Taking a New Look at Artificial Sweeteners
Posted on by Dr. Francis Collins
Diet 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 .
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?
 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.
 Microbial ecology: human gut microbes associated with obesity. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Nature. 2006 Dec 21;444(7122):1022-3.
 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.
 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.
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