Sugar Substitutes, Gut Bacteria, and Glucose Intolerance

The consumption of artificial sweeteners results in glucose intolerance mediated by changes in the gut microbiota in both mice and humans, researchers report.

By Anna Azvolinsky | September 17, 2014

WIKIMEDIA, STEVE SNODGRASSNon-caloric sweeteners can spur glucose intolerance in mice and some people, according to a study published today (September 17) in Nature. Researchers from the Weizmann Institute of Science in Israel and their colleagues have uncovered “the unexpected effect that artificial sweeteners drive changes in the [gut] microbiota, which promote glucose intolerance,” said University of Chicago pathologist Cathryn Nagler, who studies how the microbiota regulate allergic responses to food and penned an editorial accompanying the study.

Immunologist Eran Elinav and computational biologist Eran Segal, both of the Weizmann Institute, identified changes in the composition and function of the mouse gut microbiome after the animals consumed artificial sweeteners—changes similar to those previously linked to obesity and diabetes in humans, the authors noted.

A previous study showed that sucralose can alter the rat gut microbiome—specifically, by decreasing beneficial bacteria—but this latest work pinpoints a microbe-mediated mechanism by which artificial sweeteners might influence glucose metabolism, said Yanina Pepino, who studies how non-caloric sweeteners influence glucose metabolism at the Washington University in St. Louis School of Medicine.

Elinav and Segal’s team observed that mice given a 10 percent solution of one of three types of commonly consumed commercial artificial sweeteners—saccharin, sucralose, or aspartame—in place of regular drinking water had elevated blood-glucose levels after 11 weeks compared to mice given either a 10 percent glucose solution or water alone. The researchers used saccharin for subsequent experiments as this artificial sweetener showed the most pronounced effect on glucose levels in preliminary trials. Mice fed a high-fat diet plus the 10 percent saccharin solution showed the same effect on glucose metabolism as animals given an even higher saccharin dose—comparable to the US Food and Drug Administration’s (FDA’s) upper limit for safe human consumption.

Four weeks of treatment with gut bacteria-depleting antibiotics reversed the glucose intolerance in mice that continued to receive saccharin. This led the team to examine whether the microbiomes of the mice were somehow altering glucose metabolism. Transplantation of feces from non-antibiotic-treated mice that consumed saccharin- or glucose-containing water into germ-free mice within six days induced the same blood-sugar elevations in animals that were never themselves exposed to the sweeteners.

“This is the elegant and home run experiment that shows causality in mice,” said Nagler.

Using shotgun metagenomic sequencing on the fecal samples, the researchers showed that mice given saccharin or those that received a fecal transplant from saccharin-fed mice had a different microbiome composition compared to mice given sugar or no sweeteners.

The team also found similar glucose metabolism and gut microbiota changes in humans.

In a cohort of 381 non-diabetic volunteers who answered diet questionnaires, those who regularly consumed artificial sweeteners—particularly those who consumed the highest amounts—showed higher fasting glucose levels, poorer glucose tolerance, and different gut microbe profiles compared to those who did not consume such sweeteners. The difference between the two populations remained even after correcting for body mass index.

Further, the team exposed seven young, healthy volunteers who did not have a history of artificial sweetener consumption to one week of the FDA’s maximum acceptable daily saccharin intake, and continuously monitored their glucose levels. Four of the seven volunteers showed a poorer glycemic response at the end of the week compared to their baseline responses. Those who showed no metabolic response to the sweetener had no change in their gut microbiomes, while those who exhibited the worst glycemic responses at the end of the week showed a different gut microbiota profile after sweetener exposure. Fecal transplants from two artificial sweetener-responder volunteers into germ-free mice resulted in a similar gut microbe profile and glucose intolerance as did transplants from saccharin-consuming mice. But the same transplants from two non-responder volunteers had no such effect in germ-free mice.

“The extensive work done with the microbiome [in this study] continues to point to the potential importance of our dietary habits on this previously underappreciated variable in our metabolism,” Christopher Gardner, a professor of medicine at Stanford University who was not involved in the study wrote in an e-mail to The Scientist. Gardner was the former chair of the working group of the American Heart Association that generated a position statement on artificial sweeteners in 2012. He added that while the dose of artificial sweeteners used in this study is acceptable according to the FDA, this high dose—equivalent to 340 milligrams of saccharin (8.5 packets of Sweet N’ Low) per day—is an unlikely dose for the typical artificial sweetener user.

Although the human data provide some evidence that artificial sweeteners may have a detrimental effect on glucose metabolism in a subset of people, the authors cautioned that additional studies are needed to understand who is susceptible to the potential negative effects of artificial sweeteners and to further elucidate the mechanism by which gut microbes may drive metabolic changes.

“I am very excited about these results because they demonstrate the need for more research,” said Pepino. “There are many aspects of these sweeteners that we don’t understand. Artificial sweeteners may have no calories  but mounting evidence indicates that they do have metabolic consequences and may not be the solution for having a sweet taste without the calories.”

J. Suez et al., “Artificial sweeteners induce glucose intolerance by altering the gut microbiota,” Nature, doi:10.1038/nature13793, 2014.  

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Avatar of: SweetenerFacts


Posts: 1

September 17, 2014

In contrast to the assertions made by the researchers of this study, the overall evidence from studies on low-calorie sweeteners, including numerous human studies, show that these sweeteners are safe and do not have adverse effects on blood glucose control. 

Investigators of more than 40 studies in people, including a recent meta-analysis of clinical trials and other available evidence, have concluded that the use of low-calorie sweeteners does not lead to either an increased risk of obesity or diabetes.

Leading health organizations, including the Academy of Nutrition and Dietetics (AND), the American Diabetes Association (ADA) and the American Heart Association (AHA), as well as numerous scientific studies agree that low-calorie sweeteners can be used as a safe tool to help manage calorie intake, which, in turn can be helpful for both weight management and diabetes management. 

-Calorie Control Council

Avatar of: skrymsli


Posts: 1

September 17, 2014

@SweetenerFacts  The fact that an organization funded by the low calorie food industry is out posting refutations to the findings (not assertions) of the researchers in this study is disturbing and does not strengthen your position.  

If your product is causing harm to consumers, I'm sure what you meant to say is: "The Low Calorie food industry wants to commit 10 million dollars to studying the effects of our products on gut microbiota to ensure that we are not causing inadvertent harm to our customers."

Yes, I'm joking.  I know you would never say something like that. But you should.

Avatar of: John Salerno

John Salerno

Posts: 10

September 18, 2014

A 10% solution of sacharin? Or a 10% solution of sucralose? I'll start to believe this is a  'home run' finding when a significant effect shows up at any reasonable dose. A liter of diet soda might contain 100 mg of sucralose or 150 mg of saccharin, equivalent to a .01% or .015% solution. To get to the FDA cutoff, 5 mg/kg body weight, the researchers gave their animals the equivalent dose for a typical human drinking liters of soft drinks a day. I'd avoid doing that just because of the expense. The study won't make me think twice about having a Coke Zero with a burger once in a while. 

Avatar of: Seth Crosby

Seth Crosby

Posts: 16

September 18, 2014

A 10% solution in lieu of drinking water. Rats consume ~10 ml H2O/100 gm body weight/day (http://vetmed.duhs.duke.edu/GuidelinesforRodentAnalgesia.html). That translates to 100mg/kg sweetner/day.

The FDA has set the ADI for saccharin, sucralose and aspartame at 15, 5, 50mg/kg, respectively. (http://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm397725.htm#SummaryTable)

I'm just saying is all.

Avatar of: Elizabeth V H

Elizabeth V H

Posts: 3

Replied to a comment from skrymsli made on September 17, 2014

September 18, 2014

I wonder if the Sugar Association watches these types of study? 

Also, I'm pretty sure that the Sugar Association funded research over the decades to slam the low-calories sweeters.  

Avatar of: NutrFitPro


Posts: 1

September 18, 2014

What a joke!

First of all, you can't lump all artificial sweteners together. They're completely different chemicals.

So sad to see money and time devoted to looking at insignificant and questionable findings. Not a fan of saccharin or sucrolose, but aspartame is just a dipeptide that's a godsend for diabetics or anyone who wants to enjoy a sweet taste WITHOUT elevating blood sugar or insulin. Of course, any food/drink can be abused, including water! That's where all these ridiculous anecdotes come from...wackos who drink gallons of diet pop!

Focus on sugar..sugar..sugar..and refined carbs...the real culprit causing metabolic syndrome. I recall an encounter with someone eating a sugary pastry and drinking a coke, while I was drinking a dit 7-UP. That person said to me, " That's stuff's gonna kill you!"  Really????????

Persepective people!!!!!!!

Avatar of: Auros


Posts: 5

Replied to a comment from Seth Crosby made on September 18, 2014

September 18, 2014

I'd want to check on the Methods section of the original paper.  The "10% solution" may be "10% by mass", or it may be something like "10% concentrated solution + 90% pure solvent (water), by volume".

Avatar of: Paul Stein

Paul Stein

Posts: 237

September 18, 2014

Again, more mouse gut microbiome studies.  What any of this has to do with real people will never be known because all of these scientists, and those who fund the science, are stuck in mice...and with the most irrelevant sweetener choice and dose.  Because translation from mouse to man has failed more times than anyone can count, "causality in mice" means absolutely nothing to me or any other person.  When any of this moves into a real animal, using much better sweetener choices than saccharin in much more logical doses, then I might pay attention.

In the meantime, this research might be used to help me with the field mouse problem in my basement.  I'll add a bunch saccharin in water dishes all around.  Rather than snapping their little necks with regular traps, they will just quietly and humanely waste away with type 2 diabetes.  (Watch that one show up in a PeTA commercial at 3:00 a.m.)

Avatar of: MES


Posts: 1

September 18, 2014

If you're going to do a study on this, you should give more specific detail explanation in numbers to reveal the significance. Plus, it doesn't compare to mice that consume sucrose. Not very many humans eat food without any sucrose or something related to it (like HFCS) so as far as I'm concerned it's relevant impact on obesity is not representative enough. We have more sucrose and hfcs out there than we do artificial sweeteners. It's easier to do studies with less variables, but if they can add THREE different artificial sweeteners, they can add other sugars as well besides the glucose only monomer bonds.

Avatar of: Roger Davis

Roger Davis

Posts: 1

September 18, 2014

I am highly annoyed by multiple studies that:

1) Far exceed the bounds of reality in terms of "real life" quantities and applications

2) Are suspect to influence by possible influx of cash from sugar producers (these kind of links can be DEEPLY hidden).  Isn't it strange that it's always and only the substantial market competitors for sugar that are targeted in these studies?

3) Ignore obvious vital components - e.g. Stevia, a non caloric sweetener that is NOT artificial, and is a clear option in case the sugar producers foes (saccharin, sucralose, and aspartame) actually prove to cause problems in a well designed and independently funded study

4) Ignore what happens if calories are consumed (food) along with the beverages in question.

5) Don't look at the "big picture" of overall health benefits or problems resulting in use of the products being tested.  For example, compare the overall degree of health damage caused by sugars vs that caused by sweeteners

Without addressing each and all of these shortcomings in great detail, these studies are highly untrustworthy.

Avatar of: T S Raman

T S Raman

Posts: 51

September 18, 2014

@skrymsli @SweetenerFacts

I am trying to get hold of the Nature paper for making a proper comment here (a sort of "speaking order") but you might be interested in reading an article in the newsletter of "AMERICAN COUNCIL ON SCIENCE AND HEALTH" (ACSH), http://acsh.org/2014/09/israeli-study-sugar-substitutes-complete-bullsweet/. I do think ACSH is right. The Israeli study is BS.

Please read also the "News" story in "Nature" at http://www.nature.com/news/sugar-substitutes-linked-to-obesity-1.15938?WT.ec_id=NATURE-20140918. Elinav, the scientist who appears to be the leader of the team that conducted the "Israeli study" is himself quoted as saying: 

"But “this is a bit chicken-and-egg” says Elinav. “If you are putting on weight, you are more likely to turn to diet food. It doesn’t necessarily mean the diet food caused you to put on weight.”"

Avatar of: AAF


Posts: 3

September 19, 2014

Key quote: “I am very excited about these results because they demonstrate the need for more research”. Translation: "I am really happy I have a result that should enable me to keep my lab funded for the next 5 years."

This is another questionable study that has been sensationalized by the press.


Avatar of: AAF


Posts: 3

September 19, 2014

Key quote: “I am very excited about these results because they demonstrate the need for more research”. Translation: "I am really happy I have a result that should enable me to keep my lab funded for the next 5 years."

This is another questionable study that has been sensationalized by the press.


Avatar of: John Salerno

John Salerno

Posts: 10

Replied to a comment from Auros made on September 18, 2014

September 19, 2014

I did check it. It says a 10% solution. It is very, very concentrated.

Avatar of: artmez


Posts: 10

September 20, 2014

Wow! Gotta love those sarcastic and derisive comments, right? Clearly that is better than science. Even the reference to the "authority" of ACSH as "proof" is no less invalid (I scanned a half-dozen articles there and no provided any "science' only criticism and sarcasm like here).

Now my real comment: As briefly alluded to in a couple of comments, there are too many variables overlooked to be definitive, but that's part of the process. Were the effects of artificial sweetener biased by the lack of nutrition to trigger microbiome responses? In one way, using mice provides a more controlled test environment to eliminate other variables (like "what else did they eat"). Without knowing the full details of the study it is hard to either criticize or support the conclusions. After all, this article is only a 850 word synopsis of another article that is a synopsis of the research.

I'm not even a lay person on this subject, so I defer to experts. But I also am not a flatlander (http://www.theflatearthsociety.org/tiki/tiki-index.php), nor a creationist, nor a (complete) skeptic (I think we really did land on the moon!). So just examine details and if there are enough substantiated facts for a judgment, form an opinion. Otherwise, dismiss it. Why rant? Like that ever did any good. Anyway, there are too many distractions (noise) as it is.

Avatar of: Andy Bryant PhD

Andy Bryant PhD

Posts: 1

Replied to a comment from John Salerno made on September 19, 2014

September 24, 2014



It took me less than 5mins of surveying the original paper to see that they used 10% solutions of these: Sucrazit (5% saccharin, 95% glucose), Sucralite (5% Sucralose), Sweet’n Low Gold (4% Aspartame).  So 0.4-0.5% of the sweetener itself, not 10%.


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