Intestinal optogenetics elucidates the neurobiological mechanism of sucrose preference in the intestine

Sweet sensations can be induced by both sucrose and artificial sweeteners, but animals and humans prefer the former. Even mice without taste receptors are able to distinguish between sucrose and sweets. Although the tongue is responsible for sweetness perception, the duodenum is crucial in distinguishing between sucrose and sweeteners. Sweet, bitter or fresh taste receptor cells in the tongue form purinergic synapses with afferent nerve fibers to distinguish between tastes. In the nose, olfactory receptor cells transmit odor stimuli to monk's cap cells via glutamatergic synapses to help the animal discriminate between odors. In the intestine, this function is dependent on Neuropod cells for completion. Neuropod cells are a class of intestinal sensory epithelial cells that form synapses and release hormones such as CCK (cholecystokinin). CCK-positive Neuropod cells form glutamatergic synapses with vagal nodal neurons (https://neuros.creative-biolabs.com/category-primary-neurons-8.htm) and rapidly transmit sensory signals from the duodenum to the brain. On January 13, 2022, the Diego V. Bohórquez research team at Duke University explained the biological mechanism by which mice prefer to ingest sucrose—through neuropod cell glutamatergic signaling. Mice were anesthetized and given sucrose, D-glucose, D-fructose, D-galactose, sweetener, and -methylglucopyranoside (-MGP, a sucrose analogue), and practically all of the stimuli were able to induce vagal firing activity, excluding D-fructose. CCK-positive Neuropod cells were found to be partially responsive to sucrose and partially responsive to sweeteners by calcium ion indicators (https://neuros.creative-biolabs.com/category-calcium-channels-85.htm). They used single-cell sequencing of CCK-positive Neuropod cells to screen two cell populations, sweet taste receptor (T1R3) and sodium-glucose transporter protein 1 (SGLT1)-positive cells, to further differentiate the cell populations that can specifically respond to sucrose or sweetener. Sweeteners did not stimulate vagal firing activity after blocking T1R3, whereas sucrose did not induce vagal firing activity after inhibiting SGLT1. Isolated tissue culture experiments revealed that sucrose, but not the sweetener, was able to induce glutamate secretion from the intestinal epithelium, and that sucrose could not induce vagal firing activity after blocking ionotropic and metabotropic glutamate receptors, but the sweetener was still able to induce vagal firing activity, suggesting that the neurotransmitter glutamate is involved in the vagus nerve by perceiving information from sucrose. In response to sweet taste stimuli, taste receptor cells in the tongue release ATP, which stimulates purinergic receptors on sensory neurons, according to previous research. The researchers discovered that blocking purinergic receptors inhibited the vagus nerve's response to sweeteners, implying that ATP is involved in the vagus nerve's perception of sweetener information. To be able to further manipulate intestinal epithelial cells, the researchers developed an intestinal optogenetic tool. After photoinhibition of duodenal epithelial cells CCK-positive Neuropod cells, the perfusion of sucrose and sweetener did not induce firing activity of the vagus nerve. Mice normally prefer sucrose over sweeteners, but after photospecific inhibition of intestinal Neuropod cells, mice consume less sucrose and more sweeteners. Whereas activation of this cell type lead mice to consume more sweeteners, and this facilitation effect was blocked after inhibition of glutamate receptors. Findings from this study by intestinal genetic techniques suggest that duodenal Neuropod cells transmit stimulatory signals from sucrose and sweeteners via different neurotransmitters (glutamate) to different populations of vagal nodal neurons (T1R3-positive and SGLT1-positive cell populations).