Luminal Chemosensing and Mucosal Defenses in the Upper GI Tract

Recent discoveries of taste receptors in the lingual taste buds and the de-orphanization of G protein-coupled receptors (GPCRs), including nutrient receptors and olfactory receptors, in addition to the previously cloned ligand-gated cation channels such as the transient receptor potential (TRP) families and acid-sensing ion channels (ASICs), provide an understanding of luminal chemosensing in that most nutrient or nonnutrient chemical substances are sensed by membrane surface receptors or channels on the GI epithelium or on the surface subepithelial afferent nerves. Furthermore, recent technological advances have facilitated the purification of specific enteroendocrine cell types in which a fluorescent protein-tagged target hormone is expressed, including proglucagon-expressing L cells and cholecystokinin (CCK)-expressing I cells, enabling access to chemosensors that trigger the release of corresponding gut hormones. Our laboratory has studied mucosal defense mechanisms in the upper GI tract, especially in the duodenum, where the mucosa is regularly exposed to H+/CO2, bile acids, and nutrients originating from endogenous secretions and from ingested foodstuffs. The presence of physiological responses to luminal chemical substances implies that one of the physiological functions of luminal chemosensing is to initiate postprandial responses. Due to their location caudad to the stomach and the most proximal intestinal segment, the abundant expression of gut hormones and the close communication with the stomach and pancreas, the duodenum appears to be a master control center for postprandial chemosensory pathways in the upper GI tract. In this chapter, we will show how the duodenal mucosa senses luminal chemical substances under physiological conditions, focusing on nutrient sensors. Understanding how the GI mucosa “tastes” luminal chemical substances may help identify novel molecular targets in the treatment of mucosal injury, nutrient metabolism, and functional disorders.