Targeting extra-oral bitter taste receptors modulates gastrointestinal motility with effects on satiation

Abstract

Bitter taste receptors (TAS2Rs) are present in extra-oral tissues, including gut endocrine cells. This study explored the presence and mechanism of action of TAS2R agonists on gut smooth muscle in vitro and investigated functional effects of intra-gastric administration of TAS2R agonists on gastric motility and satiation. TAS2Rs and taste signalling elements were expressed in smooth muscle tissue along the mouse gut and in human gastric smooth muscle cells (hGSMC). Bitter tastants induced concentration and region-dependent contractility changes in mouse intestinal muscle strips. Contractions induced by denatonium benzoate (DB) in gastric fundus were mediated via increases in intracellular Ca2+ release and extracellular Ca2+-influx, partially masked by a hyperpolarizing K+-efflux. Intra-gastric administration of DB in mice induced a TAS2R-dependent delay in gastric emptying. In hGSMC, bitter compounds evoked Ca2+-rises and increased ERK-phosphorylation. Healthy volunteers showed an impaired fundic relaxation in response to nutrient infusion and a decreased nutrient volume tolerance and increased satiation during an oral nutrient challenge test after intra-gastric DB administration. These findings suggest a potential role for intestinal TAS2Rs as therapeutic targets to alter gastrointestinal motility and hence to interfere with hunger signalling.

Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers

“…Comparing the two 322 studies is difficult due to species and sex differences and also differences in the dosage. The Furthermore, bitter compounds induced concentration and region-dependent contractility 329 changes in mouse intestinal muscle strips (13). 330 However, the current study does not rule out that the findings related to the administration 331 of DB are mediated via a different pathway.…”

“…291 In addition we found that in women, but not in men, there was a switch in the origin of phase (22). A dose of 1 µmol/kg DB was chosen since this dosage 296 significantly inhibited gastric accommodation without inducing adverse events (13). Also in 297 the present study no adverse events were reported by the volunteers.…”

“…Moreover, DB stimulated the in 42 vitro release of glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), which are known 43 to increase satiety and satiation respectively (11,12). Intragastric administration of DB in 44 humans has been shown to impair relaxation of the proximal stomach after infusion of a liquid 45 meal and to increase satiation during an oral nutrient tolerance test (13). 46 During the fasting state, the gastrointestinal tract (GIT) exhibits a specific contractility pattern 47 known as the migrating motor complex (MMC), which can be divided into three phases 17).…”

“…Study design 69 The current study consisted of 5 independent protocols studying the following parameters: provided 80% power to detect significant differences of 15% with an alfpha of 0.05 (13,23,92 24). Based on the results obtained from the lingual (study 1) and gastrointestinal (study 2) 93 bitter sensitivity studies it was decided to only include female participants for the last 3 study 94 protocols.…”

Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells

“…This hypothesis has been verified by measuring the effect of HED on gastric motility in strips of stomach dissections in an organ bath. Avau et al (37) demonstrated that bitter compounds such as denatonium benzoate increased contractility in gastric strips of mice and caused an impairment of gastric relaxation after intragastric infusion. Whether a bittermasking compound has opposite effects by causing gastric relaxation is an open question.…”