Taking a New Look at Artificial Sweeteners

Packets of artificial sweetenersDiet sodas and other treats sweetened with artificial sweeteners are often viewed as guilt-free pleasures. Because such foods are usually lower in calories than those containing natural sugars, many have considered them a good option for people who are trying to lose weight or keep their blood glucose levels in check. But some surprising new research suggests that artificial sweeteners might actually do the opposite, by changing the microbes living in our intestines [1].

To explore the impact of various kinds of sweeteners on the zillions of microbes living in the human intestine (referred to as the gut microbiome), an Israeli research team first turned to mice. One group of mice was given water that contained one of two natural sugars: glucose or sucrose; the other group received water that contained one of three artificial sweeteners: saccharin (the main ingredient in Sweet’N Low®), sucralose (Splenda®), or aspartame (Equal®, Nutrasweet®). Both groups ate a diet of normal mouse chow.

To their surprise, the researchers discovered that many animals in the artificial sweetener groups—especially those that drank saccharin-sweetened water—developed a condition called glucose intolerance, which is characterized by high blood glucose levels and is an early warning sign of increased risk for developing type 2 diabetes. In contrast, the animals that drank sugar water remained healthy.

The result was puzzling. These mice weren’t consuming natural sugars, so what was raising their blood glucose levels? The researchers had a hunch that the answer might lie in the gut microbiome—since those microbes play a vital role in digestion. Their suspicions were borne out. When they used DNA sequencing to analyze the artificial sweetener group’s gut microbiome, they found a distinctly different collection of microbes than in the animals who drank sugar water.

The next step was to distinguish whether these changes in the microbiome resulted from high blood glucose, or caused it. When the researchers used antibiotics to wipe out the artificial sweetener group’s gut microbes, their blood glucose levels returned to normal—evidence that the gut microbes were actively causing glucose intolerance. Additional proof came from experiments in which the researchers transplanted microbes from both groups of mice into the intestines of a mouse strain that had been raised in a sterile environment from birth. The germ-free mice that received microbes from the artificial sweetener group developed glucose intolerance; those getting microbes from the sugar group did not.

But what about humans? The research team, which included Eran Elinav, an immunologist, and Eran Segal, a computational biologist, examined clinical data from 400 people taking part in an ongoing nutrition study. That analysis showed that, compared to people who didn’t use artificial sweeteners, long-term users of artificial sweeteners tended to have higher blood glucose levels and other parameters often associated with metabolic diseases like diabetes, obesity, and fatty liver.

Next, the researchers asked seven healthy human volunteers, who had never previously consumed foods or beverages containing artificial sweeteners, to consume the daily maximum dose of saccharin allowed by the U.S. Food and Drug Administration for six consecutive days. Of the seven volunteers, four developed glucose intolerance, while three maintained normal blood glucose regulation. The researchers then took intestinal microbes from human volunteers and transplanted them into germ-free mice. Microbes from humans with glucose intolerance also triggered glucose intolerance in the mice, while microbes from humans with normal blood glucose had no effect.

Previous studies have associated changes in the gut microbiome with obesity and diabetes in humans [2, 3, 4]. But the latest findings, which still must be confirmed in larger studies and by other groups, advance our knowledge one step further by suggesting that artificial sweeteners may be one of what’s likely to be an array of factors with the power to shape such changes. Who knows what the next piece of that fascinating puzzle might be?

References:

[1] Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, Elinav E. Nature. 2014 Sep 17.

[2] Microbial ecology: human gut microbes associated with obesity. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Nature. 2006 Dec 21;444(7122):1022-3.

[3] A metagenome-wide association study of gut microbiota in type 2 diabetes. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J. Nature. 2012 Oct 4;490(7418):55-60.

[4] Gut metagenome in European women with normal, impaired and diabetic glucose control. Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, Nielsen J, Bäckhed F. Nature. 2013 Jun 6;498(7452):99-103.

Links:

Diagnosis of Diabetes and Prediabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Glucose tolerance test (MedlinePlus/NIH)

Elinav Lab, Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

Segal Lab, Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel

Personalized Nutrition Project

7 thoughts on “Taking a New Look at Artificial Sweeteners

  1. Perhaps artificial sweeteners raise blood glucose levels by competing for the same access site into cells (creating the intolerance effect) the same way similar substrates compete via mass action for the same binding site on the same enzyme (i.e. competitive inhibition)…a very simple explanation for the damaging effect of glucose intolerance or “resistance.”

  2. To clarify, the “resistance” I am referring to is more correctly referred to as “INSULIN resistance” which I am assuming contributes at least in part to “GLUCOSE intolerance.” An understanding of exactly what happens to prevent normal uptake of glucose during insulin resistance may suggest possibilities for the mechanism(s) by which artificial sweeteners enhance glucose intolerance in a competitive scenario, preventing glucose uptake into cells from the bloodstream and leading to higher blood glucose levels. Mass action and/or steric hinderance may be factors by which artificial sweeteners prevent normal glucose uptake leading to the observed high blood glucose levels.

  3. Dear Dr. Collins,

    I am writing to you after reading your excellent blog “Taking a New Look at Artificial Sweeteners.” However, I was disappointed that you did not include a reference to a review paper on sucralose/Splenda with my co-author Dr. Kristina Rother, Chief, Section on Pediatric Diabetes & Metabolism, Diabetes, Endocrinology, and Obesity Branch, NIDDK:

    Susan S. Schiffman & Kristina I. Rother (2013) Sucralose, A Synthetic Organochlorine Sweetener: Overview Of Biological Issues, Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 16:7, 399-451. You can link to this article (it is a free download): http://dx.doi.org/10.1080/10937404.2013.842523

    The above paper reviews the effect of sucralose/Splenda on gut bacteria, endocrine hormones, and other biological factors.

    A paper included in our review that gives further details on gut bacteria and first pass metabolism is: Abou-Donia, M. B., El-Masry, E. M., Abdel-Rahman, A. A., McLendon, R.E., and Schiffman, S. S. 2008. Splenda alters gut microflora and increases intestinal P-glycoprotein and cytochrome P-450 in male rats. J. Toxicol. Environ. Health A 71: 1415-1429. http://www.tandfonline.com/doi/full/10.1080/15287390802328630 (also free download)

    The latter work was performed while I was at Duke. I am now at North Carolina State University. I want to tell you what a true pleasure it is to work with Dr.
    Kristina Rother who has a deep commitment to integrity in science and concern for public health.

    Susan Schiffman, PhD

  4. I DO NOT USE ARTIFICIAL SWEETENERS, BUT I DO DRINK FRUIT AND VEGETABLE JUICES IN MODERATION. FRESH RAW FRUIT AND VEGETABLES FORM A LARGE PART OF MY DAILY DIET. I DRINK EIGHT GLASSES OF FLUIDS DAILY. I DRINK FRUIT AND VEGETABLE JUICES, FAT-FREE MILK AND POTABLE WATER. I HARVEST RAIN WHICH I COLLECT IN PLASTIC TANKS. HOWEVER, I DO BOIL THE WATER AND FILTER IT TO REMOVE ROOF DUST. I DO NOT DRINK TAP WATER BECAUSE SOME MUNICIPALITIES ADD CHLORINE OR FLUORINE TO THE WATER TO KILL GERMS. THE RESULT IS THAT ONE DRINKS A POISONOUS SUBSTANCE AND DEAD AND DECAYING GERMS. … I AM 88 YEARS OF AGE AND I AM ONE OF THE STRONGEST PEOPLE IN THE WORLD IN THE AGE GROUP 80 AND OLDER. I AM A RETIRED SOUTH AFRICAN POLICE DETECTIVE SUPERINTENDENT. I AM CURRENTLY A HEALTH AND PEACE ACTIVIST.

  5. These findings surprised me. I thought artificial sweeteners didn’t have side effects. Is there any way to discover the side effects of calorie-free sweeteners?

    • I was also surprised…You may be interested in an article I just read recently: “How Diet Soda Makes You Fat (and Other Food and Diet Industry Secrets)” by Mark Hyman…You should be able to Google the title and author to find it…Apparently, artificial sweeteners can act like glucose and raise insulin levels (it is actually suggested in one of the comment replies that the brain plays a role in pancreatic (and other) hormone release). Dr. Hyman maintains that sugar and artificial sweeteners are “addictive” but that an even a stronger dependency develops on artificial sweeteners! He cites some studies but I can’t comment on the validity of the research or studies that back his claims. In some instances he may be guilty of citing hypothesis as if it were fact…

  6. I am (was) a heavy user of Sweet & Low and have just recently been diagnosed with the start of Type 2 Diabetes. This is enough information for me. No more! Thank you for posting this study, it may have saved me from a serious disease.

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