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The Gut’s Sweet Tooth May Undermine the Effectiveness of Sugar-Free Soda

The Gut’s Sweet Tooth May Undermine the Effectiveness of Sugar-Free Soda

The Gut’s Sweet Tooth May Undermine the Effectiveness of Sugar-Free Soda

The Gut’s Sweet Tooth May Undermine the Effectiveness of Sugar-Free Soda

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Sugar-free drinks and foods pass the taste test for many people looking to cut down on their calorie consumption. But a new study suggests that the gut is far harder to fool than our taste buds.

The investigation built on previous research showing that mice lacking the ability to taste can still tell calorific sugar solutions apart from sweetener or water, and still show preference for sugar.

These findings suggest that the mammalian gastrointestinal (GI) tract has some way of sensing sugar that exists south of the mouth. Researchers had previously established that when the small intestine is bypassed, this preference for sugar disappears, further narrowing the search. The latest study, published in Nature Neuroscience by a team from Duke University, claims to have found the cells responsible for our gut’s sweet tooth.

The sugar-sensing cells

“We discovered that a specific type of cell in the gut called neuropod cells sense both sugar and non-caloric sweetener. Using distinct signaling molecules, the neuropod cell synapses with nerves to direct an individual to select sugar over non-nutritive sweetener,” says Dr. Laura Rupprecht, a postdoctoral fellow in the Laboratory of Gut Brain Neurobiology at Duke Medicine.

These neuropod cells were discovered by Rupprecht’s colleagues in 2018. They sit at a critical interface between the cells in our gut and our parasympathetic nervous system (PNS). The PNS is responsible for carrying information related to a host of bodily processes, which can be roughly grouped into “rest-and-digest” behaviors. The key tract of the PNS is the vagus nerve, which connects our brain to our internal organs.

“We reasoned that the neuropod cells are positioned to drive these specific behaviors,” says Rupprecht. “Working as a team with material scientists at MIT, we developed a flexible fiber tool to control the neuropod cells using light.”

Bringing light to the gut

These experiments used a technique called optogenetics. The team bred mice who had a genetic alteration to their neuropod cells that effectively turned them off in the presence of a certain wavelength of light. The team measured the response in the vagus to sugar being introduced into the mice’s GI tracts. When the team turned on the optogenetic lights, that response disappeared, indicating that the neuropod cells carried the sugar signal.

The team’s next objective was to determine whether the cells could distinguish sugar from sweetener. Cell analysis showed that three populations of neuropods existed – some that activated in response to sugar, some to sweetener and others that responded to the presence of both compounds. The authors likened these cells to taste receptor cells in the tongue or retinal cone cells that help the eye discern color.

What Is Optogenetics?

Optogenetics is a technique, primarily used in neuromodulation, that gives researchers control over the activity of neurons or other cells or groups of cells. Animals are genetically modified so that some of their neurons express light-sensitive ion channels, allowing cell function to be turned on or off in response to light exposure.


The gut cells’ sweet sensation means that while sugar stimulated the cells to release the neurotransmitter glutamate, the artificial sweetener sucralose did not prompt such a release. The team grew organoids from both mouse and human gut cells and found that this glutamate response was similar in both, suggesting that the mouse mechanism is likely to be conserved in humans.

Finally, the team conducted behavioral experiments in a small sample of mice. These showed that when their-light sensitive neuropods were turned off, the animals’ sugar preference was eliminated. But after the laser light stimulation ended, their sugar affinity returned. In their paper’s discussion, the authors say that this suggests that “the animals did not lose their preference for sucrose but rather their ability to discern the preferred sugar from the sweetener.”

The big business of artificial sweeteners

These findings don’t just have ramifications for sugar-loving mice. Artificial sweeteners are a big business. The carbonated drink market in the US was worth roughly $70 billion in 2018, and Diet Coke alone has a roughly eight percent slice of that pie. For people that swear by diet sodas, the dietary benefits they present are clear – you can get a sugary rush while bypassing the calories. But Rupprecht’s research suggests that the gut can see through the trick, and that might have implications for these drinks’ efficacy at keeping us away from calories.

“The data on the efficacy on artificial sweeteners are mixed – in some situations, they can help people lose weight and curb cravings, but in other situations, they have no impact or even an opposite impact on eating,” Rupprecht explains. “Our data may explain some of these mixed findings. We find that artificial sweeteners signal to the brain, but do not direct behavior in the same way as caloric sugars.” In short, artificial sweeteners might fool our taste neurons, but the cells working out the hard math of the energy we consume are unconvinced by the illusion.

For individuals who lean on diet sodas to help keep their calorie consumption down (or those who just cannot stop drinking it) these findings are the latest in a series of studies that questions these drinks’ effects on our bodies. But Rupprecht says their analysis also offers a new route for treatment targeting excessive sugar and calories consumption that may sweeten the picture. “The current medications to help control weight or food intake target gut hormone signals. Our findings suggest that targeting the gut synapse may be a novel route to help people struggling with sugar intake,” she concludes.

Reference: Buchanan KL, Rupprecht LE, Kaelberer MM, et al. The preference for sugar over sweetener depends on a gut sensor cell. Nat Neurosci. 2022;25(2):191-200. doi:10.1038/s41593-021-00982-7

Meet the Author
Ruairi J Mackenzie
Ruairi J Mackenzie
Senior Science Writer