Are Artificial Sweeteners Really Harmless?

Medscape Medical News - August 19, 2022

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 19,20-22 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.”

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 six sachets of either saccharin or sucralose mixed with glucose per day," 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," Mellor suggests.

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.

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

"We still have a lot to learn about the human microbiome, and although this study suggests two 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."

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. 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. Barrett, McConway, and Redfern report no relevant financial relationships. 

Cell. Published online August 19, 2022. <https://www.cell.com/cell/fulltext/S0092-8674(22)00919-9>

Artificial sweetener may not be what you desire if you're trying to lose weight....

 

Artificial Sweetener Ups Appetite in Women, People With Obesity

A new study (September 28, 2021), suggests that replacing sugar (sucrose) with the nonnutritive sweetener sucralose may not have the desired weight-loss effect, and in fact, it appears to increase appetite in women and people with obesity.

These are novel insights and further studies are needed, experts say.

After consuming a drink sweetened with sucralose versus sucrose, women and people with obesity had increased activity in the reward center of the brain and women ate more food at a post-fasting buffet.

"We were able to show that females and people with obesity may be more sensitive to artificial sweeteners," senior author Kathleen Page, MD, an associate professor of medicine at the Keck School of Medicine, University of Southern California, Los Angeles, summarized in a press release from the university.

"For these groups, drinking artificially sweetened drinks may trick the brain into feeling hungry, which may in turn result in more calories being consumed," she added.

Although many people use artificial sweeteners to try to lose weight, Page noted their place in a healthy diet is controversial. Some studies suggest they may be helpful, while others show they may contribute to weight gain, type 2 diabetes, and other metabolic disorders.

The new findings may partly explain these previous differences, she said.

The results also highlight the need to consider gender and body mass index in future research of nonnutritive sweeteners.

The study, by Alexandra G. Yunker, an MPH candidate in nutrition at Harvard University, Boston, Massachusetts, and colleagues, was published onlineSeptember 28 in JAMA Network Open.

Novel Findings, Need to Consider Sex, Adiposity in Future Research 

The current study "is of great importance as it provides novel insights into how adiposity and sex are associated with neural and behavioral outcomes of [nonnutritive sweetener] ingestion," Stephanie Kullmann, PhD, writes in an accompanying invited commentary.

Invited to comment, John L. Sievenpiper, MD, PhD, associate professor in the Department of Nutritional Sciences and Medicine at the University of Toronto, Ontario, Canada, agreed that the data need to be reproduced.

Several questions remain, he stressed in an email to Medscape Medical News: "Was it the sucralose per se or the absence of calories that explains these findings? And the bigger question is, do these differences by adiposity and sex translate into weight gain?"

Systematic reviews and meta-analyses of the available randomized controlled trials of low and no calorie sweeteners including sucralose show the expected decrease in caloric intake and downstream weight loss in both males and females who are overweight or obese, he noted.

"It would be useful to understand if there are important interactions by adiposity and sex in future trials," Sievenpiper added.

Young Men and Women of Diverse Weight

Nonnutritive sweeteners are now used by more than 40% of US adults, the researchers write, but studies have reported mixed results on appetite, glucose metabolism, and body weight, and it is not clear whether these sweeteners are beneficial or harmful to health.

Prior research that was mainly in men and lean participants showed that brain areas involved in the regulation of taste, reward, and homeostasis may respond differently to nonnutritive versus nutritive sugars.

The researchers aimed to investigate this using initial data from the Brain Response to Sugar study (clinicaltrials.gov).  

They analyzed data from 74 healthy 18- to 35-year-olds (58% women) with a mean age of 23. Overall, 37% had a healthy weight, 32% were overweight, and 31% had obesity.

Participants made three separate visits to the study center after a 12-hour overnight fast.

At each visit they drank 300 mL of water, a sucralose-sweetened drink, or a sucrose-sweetened drink.

They had blood drawn at baseline and at 10, 35, and 120 minutes after ingesting the drink.

At 20 minutes after consuming the drink, they had a functional MRI, during which they were shown 12 pictures of high-calorie, low-calorie, sweet, or savory foods and four pictures that were not foods and were asked to rank their appetite.

At 125 minutes after they ingested the drink, participants had access to a buffet meal.

"As expected, endocrine responses" — blood levels of glucose, insulin, and glucagon-like peptide-1 — "were greater after sucrose than sucralose ingestion," Kullmann noted, "but there were no significant differences based on sex and adiposity."  

However, "the most prominent and novel findings were observed on a neurobehavioral level," according to Kullmann.

That is, individuals with obesity (but not those with overweight or a healthy weight), had greater neural activity in the prefrontal reward-related areas of the brain, in response to savory food images, after ingesting a drink containing sucralose versus sucrose.

Similarly, after consuming a sucralose-sweetened drink as opposed to a sucrose-sweetened drink, female participants had greater activity in reward areas of the brain in response to food cues, especially high-calorie and sweet foods.

Women also consumed more calories at the buffet meal after they had ingested a sucralose-sweetened drink than after a sucrose-sweetened drink.

The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). The Research Electronic Data Capture (REDCap) database used is supported by the Southern California Clinical and Translational Science Institute through an NIH grant. The researchers and editorialist have reported no relevant financial relationships.

JAMA Netw Open. 2021;4:e2126313, e2128047. Article, Editorial