Published: Sep 22, 2014 | Updated: Sep 23, 2014

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By Salynn Boyles, Contributing Writer, MedPage Today

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Noncaloric artificial sweeteners appear to induce glucose intolerance.
The mechanism appears to involve alteration of gut microbial metabolic pathways.

Consumption of noncaloric artificial sweeteners appeared to induce glucose intolerance in both mice and humans by altering gut microbiota in a series of experiments conducted by researchers in Israel.

Rather than helping to prevent obesity and metabolic disease, use of noncalorie sweeteners may have contributed to the epidemic rise of these conditions, wroteEran Elinav, MD, of the Weizmann Institute of Science in Rehovot, Israel, and colleagues, online in the journal Nature.

Their research is among the first to examine the impact of a specific food additive on gut microbiota and the findings are compelling, said microbiome researcher Suzanne Devkota, PhD, of Joslin Diabetes Center and Harvard Medical School. Devkota was not involved with the research.

“This was a very well done study, and the fact that they had a human component was a big plus,” she told MedPage Today.

Artificial Sweetener Research Mixed

Five no-calorie or low-calorie artificial sweeteners — saccharin, sucralose, aspartame, neotame and acesulfame K — are approved for use in the U.S. by the FDA and sweeteners derived from theStevia plant extract Reb-A have been designated “generally recognized as safe.”

While some studies have linked noncaloric sweetener use to an increased risk for obesity and diabetes, others suggest a protective effect or no effect at all. Interpretation of these studies has been complicated by the fact that noncaloric artificial sweeteners are often consumed by people who have some manifestations of metabolic syndrome, the researchers wrote.

They further noted that most noncaloric artificial sweeteners (NAS) pass through the human gastrointestinal tract without being digested, so they directly encounter intestinal microbiota.

“Microbiota compositions and function are modulated by diet in the healthy lean state as well as in obesity and diabetes mellitus, and in turn microbiota alterations have been associated with propensity to metabolic syndrome,” Elinav and colleagues wrote.

Their studies in animals and humans examined NAS-mediated modulation of microbiota composition and function and their effects on host glucose metabolism.

NAS Fed Mice Developed Glucose Intolerance

In an effort to better understand the effects of NAS on glucose homeostasis, the researchers added commercial formulations of saccharin, sucralose, or aspartame to the drinking water of 10-week-old C57/BI/6 mice. Control mice were fed only water or water supplemented with either glucose or sucralose.

At week 11, the three groups that consumed water alone, glucose and sucrose had comparable glucose tolerance curves, while the three NAS-fed mouse groups developed marked glucose intolerance (P<0.001). Saccharin exerted the most pronounced effect, and the researchers further studied this sweetener by feeding the mice a high-fat (60% calories from fat) diet while they consumed either commercial saccharine or pure glucose. As in the earlier experiment, the saccharin-fed mice developed glucose intolerance and the control mice did not.

“Taken together, these results suggest that NAS promote metabolic derangements in a range of formulations, doses, mouse strains, and diets paralleling human conditions, in both the lean and the obese state,” the researchers wrote.

To test whether the observed NAS effect was regulated in the gut microbiota, the researchers treated mouse groups consuming commercial or pure NAS in the lean and high-fat diet states with a Gram-negative-targeting broad-spectrum antibiotic regimen (ciprofloxacin and metronidazole) while maintaining the mice on their diet and sweetener regimens.

After 4 weeks of antibiotic treatment, differences in glucose intolerance between NAS-consuming mice and controls were abolished in both the lean and obese states. Similar effects were seen with the Gram-positive-targeting antibiotic vancomycin.

“These results suggest that NAS-induced glucose intolerance is mediated through alterations to the commensal microbiota, with contributions from diverse bacterial taxa,” the researchers wrote.

Fecal Experiments Studied Causal Link

In an effort to determine if the microbiota role was causal, the researchers performed fecal transplantation experiments, by transferring the microbiota configuration from mice on normal-chow diet drinking commercial saccharin or glucose (control) into normal-chow-consuming germ-free mice. Recipients of microbiota from mice consuming commercial saccharin exhibited impaired glucose tolerance compared with control microbiota recipients 6 days after transfer (P<0.03)

The researchers also examined the fecal microbiota composition of the various mouse groups by sequencing their 16S ribosomal RNA gene. In this series of experiments, they demonstrated that saccharin directly modulated the composition and function of the microbiome to induce a harmful imbalance of intestinal microbes (dysbiosis), accounting for the downstream glucose intolerance phenotype in the mammalian host.

NAS Raised Metabolic Risk in Humans

To study the effects of NAS in humans, the researchers examined the relationship between long-term NAS consumption (determined through food frequency questionnaires) and dysbiosis and various parameters of metabolic risk using data collected from 381 people who did not have diabetes (44% male; mean age 43.3, SD 13.2) participating in an ongoing clinical nutritional study.

“We found significant positive correlations between NAS consumption and several metabolic-syndrome-related clinical parameters, including increased weight and waist-to-hip ratio, higher fasting blood glucose, glycosylated HbA1c [percentage] and glucose tolerance test (GTT, measures of impaired glucose tolerance), and elevated serum alanine aminotransferase,” the researchers wrote.

Levels of HbA1c, indicative of glucose concentration over the previous 3 months, were significantly increased when comparing a subgroup of high NAS consumers (40 people) to non-NAS consumers (236 people, rank sumP<0.002). The increase remained significant when adjusted for body mass index (rank sum P<0.015).

When Elinav and colleagues characterized 16S rRNA in 172 randomly selected members of the cohort, they found statistically significant positive correlations between multiple taxonomic entities and NAS consumption, including the Enterobacteriaceae family and the Actinobacteria phylum.

“Importantly, we did not detect statistically significant correlations between operational taxonomic unit abundances and BMI, suggesting that the correlations are not due to the distinct BMI of NAS consumers,” they wrote.

In an effort to determine if the relationship between human NAS consumption and blood glucose control is causative, the researchers followed seven healthy volunteers (five males and two females, ages 28-36) who did not normally consume NAS or foods containing NAS for 1 week (days two-seven). During this week, participants consumed the FDA’s maximal acceptable daily intake of commercial saccharin (5 mg per kg body weight as three divided daily doses equivalent to 120 mg). The participants were monitored by continuous glucose measurements and daily GTT.

“Notably, even in this short-term, 7-day exposure period, most individuals (four of seven) developed significantly poorer glycemic response 5-7 days after NAS consumption, compared with their individual glycemic response on days one-four,” the researchers wrote.

Personalized Response to NAS Found

The microbiome configurations of theses NAS responders, assessed using 16S rRNA analysis, also clustered differently from the three nonresponders. Microbiomes from nonresponders showed little changes in composition during the study week, wheres pronounced compositional changes were seen in NAS responders.

To further examine whether this NAS-induced dysbiosis had a causal role in glucose intolerance, the researchers transferred stool from before day one or after day seven NAS exposure from two NAS responders and two nonresponders into groups of normal chow-fed germ-free mice.

Transfer of day seven stool from NAS responders was found to induce significant glucose intolerance in the mice, compared with day one stool from the same people. In contrast, D7 stools transferred from two NAS nonresponders induced normal glucose tolerance which was similar to that of mice transferred with day one stool.

“Our results from short- and long-term human NAS consumer cohorts suggest that human individuals feature a personalized response to NAS, possibly stemming from differences in their microbiota composition and function,” the researchers wrote.

The researchers further suggested that these individualized nutritional responses may be driven by personalized functional differences in the microbiome.

Expert: All Things in Moderation

Diabetes researcher Robert Rizza, MD, of the Mayo Clinic in Rochester, Minn., who was not involved with the research, called the findings “fascinating.”

He noted that earlier research suggests people who eat large amounts of artificial sweeteners have higher incidences of obesity and diabetes. The new research, he said, suggests there may be a causal link.

“This was a very thorough and carefully done study, and I think the message to people who use artificial sweeteners is they need to use them in moderation,” he said. “Drinking 17 diet sodas a day is probably a bad idea, but one or two may be OK.”