Non-nutritive sweeteners affect human microbiomes and can alter glycemic responses

Since the late 1800s non-nutritive sweeteners have promised to deliver all the sweetness of sugar with none of the calories. They have long been believed to have no effect on the human body, but researchers publishing in the journal Cell on August 19 challenge this notion by finding that these sugar substitutes are not inert, and, in fact, some can alter human consumers' microbiomes in a way that can change their blood sugar levels.

In 2014, senior author Eran Elinav an immunologist and microbiome researcher at the Weizmann Institute of Science and the German National Cancer Center (DKFZ) and his team found that non-nutritive sweeteners affected the microbiomes of mice in ways that could impact their glycemic responses. The team was interested in whether these results would also be found in humans.

To address this important question, the research team carefully screened over 1300 individuals for those who strictly avoid non-nutritive sweeteners in their day-to-day lives, and identified a cohort of 120 individuals. These participants were broken into six groups: two controls and four who ingested well below the FDA daily allowances of either aspartame, saccharin, stevia, or sucralose.

"In subjects consuming the non-nutritive sweeteners, we could identify very distinct changes in the composition and function of gut microbes, and the molecules they secret into peripheral blood. This seemed to suggest that gut microbes in the human body are rather responsive to each of these sweeteners," says Elinav. "When we looked at consumers of non-nutritive sweeteners as groups, we found that two of the non-nutritive sweeteners, saccharin and sucralose, significantly impacted glucose tolerance in healthy adults. Interestingly, changes in the microbes were highly correlated with the alterations noted in people's glycemic responses."

To establish causation, the researchers transferred microbial samples from the study subjects to germ-free mice -- mice that have been raised in completely sterile conditions and have no microbiome of their own.

"The results were quite striking," says Elinav. "In all of the non-nutritive sweetener groups, but in none of the controls, when we transferred into these sterile mice the microbiome of the top responder individuals collected at a time point in which they were consuming the respective non-nutritive sweeteners, the recipient mice developed glycemic alterations that very significantly mirrored those of the donor individuals. In contrast, the bottom responders' microbiomes were mostly unable to elicit such glycemic responses," he adds. "These results suggest that the microbiome changes in response to human consumption of non-nutritive sweetener may, at times, induce glycemic changes in consumers in a highly personalized manner."

Elinav says that he expects the effects of the sweeteners will vary person to person because of the incredibly unique composition of our microbiome. "We need to raise awareness of the fact that non-nutritive sweeteners are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies."

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Your gut senses the difference between real sugar and artificial sweetener

Your taste buds may or may not be able to tell real sugar from a sugar substitute, but there are cells in your intestines that can and do distinguish between the two sweet solutions. And they can communicate the difference to your brain in milliseconds.

Not long after the sweet taste receptor was identified in the mouths of mice 20 years ago, scientists attempted to knock those taste buds out. But they were surprised to find that mice could still somehow discern and prefer natural sugar to artificial sweetener, even without a sense of taste.

The answer to this riddle lies much further down in the digestive tract, at the upper end of the gut just after the stomach, according to research led by Diego Bohórquez, an associate professor of medicine and neurobiology in the Duke University School of Medicine.

In a paper appearing Jan. 13 in Nature Neuroscience, "we've identified the cells that make us eat sugar, and they are in the gut," Bohórquez said. Infusing sugar directly into the lower intestine or colon does not have the same effect. The sensing cells are in the upper reaches of the gut, he said.

Having discovered a gut cell called the neuropod cell, Bohórquez with his research team has been pursuing this cell's critical role as a connection between what's inside the gut and its influence in the brain. The gut, he argues, talks directly to the brain, changing our eating behavior. And in the long run, these findings may lead to entirely new ways of treating diseases.

Originally termed enteroendrocrine cells because of their ability to secrete hormones, specialized neuropod cells can communicate with neurons via rapid synaptic connections and are distributed throughout the lining of the upper gut. In addition to producing relatively slow-acting hormone signals, the Bohórquez research team has shown that these cells also produce fast-acting neurotransmitter signals that reach the vagus nerve and then the brain within milliseconds.

Bohórquez said his group's latest findings further show that neuropods are sensory cells of the nervous system just like taste buds in the tongue or the retinal cone cells in the eye that help us see colors.

"These cells work just like the retinal cone cells that that are able to sense the wavelength of light," Bohórquez said. "They sense traces of sugar versus sweetener and then they release different neurotransmitters that go into different cells in the vagus nerve, and ultimately, the animal knows 'this is sugar' or 'this is sweetener.'"

Using lab-grown organoids from mouse and human cells to represent the small intestine and duodenum (upper gut), the researchers showed in a small experiment that real sugar stimulated individual neuropod cells to release glutamate as a neurotransmitter. Artificial sugar triggered the release of a different neurotransmitter, ATP.

Using a technique called optogenetics, the scientists were then able to turn the neuropod cells on and off in the gut of a living mouse to show whether the animal's preference for real sugar was being driven by signals from the gut. The key enabling technology for the optogenetic work was a new flexible waveguide fiber developed by MIT scientists. This flexible fiber delivers light throughout the gut in a living animal to trigger a genetic response that silenced the neuropod cells. With their neuropod cells switched off, the animal no longer showed a clear preference for real sugar.

"We trust our gut with the food we eat," Bohórquez said. "Sugar has both taste and nutritive value and the gut is able to identify both."

"Many people struggle with sugar cravings, and now we have a better understanding of how the gut senses sugars (and why artificial sweeteners don't curb those cravings)," said co-first author Kelly Buchanan, a former Duke University School of Medicine student who is now an Internal Medicine resident at Massachusetts General Hospital. "We hope to target this circuit to treat diseases we see every day in the clinic."

In future work, Bohórquez said he will be showing how these cells also recognize other macronutrients. "We always talk about 'a gut sense,' and say things like 'trust your gut,' well, there's something to this," Bohórquez said.

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