Dietary sugars are transported from the intestinal lumen into absorptive enterocytes by the sodium-dependent glucose transporter isoform 1 (SGLT1). Regulation of this protein is important for the provision of glucose to the body and avoidance of intestinal malabsorption. Although expression of SGLT1 is regulated by luminal monosaccharides, the luminal glucose sensor mediating this process was unknown. Here, we show that the sweet taste receptor subunit T1R3 and the taste G protein gustducin, expressed in enteroendocrine cells, underlie intestinal sugar sensing and regulation of SGLT1 mRNA and protein. Dietary sugar and artificial sweeteners increased SGLT1 mRNA and protein expression, and glucose absorptive capacity in wild-type mice, but not in knockout mice lacking T1R3 or ␣-gustducin. Artificial sweeteners, acting on sweet taste receptors expressed on enteroendocrine GLUTag cells, stimulated secretion of gut hormones implicated in SGLT1 upregulation. Gut-expressed taste signaling elements involved in regulating SGLT1 expression could provide novel therapeutic targets for modulating the gut's capacity to absorb sugars, with implications for the prevention and/or treatment of malabsorption syndromes and diet-related disorders including diabetes and obesity.carbohydrate absorption ͉ gastrointestinal chemosensation ͉ glucose sensor ͉ glucose uptake T o date, the only identified sugar sensors in the mammalian gastrointestinal tract are those involved in taste transduction (1). Although the gut epithelium senses luminal sugars and modulates its glucose absorptive capacity accordingly, the nature of the sugar-sensing molecule(s) and downstream events remain unknown. Several studies have shown that in many species expression of the intestinal sodium-dependent glucose transporter 1 (SGLT1) is directly regulated by monosaccharides in the lumen of the gut independently of metabolism and appears to involve a G protein-linked second messenger pathway (2-6). Furthermore, the addition of membrane-impermeable glucose analogues to the lumen of the intestine stimulates SGLT1 expression, implying that a glucose sensor on luminal membranes is involved (6).In taste cells, the detection of sugars and sweeteners depends on T1R2ϩT1R3, a heterodimer of type 1 taste receptor subunits (T1Rs) (7,8). The taste receptor cells of the anterior tongue that express T1R2ϩT1R3 typically also express gustducin, a transducin-like heterotrimeric G protein (9). Gustducin's ␣-subunit (G␣ gust ) has been detected in brush cells of the rat stomach, duodenum, and pancreatic ducts (10). G␣ gust and bitter-responsive type 2 taste receptors (T2Rs) are expressed in mouse intestinal endocrine cells and in the murine enteroendocrine cell line STC-1 (11).We reported previously that T1R taste receptors and G␣ gust are expressed in the mouse small intestinal epithelium and proposed that they function as luminal sugar sensors to control SGLT1 expression in response to dietary sugar (12). Here, we provide three lines of evidence in favor of T1R taste receptors an...