Artificial Sweeteners Linked to Glucose Intolerance

Beth Skwarecki

September 17, 2014

The artificial sweeteners aspartame, sucralose, and saccharin cause blood glucose abnormalities in mice and some humans, a team reports in an article published online September 17 in Nature. The changes in glucose tolerance seem to be driven by the microbiome and can be reproduced in germ-free mice by giving them gut microbes from a person who has consumed the sweeteners.

"We found that artificial sweeteners may drive...an exaggerated elevation in blood glucose levels, the very same condition that we often aim to prevent by consuming them," Eran Elinav, MD, PhD, from the Department of Immunology at the Weizmann Institute of Science, Rehovot, Israel, said at a press briefing.

The investigators began with experiments in mice, giving each animal 1 of 3 artificial sweeteners in its water: aspartame, sucralose, or saccharin. Because commercial preparations of these sweeteners also contain some glucose, researchers used glucose, fructose, or plain water for the control mice to ensure it was the artificial sweetener and not any added sugar that was responsible for the effect. "To our surprise, we found they all induced a blood sugar disturbance even compared to mice who drank sugary water," Dr. Elinav said. This effect occurred on both a normal diet of rat chow (P < .001) and a high-fat diet in which 60% of calories came from fat (P < .03).

Because these artificial sweeteners are not digested or absorbed by the human body, the investigators hypothesized that gut microbes were responsible for the results. They administered antibiotics to the mice: 1 group received ciprofloxacin and metronidazole, a broad-spectrum approach focusing on gram-negative bacteria, and another group received vancomycin, aimed against gram-positive bacteria. Both treatments, when given for 4 weeks, eliminated the differences in glucose tolerance between sweetener-fed mice and controls.

The symptoms could also be triggered by a microbial transplant. Microbes from mice who had been drinking saccharin were transplanted via feces into germ-free mice and caused the recipients to show impaired glucose tolerance, whereas microbes from mice who had been drinking glucose did not (P < .03). Further, to show that the microbes were responsible, and not some other component of the feces, the researchers cultured bacteria from mice who were not eating sweeteners and added saccharin to the growth media. These bacteria were then transplanted into germ-free mice, resulting in impaired glucose tolerance compared with mice that received a control culture (P < .002).

Bacterial Profiles

The researchers performed both 16S sequencing, to identify the bacteria that were over- or underrepresented in mice with impaired glucose tolerance, and metagenomic sequencing, to identify what those bacteria are doing. In the microbial ecosystems from mice that ate artificial sweeteners, the pathways that were overrepresented included several that had previously been linked to diabetes and glucose intolerance. Glycan degradation, for example, occurs when microbes digest certain chains of sugars and create short-chain fatty acids that the body can use for energy, providing extra calories. The investigators confirmed that the sweetener-fed mice had increased amounts of this end product, the short chain fatty acids, in their guts.

In Humans

Artificial sweeteners caused changes in glucose tolerance in humans, as well, but only for some participants the investigators consider to be "responders." A group of 7 healthy volunteers who do not normally consume artificial sweeteners were given saccharin for 6 days at a dose that met the US Food and Drug Administration's maximum acceptable daily intake of saccharin for humans. No participants saw improvements in glucose tolerance, but 4 showed impairment.

Even before the experiment began, the microbial ecosystems from the 4 responders were different from those of the 3 nonresponders, suggesting their microbiome was somehow more susceptible. These results, said Dr. Elinav, "point to the personalized nature of our food responses and the need to understand this personalized effect in order to fight the metabolic syndrome, which as we all know, is one of the most common and serious epidemics in all history."

Bacteria from responders, sampled at the end of the trial, were able to induce glucose intolerance when introduced into germ-free mice (P < .02), whereas baseline samples from the responders (taken before they had consumed the artificial sweeteners) did not have this effect, nor did bacteria from the nonresponders.

Trend Seen With Long-Term Consumption

A further experiment involving 381 nondiabetic participants showed that long-term consumption of artificial sweeteners was associated with measures of central obesity and glucose intolerance, even when corrected for body mass index.

The authors caution that the results from the human experiments are not yet enough to make recommendations about whether or not people should consume sweeteners. They also point out that the mechanism for the sweeteners' effect is unknown: it may be causing less desirable bacteria to thrive, or it may be poisoning certain normal bacteria, allowing detrimental species to take their place.

In an accompanying editorial, Taylor Feehley, BA, and Cathryn Nagler, PhD, both from the Department of Pathology at the University of Chicago, note that "Whether the bacterial populations or metabolic pathways altered by the consumption of [artificial sweeteners] are similar to those described in people with or developing diabetes remains to be seen."

The authors have disclosed no relevant financial relationships.

Nature. Published online September 17, 2014. Abstract

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