Abstract

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.

Highlights

  • Both sugar and artificial sweeteners elicit a sweet taste, but sugar is preferred by animals and humans

  • We found that nodose neurons expressed purinergic receptors and that CCK–GFP cells expressed the vesicular nucleotide transporter for ATP Slc17a9 (VNUT) (Fig. 3b and Extended Data Fig. 4d)

  • Uncoupling the synapses between neuropod cells and vagal neurons will inform how appetitive functions beyond choice are continuously modulated by fast neurotransmission from the gut epithelium. In his classic book Behave, the neuroendocrinologist Robert Sapolsky states ‘What occurred in the prior seconds to minutes that triggered the nervous system to produce the behavior, this is the world of sensory stimuli, much of it sensed unconsciously’[39]

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Summary

Introduction

Both sugar and artificial sweeteners elicit a sweet taste, but sugar is preferred by animals and humans. Sweet, bitter or umami taste receptor cells form purinergic synapses with afferent nerve fibers to guide an animal in distinguishing tastants[12]. In the gut, this function seems to be performed by neuropod cells[13,14]. In 2018, CCK-labeled duodenal neuropod cells were shown to form glutamatergic synapses with the vagus nerve[14]. These cells use the neurotransmitter glutamate to transduce a d-glucose stimulus from the gut to the brain in milliseconds We hypothesized that duodenal neuropod cells discern nutritive sugars from non-caloric artificial sweeteners to guide the animal’s preference for sugar over sweetener

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