Mammals recognize bitter constituents in food through individual small "bitter" molecule agonists stimulation of individual cell surface receptors. These taste 2 receptors (T2Rs) are encoded by a family of single-exon g- protein coupled receptor (GPCR) genes and are predominantly expressed in taste receptor cells (TRCs) on the surface of the tongue and surrounding oral tissue. There is a lone GPCR involved in the majority of sweet taste sensing which is a heterodimer of Taste 1 Receptor (T1R) monomers T1R2 and T1R3. The single sweet and the entire family of bitter T2 receptors are also expressed in areas outside of the oral cavity including the lung, pancreas, and small intestine. Their function in the tongue is obviously to allow taste discrimination between differen potential food sources, however, the physiologic role for taste receptors outside of the oral cavity is not intuitively obvious. In recent publications, we showed that activation of intestinal T2R signaling leads to an increase in secretion of polypeptide hormones cholecystokinin (CCK) and glucagon-like-peptide-1 (GLP-1) from enteroendocrine cells and two major actions of CCK are to limit food intake and slow gastric motility. These results suggest intestinal T2Rs may limit absorption of bitter and potentially toxic molecules that are ingested despite the taste aversion in the mouth. We also showed that intestinal expression and activity of the T2Rs is regulated by the sterol regulatory element binding protein -2 (SREBP-2) transcription factor, which is induced when cellular cholesterol levels are low and activates genes required for accumulating new cell cholesterol. Plant enriched diets are both low in cholesterol and have a higher proportion of bitter tasting and potentially toxic substances relative to diets rich in cholesterol-laden animal flesh. Thus, induction of T2R activity through SREBP-2 on low-cholesterol plant diets provides a mechanism to "sensitize" the gut to the presence of potentially toxic molecules to limit their absorption through CCK dependent suppression of both gut motility and food in take. It should be noted that CCK and the gut peptide hormone gastrin have identical carboxyl termini and the ELISA we used in our early studies detects both hormones with similar sensitivity. Thus, gastrin may be the relevant hormone that is induced by T2R signaling in the gut and our current project is designed to address this key issue. We also showed CCK/gastrin increases expression and activity of the ABCB1 efflux transporter, which is known to prevent cellular uptake of a wide range of toxic organic small molecules. This provides a more active mechanism to limit absorption of toxic molecules consumed during a meal or by accident. Taken together, these studies provide a molecular mechanism connecting nutrient sensing with protection from toxin ingestion. The current proposal combines physiologic studies in select mouse models that have mutations in genes encoding critical proteins of the nutrient sensing and toxin efflux pathways to rigorously test the mechanism. We also propose to adopt a novel in situ assay with isolated small intestine to monitor the connection between T2R signaling and toxin efflux directly.

Public Health Relevance

Bitter tasting dietary substances are more naturally prevalent in plant based foods and there is a correlation between whether a compound tastes bitter and is also toxic. Thus, the evolutionary role for the aversive response to bitter-tasting foods was to prevent the ingestion of potentially toxic dietary contents. The same receptor proteins that recognize bitter tasting substances in your mouth are also expressed in the enteroendocrine cells (EEC) that line your gastrointestinal (GI) tract. The physiologic role for the bitter receptos in the GI tract has been enigmatic but our recent studies suggest bitter receptor signaling in the gut limits absorption of dietary bitter/toxic molecules by increasing expression of the ABCB1 efflux transporter that is known to limit cellular uptake of a wide variety of toxic small organic molecules. This proposal is focused on defining the mechanism for how bitter receptor signaling in the GI tract regulates ABCB1 activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK097757-01A1
Application #
8528267
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Grey, Michael J
Project Start
2013-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$424,125
Indirect Cost
$206,625
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037