Sweet taste receptor expression in ruminant intestine and its activation by artificial sweeteners to regulate glucose absorption

Abstract

Absorption of glucose from the lumen of the intestine into enterocytes is accomplished by sodium-glucose co-transporter 1 (SGLT1). In the majority of mammalian species, expression (this includes activity) of SGLT1 is upregulated in response to increased dietary monosaccharides. This regulatory pathway is initiated by sensing of luminal sugar by the gut-expressed sweet taste receptor. The objectives of our studies were to determine (1) if the ruminant intestine expresses the sweet taste receptor, which consists of two subunits [taste 1 receptor 2 (T1R2) and 3 (T1R3)], and other key signaling molecules required for SGLT1 upregulation in nonruminant intestines, and (2) whether T1R2-T1R3 sensing of artificial sweeteners induces release of glucagon-like peptide-2 (GLP-2) and enhances SGLT1 expression. We found that the small intestine of sheep and cattle express T1R2, T1R3, G-protein gustducin, and GLP-2 in enteroendocrine L-cells. Maintaining 110-d-old ruminating calves for 60d on a diet containing a starter concentrate and the artificial sweetener Sucram (consisting of saccharin and neohesperidin dihydrochalcone; Pancosma SA, Geneva, Switzerland) enhances (1) Na(+)-dependent d-glucose uptake by over 3-fold, (2) villus height and crypt depth by 1.4- and 1.2-fold, and (3) maltase- and alkaline phosphatase-specific activity by 1.5-fold compared to calves maintained on the same diet without Sucram. No statistically significant differences were observed for rates of intestinal glucose uptake, villus height, crypt depth, or enzyme activities between 50-d-old milk-fed calves and calves maintained on the same diet containing Sucram. When adult cows were kept on a diet containing 80:20 ryegrass hay-to-concentrate supplemented with Sucram, more than a 7-fold increase in SGLT1 protein abundance was noted. Collectively, the data indicate that inclusion of this artificial sweetener enhances SGLT1 expression and mucosal growth in ruminant animals. Exposure of ruminant sheep intestinal segments to saccharin or neohesperidin dihydrochalcone evokes secretion of GLP-2, the gut hormone known to enhance intestinal glucose absorption and mucosal growth. Artificial sweeteners, such as Sucram, at small concentrations are potent activators of T1R2-T1R3 (600-fold>glucose). This, combined with oral bioavailability of T1R2-T1R3 and the understanding that artificial sweetener-induced receptor activation evokes GLP-2 release (thus leading to increased SGLT1 expression and mucosal growth), make this receptor a suitable target for dietary manipulation.

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

“…Similar effects of GLP-2 treatment of calves, including increased weight of both the small and large intestines and increased tissue density of the small intestine, were reported by Connor et al [89]. Most recently, Moran et al [25] reported that stimulation of GLP-2 release via sweet taste receptor activation by the feeding of an artificial sweetener containing nonmetabolizable saccharin (Sucram; Pancosma SA, Geneva, Switzerland) increased the activity of digestive enzymes such as maltase and alkaline phosphatase in the intestinal brush border of ruminating calves and tended to increase their feed conversion efficiency measured as gainto-feed ratio (G:F) [90]. In addition, Sucram feeding to mature, lactating cows enhanced their mucosal growth through elevated intestinal glucose transporter (SGLT1) expression and enhanced glucose absorption [25].…”

“…This primarily was due to the discovery that enteric peptides, such as glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide, and peptide YY, play key roles in the regulation of appetite, energy metabolism [15][16][17], and gut function [18][19][20], making them targets for managing prevalent human diseases of obesity and diabetes. As knowledge has continued to grow, the potential to improve gut function and health of food animals through the manipulation of enteric peptide secretion has become increasingly more apparent [21][22][23][24][25][26].…”

Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK

“…Signals from T1R2/T1R3 receptors in the apical mucosal membrane that sense but do not absorb luminal sugars in mammalian intestine (36,56) upregulate SGLT1 and may also directly stimulate expression of fructolytic and gluconeogenic genes as part of an adaptation to a sweeter diet. Because fructose-induced increases in the expression of these genes are abrogated in GLUT5-KO mice, potential signaling from these sweet receptors is either insufficient or unrelated to fructose metabolism.…”

“…Using genetically modified mice, we tested the hypothesis that GLUT5-mediated fructose transport, KHK-mediated fructolysis, and Rab11a-mediated GLUT5 trafficking are each required for fructose to induce expression of enzymes involved in fructolysis and gluconeogenesis. Because sweet taste receptors able to sense luminal sugars and artificial sweeteners have been localized in the small intestine (36), fructose may need not enter the enterocytes for induction to occur. The role of fructose transport in fructolytic and gluconeogenic enzyme regulation was evaluated using GLUT5 knockout (KO) mice.…”

High-intensity sweetener consumption and gut microbiome content and predicted gene function in a cross-sectional study of adults in the United States

“…Gut regulation of glucose uptake or tolerance may influence host health. Animal and human studies suggest that high-intensity sweeteners can modulate gut absorption of sugars (20)(21)(22)(23). In recent work, Suez et al (2014) demonstrated using mouse models and in vitro cultures of stool microbiota that saccharin mediates glucose intolerance through alterations in the gut microbiota (24).…”