Non-nutritive sweeteners, including aspartame, saccharin, acesulfame K, stevia, sucralose, and cyclamate, are widely used as alternatives to sugar due to their low or zero calorie content. Their consumption has increased significantly across all age groups, including among women of childbearing age, often as part of weight management or diabetes control strategies.

However, growing evidence suggests that these substitutes may not be metabolically inert. High-sugar diets are already known to contribute to adiposity, hyperinsulinemia, and impaired glucose tolerance, increasing the risk of noncommunicable diseases. In contrast, NNS have been promoted as healthier alternatives, but their long-term biological effects remain debated.

According to a survey conducted by LocalCircles following warnings by the World Health Organisation (WHO) regarding aspartame, about 38% of surveyed urban Indians reported consuming artificial sweeteners at least once a month. At the same time, WHO guidelines caution that long-term use of NNS may be associated with adverse outcomes, including a higher risk of cardiovascular diseases and diabetes.

Despite their growing popularity, particularly among women of reproductive age, and the limited understanding of how parental intake may affect future generations, this study may help fill that gap by offering early insights into possible intergenerational effects.

Do sugar substitutes affect children even before they are born?

The study is based on the Developmental Origins of Health and Disease (DOHaD) hypothesis, which suggests that parental diet can influence the long-term health of their children. Here, the gut microbiota plays a key role in shaping metabolism and immunity across generations.

“The role of non-nutritive sweeteners (NNS) in the development of metabolic alterations and chronic non-communicable diseases is controversial. It is also unclear whether these alterations are transmitted to offspring or whether the gut microbiota is involved in these processes,” the researchers noted.

To explore this, researchers studied mice across three generations. The parent group (F0) consumed sucralose or stevia, while their offspring (F1 and F2) were not exposed.

The findings showed that while parents had no major changes, their offspring, especially males, did. “No changes in the glucose oral tolerance test were observed in the F0 generation, while the glycemic response was mildly altered in the F1 and F2 male mice in the Sucralose group.”

The study also found increased activity of inflammation-related genes like Tlr4 and Tnf in both parents and offspring. “Tlr4 and Tnf were overexpressed in the intestine of the F0/F1 Sucralose group.”

Overall, the results suggest that sugar substitutes may affect metabolism and inflammation in offspring, possibly through changes in gut bacteria, with effects lasting across generations.

Gut microbiota disruption and reduced beneficial metabolites

Another key part of the study looked at how these sweeteners affect gut microbiota – the bacteria in our digestive system that are important for metabolism, immunity, and overall health.

The researchers found that both sucralose and stevia changed the gut bacteria in the parent mice, and these changes were passed on to their offspring. However, the impact of sucralose was stronger and lasted longer.

“Compositional changes in the faecal microbiota were greater in the F0 and F1 generations, particularly the Sucralose group,” the study noted.

Sucralose reduced helpful bacteria like Oscillibacter, which produces butyrate—a substance that helps reduce inflammation and supports gut health. At the same time, it increased bacteria linked to inflammation, such as Candidatus_Saccharimonas.

These changes were also linked to lower levels of important compounds called short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate. “Animals from the F0 Sucralose and Stevia groups had lower SCFA concentrations, and this trait was passed on to next generations.”

SCFAs are essential for keeping the gut healthy and controlling inflammation. A drop in these levels may increase the risk of metabolic problems over time.

The study adds that these effects were not due to diet differences, since fibre intake was the same across groups. “These reductions are likely due to changes in microbial composition.”

Importantly, these changes continued in future generations, showing that the effects of these sweeteners may last beyond those who consume them directly.

Researchers also found that sucralose had a stronger impact because it is not easily broken down in the body. “Sucralose is poorly metabolised and largely excreted in stools… and could exert greater selective pressure on gut microbiota,” they noted.

In comparison, stevia is more easily processed by gut bacteria, which may explain why its effects were milder.

Limitations of the study

Despite its comprehensive design, the study acknowledges several limitations that must be considered when interpreting the findings.

One major limitation is the inability to distinguish between different types of parental exposure. “The experimental design does not allow us to disentangle the intergenerational effects of perinatal exposure from those of gestational exposure.”

This means that the study cannot determine whether the observed effects are primarily due to exposure during pregnancy, early life, or a combination of both. Future research is needed to isolate the contributions of maternal and paternal influences.

Another limitation relates to the use of animal models. While mice studies provide valuable insights into biological mechanisms, their findings may not directly translate to humans. The researchers emphasise the need for further studies to assess the relevance of these results in human populations.

The study also focused on faecal microbiota rather than cecal microbiota, which may influence the interpretation of microbial changes. “We focused on faecal microbiota rather than cecal microbiota because faecal samples more accurately reflect the microbial communities transmitted from the dam to the offspring.”

Additionally, the use of a single housekeeping gene for gene expression analysis may limit the robustness of the findings. “Although the use of multiple reference genes is increasingly recommended, we used a single validated housekeeping gene,” the study notes, acknowledging that while acceptable, this approach has limitations.

Finally, the study design does not fully account for potential variability in environmental factors that could influence microbiota and metabolic outcomes. These limitations highlight the need for more detailed and human-focused research to better understand the long-term implications of NNS consumption.

Is it time to rethink sugar substitutes? What experts say

Dr Rajiv Kovil, Head of Diabetology and Weight Loss Expert at Zandra Healthcare, described the study as an early signal rather than a cause for alarm. He said the findings highlight a possible link between parental intake of non-nutritive sweeteners and changes in offspring biology, but should be interpreted cautiously.

“It’s a warning signal, not a reason to panic. It suggests that parental exposure to sucralose and stevia can alter gut microbiota and may change gene expression and inflammation in offspring. It’s nothing more than that,” he said.

He emphasised that the study was conducted in mice and that translating such findings directly to humans remains uncertain. “Commenting on mouse-to-human translation is quite uncertain. Mechanistically, yes, it raises questions, but I don’t think it is practice-changing,” he noted.

Dr Kovil added that while there is existing evidence that non-sugar sweeteners can influence gut microbiota and metabolism, there is currently no strong human data to confirm intergenerational or epigenetic effects. “Whether they cause the same intergenerational harm in humans, we don’t know. The human data are very limited.”

On safety, he pointed out that global guidelines, including those from the WHO, consider non-nutritive sweeteners safe within prescribed limits, but caution against expecting long-term health benefits. “They are safe at approved dosages, but one should not expect long-term health benefits.”

At the same time, he noted that scientific opinion on these sweeteners remains divided. “There have always been two schools of thought – one that they increase cravings and another that they help reduce them. Evidence exists on both sides.”

Speaking about pregnancy and preconception, Dr Kovil stressed a more cautious approach. He said that both sugar and artificial sweeteners are generally advised to be limited during this period. “When we talk about pregnancy or planning pregnancy, we usually advise avoiding both regular sugar and habitual intake of diet beverages. Stevia and sucralose are not typically recommended during that period.”

However, he clarified that safety data for pregnant women remains insufficient. “These sweeteners have defined acceptable daily intake levels – for example, around 4 mg/kg/day for stevia and 5 mg/kg/day for sucralose, and are considered safe for the general population. But they are not adequately tested in pregnant women.”

On alternatives, Dr Kovil said there is no real substitute for artificial sweeteners. “There’s no substitute as such. If someone does not have gestational diabetes, they can consume normal sugar in moderation,” he advised.

Also read: FACT CHECK: Does sugar affect children’s mood and behaviour?