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Can Sugar Substitutes Alter Gut Microbiota?

  • Authors: News Author: Megan Brooks; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 10/21/2022
  • Valid for credit through: 10/21/2023
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This activity is intended for primary care physicians, endocrinologists, gastroenterologists, nurses, nurse practitioners, pharmacists, physician assistants and other clinicians who treat and manage patients at risk for hyperglycemia and diabetes.

The goal of this activity is for learners to be better able to assess the effects of nonnutritive sweeteners on glucose metabolism and the gut microbiome.

Upon completion of this activity, participants will:

  • Analyze previous research regarding the effects of nonnutritive sweeteners on body weight and HbA1c
  • Assess the effects of nonnutritive sweeteners on glucose metabolism and the gut microbiome
  • Outline implications for the healthcare team


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News Author

  • Megan Brooks

    Freelance writer, Medscape


    Megan Brooks has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

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  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Can Sugar Substitutes Alter Gut Microbiota?

Authors: News Author: Megan Brooks; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 10/21/2022

Valid for credit through: 10/21/2023


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]

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, 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."

Weighing the Evidence

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.

Study Highlights

  • Study participants were in good metabolic health and had abstained from NNS before the study.
  • Researchers divided study participants into 1 of 6 groups: 4 groups received 3 fixed doses of NNS per day, 1 group received the same schedule of a glucose supplement, and the final group received no supplements. The 4 NNS included were aspartame, saccharin, sucralose, and stevia.
  • Participants had baseline metabolic measures over the course of 7 days. After that, they went through the study intervention for 2 weeks, followed by 1 week of measuring study outcomes after the 2-week trial of supplements.
  • The study had several outcomes. First, researchers followed the effects of study interventions on glucose metabolism through 9 separate glucose tolerance tests and data from continuous glucose monitors. Second, participants underwent stool testing to assess any difference in the gut microbiome during study interventions. Finally, researchers colonized germ-free mice with the microbiome of participants from different NNS groups to provide support for causation between NNS effects on the microbiome and changes in glucose metabolism.
  • 120 adults participated in the study; 65% were women, and the median age of participants was 29.95 years. Other than study supplements, other dietary variables were similar across randomization groups during the trial.
  • Saccharin and sucralose were associated with higher glucose values on glucose tolerance tests compared with both glucose supplements and no supplements, and this effect was noted during the first week of the intervention and then resolved during the final week without supplementation. Aspartame and stevia did not affect glucose tolerance tests.
  • None of the NNS interventions was associated with a significant difference in continuous glucose monitoring values compared with the glucose group.
  • Plasma insulin levels rose during the active intervention in the stevia and glucose groups. Body mass index, blood pressure, and pulse were not affected by the study interventions.
  • Baseline stool composition was similar between groups at baseline. During treatment, sucralose and saccharin induced significant changes in the microbiome composition, whereas all 4 NNS significantly affected microbiome function. There was heterogeneity between participants with regard to the microbiome response to NNS.
  • Many of the microbiome pathways affected by NNS were related to glycolysis and glycan degradation.
  • Microbiome samples from 42 participants were transferred to mice. Samples from top responders to aspartame and stevia in terms of changes in their microbiome induced hyperglycemia in the mouse model, whereas there were no such effects among top responders in the glucose and no supplement cohorts.

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.

Implications for the Healthcare Team

The healthcare team should discourage the regular consumption of NNS in favor of known healthy options until more data are available on their safety.


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