral glucose tolerance. However, the glycemic response was mildly altered in the F1 and F2 male mice in the sucralose group.

Compared to the control animals, mice from the F0 sucralose and stevia groups had lower SCFA concentrations; this was then passed onto their F1 and F2 generations. This pattern was similarly reflected in altered microbial diversity among the two sweetener groups.

Then, the researchers assessed the gene expression related to gut inflammation and metabolism from the liver and/or intestinal tissues by focusing on genes encoding sterol regulatory element-binding protein 1 (Srebp1), toll-like receptor-4 (Tlr4), tumor necrosis factor (Tnf), and zonula occludens 1.

They found that in the F0 and F1 sucralose group, Tlr4 and Tnf were overexpressed in the intestine, while Srebp1 expression decreased in the liver of the F0; this change persisted in their descendants. Stevia also affected gene expression to a lesser degree, but the effect was not passed on for more than one generation.

Based on these observations, the offspring of mice who never ate the artificial sweeteners still acquired their negative effects. Concha Celume noted, “It may be reasonable to consider moderation in the consumption of these additives and to continue studying their long-term biological effects.”