Glutamatergic neurotransmission in gut neuropod cells

SUMMARY
Despite the clear link between sugar overconsumption and metabolic syndrome, how the gut senses and
communicates the presence of sugar to the brain remains unknown. Studies have shown that preference for
sugars depends not on their sweet taste in the oral cavity, but rather on their entrance into the intestine.
Therefore, understanding how the gut communicates information about ingested sugars could open a new path
for pharmacotherapeutics for treating metabolic disease. The mechanisms of sensing nutrients in the gut are
thought to involve the slower paracrine and endocrine action of peptides released from enteroendocrine cells.
In recent years it has become evident that in addition to their canonical paracrine function, enteroendocrine
cells also form synapses with nerves in the underlying intestinal and colonic mucosa. These gut epithelial cells
that form synapses are known as neuropod cells. Our overall hypothesis is that glutamatergic neuropod cells
in the small intestine transduce sugar stimuli to guide sugar preference. This hypothesis builds on recent
observations: 1) the duodenal epithelium contains a population of glutamatergic neuropod cells labeled by the
vesicular glutamate transporter 1; 2) vagal nerve firing in response to intraduodenal sugar stimuli depends on
glutamatergic signaling; and 3) a mouse's preference for sugar over non-caloric sweetener is abolished by
silencing a subset of enteroendocrine cells. The objectives in this application are three-fold: 1) to determine
how glutamatergic neuropod cells are activated by sugar; 2) to establish the glutamatergic gut-to-vagus nerve
signaling pathway activated by sugars; and 3) to determine the role of glutamatergic neuropod signaling on
sugar preference. The outcomes of this research could serve as a foundation to design gut-based
pharmacotherapies that seek to curb the desire to consume sugar by targeting the receptors and signaling
molecules of glutamatergic epithelial cells.

Grant Number: 5R01DK131112-05
NIH Institute/Center: NIH
Principal Investigator: Diego Bohorquez