Astringent Gallic Acid in Red Wine Regulates Mechanisms of Gastric Acid Secretion via Activation of Bitter Taste Sensing Receptor TAS2R4.

Red wine is rich in phenolic compounds, which chiefly determine its characteristic taste. One of its major phenolic acid constituents for which an astringency, yet no clear contribution to bitter taste has been reported, is gallic acid (GA). In previous studies, we have demonstrated bitter-tasting constituents to regulate cellular proton secretion (PS) as a key mechanism of gastric acid secretion via activation of bitter taste sensing receptors (TAS2Rs). Here, we hypothesized a contributing role of GA to the red wine-stimulated effect on PS in human gastric tumor cells (HGT-1 cells). Sensory analyses revealed that 10 µM GA as the lowest concentration tested more bitter than tap water, with increasing bitter ratings up to 1000 µM. In HGT-1 cells, the concentration of 10 µM GA evoked the most pronounced effect on PS secretion, either when added to cells as in-water solution or when spiked to a red wine matrix. GA-spiking of Zweigelt and Blaufränkisch red wine samples up to a concentration of 10 µM resulted in an equally stimulated PS, whereas the non-GA-spiked wine samples demonstrated contrary effects on PS, indicating a functional role of GA on PS. Involvement of TAS2R4 in the GA-induced PS was verified by means of an HGT-1 homozygote CRISPR-Cas9 TAS2R4 knockout approach. Moreover, gene expression analyses revealed GA to increase TAS2R4. These results demonstrate a functional role of TAS2R4 in GA-evoked PS as a key mechanism of gastric acid secretion aiding digestion. Moreover, our data provide mechanistic insights, which will help to produce stomach-friendly red wines.

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

Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor, TAS2R43, and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine's bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bitter-masking compounds could be potentially useful therapeutics to regulate gastric pH.

Identification of Catechin, Syringic Acid, and Procyanidin B2 in Wine as Stimulants of Gastric Acid Secretion.

Organic acids of wine, in addition to ethanol, have been identified as stimulants of gastric acid secretion. This study characterized the influence of other wine compounds, particularly phenolic compounds, on proton secretion. Forty wine parameters were determined in four red wines and six white wines, including the contents of organic acids and phenolic compounds. The secretory activity of the wines was determined in a gastric cell culture model (HGT-1 cells) by means of a pH-sensitive fluorescent dye. Red wines stimulated proton secretion more than white wines. Lactic acid and the phenolic compounds syringic acid, catechin, and procyanidin B2 stimulated proton secretion and correlated with the pro-secretory effect of the wines. Addition of the phenolic compounds to the least active white wine sample enhanced its proton secretory effect by 65 ± 21% (p < 0.05). These results indicate that not only malic and lactic acid but also bitter and astringent tasting phenolic compounds in wine contribute to its stimulatory effect on gastric acid secretion.

Identification of organic acids in wine that stimulate mechanisms of gastric acid secretion.

Wine may cause stomach irritation due to its stimulatory effect on gastric acid secretion, although the mechanisms by which wine or components thereof activate pathways of gastric acid secretion are poorly understood. Gastric pH was measured with a noninvasive intragastric probe, demonstrating that administration of 125 mL of white or red wine to healthy volunteers stimulated gastric acid secretion more potently than the administration of equivalent amounts of ethanol. Between both beverages, red wine showed a clear trend for being more active in stimulating gastric acid secretion than white wine (p = 0.054). Quantification of the intracellular proton concentration in human gastric tumor cells (HGT-1), a well-established indicator of proton secretion and, in turn, stomach acid formation in vivo, confirmed the stronger effect of red wine as compared to white wine. RT-qPCR experiments on cells exposed to red wine also revealed a more pronounced effect than white wine on the fold change expression of genes associated with gastric acid secretion. Of the quantitatively abundant organic acids in wine, malic acid and succinic acid most actively stimulated proton secretion in vitro. However, addition of ethanol to individual organic acids attenuated the secretory effect of tartaric acid, but not that of the other organic acids. It was concluded that malic acid for white wine and succinic acid for red wine are key organic acids that contribute to gastric acid stimulation.