New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.

In a study, researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.

The study was published online August 19 in the journal Cell.

Gut Reaction?

Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that NNS affect the microbiome of mice in ways that could affect glycemic responses.

They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.

Before the study, all participants strictly avoided NNS. During the trial, some remained NNS-free, while others used saccharin, sucralose, aspartame, or stevia daily for 2 weeks in doses lower than the acceptable daily intake.

Each NNS “significantly and distinctly” altered stool and oral microbiome, and two of the sweeteners (saccharin and sucralose) significantly impaired glucose tolerance, the researchers report.

“Importantly, by performing extensive fecal transplantation of human microbiomes into germ-free mice, we demonstrate a causal and individualized link between NNS-altered microbiomes and glucose intolerance developing in non-NNS-consuming recipient mice,” they say.

They note that the effects of these sweeteners will likely vary from person to person because of the unique composition of an individual’s microbiome.

“We need to raise awareness of the fact that NNS are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies,” Elinav said in a news release.

For now, Elinav says it’s his personal view that “drinking only water seems to be the best solution.”

Experts Weigh In

Several experts weighed in on the results in a statement from the UK nonprofit  organization, Science Media Centre.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, School of Medicine, said: ‘The present study is a large step forward to understanding the impact of NNS in humans, with a very rigorous design and follow-up work in mice to assess underlying mechanisms and causality. Importantly, the work is a major advance because the authors were careful to exclude participants who knowingly or unknowingly ingest NNS in their normal diet. They found that, while there was variability between subjects, two NNS, saccharin and sucralose, provoked intolerance to a glucose load (a marker of metabolic dysfunction) and also caused specific changes in the gut microbiome and the chemicals these microorganisms produce.

“Furthermore, by implanting the fecal microbiome from those subjects who showed greater or minimal glucose intolerance responses into germ-free mice, they could reproduce the respective glucose intolerance in the mice, implicating the effect of the NNS on the microbiome as the cause of the metabolic dysfunction. Caveats about the study include the fact that only young, healthy subjects were included, and the NNS were only given for two weeks. Nevertheless, this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals, and should prompt additional work as well as, perhaps, providing an explanation that diet drink consumption is often associated with greater rather than reduced levels of obesity,” she adds.

“Ultimately, perhaps we should not be surprised by the findings, since NNS are recognized by human taste receptors even though they are noncaloric, and bacteria are also well known to have the capacity to sense chemicals in their environment and to change their behavior accordingly.”

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, United Kingdom, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).

“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Mellor says.

Kevin McConway, PhD, with the Open University, Milton Keynes, United Kingdom, says it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.

“But exactly what the health consequences of all this, if any, might be is a subject for future research,” McConway adds.

Ascensión Marcos, PhD, research professor and director of the Immunonutrition Group at the Institute of Food Science and Technology and Nutrition of the Spanish National Research Council, noted: “This is a good study. However, as usual, one can always see ‘drawbacks.’ Of the 19 sweeteners approved in the EU, only four appear in this article, so no results can be extrapolated. As we also found in a recently published review, the authors go so far as to observe an effect on the gut microbiota with altered glycemic response for saccharin and sucralose.

“In any case, although the N (the number of participants in the study) is fine (120), there are only 20 in each arm of the study…and the intervention time is short, only 2 weeks. In terms of nutritional status, there are several groups, and obesity is not taken into account, only overweight.

“In principle, it would be preferable to differentiate by case, by nutritional situation, by pathology, even by geographical area, since in Latin America the population has been consuming different types of sweeteners for years and could possibly have adapted their microbiota.

“I think that, in general, taking these points into account, it may be difficult to draw conclusions.”

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth, United Kingdom, said the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”

The study had no specific funding. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. McConway and Redfern report no relevant financial relationships.

Cell. Published online August 19, 2022. Full text

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