People who are watching their weight will often opt for a diet soda, reasoning that the fewer calories, the better. But the availability of drinks and foods made with artificial sweeteners like saccharin, sucralose, and aspartame hasn't seemed to help much with our booming obesity levels. Now, some researchers might have identified a reason for this: the sweeteners leave their users with elevated blood glucose levels. But they don't seem to act directly on human metabolism. Instead, the effects come through alterations in the bacterial populations that live inside us.

The paper that describes this work, which was performed by a large collaboration of researchers from Israel, is being released by Nature today. The researchers note that epidemiological studies about the effects of artificial sweeteners have produced mixed results; some show a benefit, while others indicate that they're associated with weight gain and diabetes risk. Given that human populations haven't given us a clear answer, the researchers turned to mice, where they could do a carefully controlled study.

They started taking a group of genetically matched mice and spiking their drinking water with either sucrose or a commercial prep of an artificial sweetener (either saccharin, sucralose, or aspartame). After five weeks, they checked the blood glucose levels of these animals. Eleven weeks later, the groups that were given the artificial sweeteners all had elevated blood glucose levels compared to those that received sucrose. This is typically a sign of metabolic problems, most often caused by insulin losing its effectiveness. It can be a precursor to type 2 diabetes.

The same held true if the animals were given a high-fat diet, which indicates the same problem occurs in the population that is likely to be using the artificial sweeteners: the obese.

That's a striking result, but it doesn't tell us anything about how the artificial sweeteners are causing this effect. Over the past few years, however, diabetes research has pointed a finger at the symbiotic bacteria that live in our digestive tract—termed the "gut microbiome." These organisms get a chance to digest anything we eat as well, and they can both alter the nutrients our own cells have access to and release chemicals that influence human health.

The authors wondered whether the gut bacteria might be acting as intermediaries between the artificial sweeteners and the glucose response. Their first test of this idea was simply to wipe out the bacteria with a heavy dose of antibiotics. When they did so, the difference between the animals getting glucose and the animals getting artificial sweeteners vanished. To really nail down the case, the authors obtained fecal material from the mice given artificial sweeteners and transferred it to mice that had been treated with antibiotics. The mice receiving the transplants showed reduced tolerance to glucose.

Could this really be relevant to human health? To get a hint, the team got seven healthy volunteers to start consuming high levels of saccharin (the FDA's recommended maximum daily dose). At the end of a week, four of them ended up with a reduced insulin response. Again, the researchers took stool samples and gave them to germ-free mice. Fecal transplants from those who had a poor insulin response transferred this response to the mice; fecal transplants from the ones who were unaffected by the saccharine had no effect.

What could possibly be happening with these bacteria? To find out, the researchers did a sampling of the DNA in the fecal samples. Having artificial sweeteners clearly shifted the bacterial species present in the gut microbiome, causing the numbers of some groups to rise and others to fall. The same result occurred if the samples were grown in culture. In addition, the genes expressed by the resulting populations were different. Some metabolic pathways became more active, while others were toned down. (It's not clear whether this shift is from the changing bacterial populations or from different metabolic behavior among whatever bacterial species are present.)

This will have two effects: it will both change the nutrients available for human cells, and it will change the metabolic products that are released by the bacteria. Presumably, one or both of these effects alters how the body handles insulin and glucose, although the precise mechanism will need to await further studies.

For those of you who remember early health scares about artificial sweeteners and are thinking "aha, they were right!"—they weren't. Those worries focused on effects specific to the chemicals themselves. These findings are general to any artificial sweetener, even though the three have distinctive chemical properties.

This also doesn't mean that these sweeteners are unadulterated evil. The human trials were extremely short and had a small population, so they will need a more thorough follow-up. Even then, it was clear that not everyone has the same response to artificial sweeteners. This shouldn't be a surprise. People have a far more varied microbiome than genetically identical lab mice raised in sterile conditions will, and that microbiome will interact with the different things that people eat as a normal part of their diets.

Understanding the details of when and how the microbiome influences insulin levels will take a lot of additional work. Only when that work is done will we have a clear picture of who is likely to see a negative effect from using artificial sweeteners. So although this was a comprehensive study about what happens in mice, the emphasis has to be on the word "may" when the authors conclude, "Our findings suggest that NAS may have directly contributed to enhancing the exact epidemic that they themselves were intended to fight."

Nature, 2014. DOI: 10.1038/nature13793 (About DOIs).