Clinical Context

Nonnutritive sweeteners (NNS) are one of the more controversial and confounding dietary elements affecting the well-being of children and adults. Although first hailed as a means to replace sugar's sweetness without any calories, enthusiasm cooled regarding NNS when reports emerged of potential negative metabolic effects. A meta-analysis of randomized controlled trials by Lohner and colleagues, published in the May 25, 2020, issue of the Cochrane Database of Systematic Reviews, sought to find the balance for the health effects of NNS.^[1]

Nine trials with a total of 979 participants were included in the analysis, and no study was found to have a low risk for bias. In the 3 trials that compared NNS with sugar, there was no difference between groups in terms of body weight or HbA1c level at the end of the trial period. Similarly, there was no separation between NNS and placebo in these outcomes. The rate of adverse events between NNS and comparators was also similar.

The results of this meta-analysis suggest that NNS are inert compounds that do little to alter metabolism. The current study examines the hypothesis that NNS may have active effects on glucose metabolism mediated by the gut microbiome.

Study Synopsis and Perspective

New research discounts the long-held notion that aspartame and other 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 Cell.^[2]

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, whereas 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 2 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," Dr Elinav said in a news release.

For now, Dr Elinav says it is his personal view that "drinking only water seems to be the best solution."

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

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 6 sachets of either saccharin or sucralose mixed with glucose per day," Dr Mellor says.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, School of Medicine, concurs, saying, "this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals."

The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.

"Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a 'stepping stone,' allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake, and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet," Dr Mellor suggests.

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

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

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth, United Kingdom, agrees.

"We still have a lot to learn about the human microbiome, and although this study suggests 2 of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small," she says.

The International Sweeteners Association also weighs in, saying, "No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes."

They add that "a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota."^[3]

Nevertheless, Redfern says 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. Dr 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. Dr 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. Dr Barrett, Dr McConway, and Dr Redfern have disclosed no relevant financial relationships.

Cell. Published online August 19, 2022.

Clinical Implications

• A previous meta-analysis of randomized trials of NNS found no difference between NNS and either sugar or placebo on the outcomes of body weight, HbA1c, or adverse events.
• In the current study, saccharin and sucralose were associated with a blunted insulin response associated with a rise in blood glucose levels, whereas aspartame and stevia were not. All NNS affected microbiome function, and mouse models suggest that these changes may underlie the effects of NNS on glucose metabolism.

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