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The sweet spot: how a gut sensory cell determines preference for sugar over artificial sweetener

Researchers have discovered how gut sensory cells discern nutritive sugars from non-caloric artificial sweeteners to guide an animal’s preference for sugar.

Packets of artificial sweeteners

It has been known for decades that animals and humans generally prefer sugar to artificial sweeteners, that sweet-sensing taste buds on the tongue are not essential to drive sugar intake, and that this preference for sugar relies on feedback from the gut. But how the gut steers such preferences has remained elusive. The current study builds upon research from the same team who previously identified a direct line of communication between neuropod cells (sensory cells in the gut) and the brain that allows for sensing and rapid signaling of information about food intake. Here, they delved deeper to determine whether this gut-to-brain pathway can discriminate between nutrient stimuli, and if so, which neural mechanisms underlie this differentiation. Using lab-grown “mini-organs” derived from mouse and human cells to represent the small intestine, the researchers showed that real sugar stimulated neuropod cells to release a chemical neurotransmitter called glutamate that is relayed to the brain, while artificial sweetener triggered the release of a different neurotransmitter, ATP, likely activating a different gut-brain pathway.

Next, the scientists aimed to determine whether neuropod cells are necessary for the animals’ sugar preference by using a technique called optogenetics to control the activity of the cells with light. To do this, the scientists first developed a novel, flexible fiber-optic cable adapted to the unique biological conditions of the gut. They were then able to turn the neuropod cells “on” and “off” in the guts of genetically engineered, live mice. The mice exposed to a wavelength of light that silences neuropods lost their preference for consuming sugar over sweetener, while mice exposed to a neutral wavelength of light did not, suggesting that neuropod cells are essential for the gut to send signals to the brain that help the animal discriminate between sugar and artificial sweeteners. Moreover, when the researchers inhibited glutamate signaling with a drug delivered to neuropod cells in the gut, sugar preference was reduced, indicating that glutamate signaling from neuropod cells enables mice to discern sugar from sweetener.

Taken together, these results demonstrate the sensory role of neuropod cells in the gut and show that they can differentiate among different stimuli similar to other sensory cells (e.g., taste buds on the tongue detecting different flavors or retinal cells in eyes detecting different colors). This study lays the foundation for future research to determine how other nutritional stimuli, such as fats and proteins, are sensed by the gut and transmitted to the brain to influence food choices. It also raises the possibility that interventions could eventually be developed to help people reduce sugar intake.

Buchanan KL, Rupprecht LE, Kaelberer MM, …Bohórquez DV. The preference for sugar over sweetener depends on a gut sensor cell. Nat Neurosci 25: 191-200, 2022.

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