Molecular Medicine Israel

The preference for sugar over sweetener depends on a gut sensor cell


Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.


Both sugar and artificial sweeteners elicit a sweet taste, but sugar is preferred by animals and humans. Even mice lacking taste receptors can distinguish sugar from sweetener or water1,2,3. Although sensing sweetness depends on the tongue, flavor-conditioning tests show that the duodenum is needed to discern sugar from sweeteners.

Table sugar, or sucrose, is a disaccharide made of D-glucose and D-fructose. Unlike D-fructose or the sweetener sucralose, D-glucose conditions a robust preference when infused into the duodenal lumen3,4,5,6,7. In fact, animals with prior D-glucose exposure identify the sugar entering the intestine within minutes8. This ability to identify D-glucose vanishes when the small intestine is bypassed9,10, suggesting that the duodenal epithelium is where the ‘sugar transducer’ cell resides. But up until now, the identity of these cells has remained elusive because of the lack of tools to control gut sensory processing with temporal and spatial precision.

In other epithelial surfaces, electrically excitable cells use molecular receptors to detect and transduce sensory stimuli onto a cranial nerve to guide behavior. In the nose, for instance, olfactory receptor cells transduce odorant stimuli through glutamatergic synapses onto second-order mitral cells to assist the animal in distinguishing odors11. In the tongue, sweet, bitter or umami taste receptor cells form purinergic synapses with afferent nerve fibers to guide an animal in distinguishing tastants12. In the gut, this function seems to be performed by neuropod cells13,14.

Neuropod cells were first documented when enteroendocrine cells, known for their release of hormones such as CCK, were found to form synapses with underlying mucosal nerves15,16. In 2018, CCK-labeled duodenal neuropod cells were shown to form glutamatergic synapses with the vagus nerve14. These cells use the neurotransmitter glutamate to transduce a D-glucose stimulus from the gut to the brain in milliseconds (see video

We hypothesized that duodenal neuropod cells discern nutritive sugars from non-caloric artificial sweeteners to guide the animal’s preference for sugar over sweetener.


The vagus nerve responds to sugars and sweeteners

We first assessed whether a broad range of sugars, sugar analogs and non-caloric sweeteners perfused into the proximal small intestine would elicit rapid vagal responses. The vagus nerve responds to intraluminal sucrose14,17, but the response to other sugars and sweeteners commonly found in foods was unknown. Vagal firing rate was recorded in response to sugars (sucrose (300 mM), D-glucose (150 mM), D-fructose (150 mM) and D-galactose (150 mM)), sugar analogs (α-methylglucopyranoside (α-MGP; 150 mM) and maltodextrin (8%)) and sweeteners (sucralose (15 mM), acesulfame K (15 mM) and saccharin (30 mM)). All stimuli were perfused at physiological concentrations (see Methods)14 through the proximal duodenum, bypassing gustatory or gastric activation. Neural responses were recorded using electrodes placed at the cervical vagus nerve….

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