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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Major newspapers, wire sources, and Internet consumer health outlets cover a study suggesting that the use of artificial sweeteners may interfere with how the body metabolizes sugar and in some individuals may even alter bacteria in the gut.
USA Today (9/18, Weintraub) reports that according to a study published online Sept. 17 in the journal Nature, “reaching for artificial sweeteners to avoid sugar may be trading one evil for another.” Researchers from the Weizmann Institute of Science in Israel posit that “differences in gut microbes may explain why some people can handle artificial sweeteners just fine while in an unknown percentage of others the sweeteners lead to diabetes.”
The Wall Street Journal (9/18, A6, Naik, Subscription Publication) reports that in work with mice and then with people, researchers examined the effects of sucralose, aspartame and saccharin on the gut microbiota and on levels of blood glucose.
The Washington Post (9/18, Dennis) reports that mice fed the artificial sweeteners experienced “increased risk of glucose intolerance, a condition that can lead to diabetes.” Researchers then “monitored what happened to seven human volunteers who did not typically use artificial sweeteners but were given regular doses of saccharin over the course of a week.” Four volunteers went on to develop “significant glucose intolerance.” The Post also notes that “the American Medical Association and the American Diabetes Association have cautiously backed the use of non-caloric sugar substitutes as a way to fight obesity and diabetes, saying that the products can be part of a healthy diet as long as the calories saved aren’t replaced by consuming more food over the course of a day.”
The Los Angeles Times (9/18, Netburn) “Science Now” blog reports “genetic analysis” also “revealed that the composition of the gut bacteria in mice had indeed changed after exposure to the artificial sweetener – some types of bacteria became more abundant, while others shrank.” The researchers also “said a computer algorithm looked at the gut microbes of the seven people and clustered them into two groups,” one group with people “affected by the artificial sweeteners, and the other group” with people who seemed to be unaffected by them.
The New York Times (9/18, Chang) “Well” blog reports that the latter finding “suggests that any effects of artificial sweeteners are not universal.” In addition, it “suggests probiotics – medicines consisting of live bacteria – could be used to shift gut bacteria to a population that reversed the glucose intolerance.”
According to the AP (9/18, Ritter), the study “authors said they are not recommending any changes in how people use artificial sweeteners based on their study.” Instead, they, along with “outside experts, said more study is needed, while industry groups called the research limited and said other evidence shows sweeteners are safe and useful for weight control.” The Food and Drug Administration, in a statement, “said the sweeteners ‘have been thoroughly studied and have a reasonable certainty of no harm to consumers.’”
Also covering the study are the NBC News (9/18, Fox) website, Reuters (9/18, Kelland), Nature (9/18, Abbott), TIME (9/18, Park), HealthDay (9/18, Thompson) and Medscape (9/18, Skwarecki).
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