Duodenal chemosensing and mucosal defenses

Abstract

The duodenal mucosa is exposed to endogenous and exogenous chemicals, including acid, CO(2), bile acids and nutrients. Mucosal chemical sensors are necessary to exert physiological responses such as secretion, digestion, absorption, and motility. We propose a mucosal chemosensing system by which luminal chemicals are sensed via mucosal acid sensors and G-protein-coupled receptors. Luminal acid/CO(2) sensing consists of ecto- and cytosolic carbonic anhydrases, epithelial ion transporters, and acid sensors expressed on the afferent nerves in the duodenum. Furthermore, a luminal L-glutamate signal is mediated via mucosal L-glutamate receptors, including metabotropic glutamate receptors and taste receptor 1 family heterodimers, with activation of afferent nerves and cyclooxygenase, whereas luminal Ca(2+) is differently sensed via the calcium-sensing receptor in the duodenum. Recent studies also show the involvement of enteroendocrine G-protein-coupled receptors in bile acid and fatty acid sensing in the duodenum. These luminal chemosensors help activate mucosal defense mechanisms in or- der to maintain the mucosal integrity and physiological responses. Stimulation of luminal chemosensing in the duodenal mucosa may prevent mucosal injury, affect nutrient metabolism, and modulate sensory nerve activity.

Fig. 1

Luminal chemosensing and mucosal defenses via GLP-2 in the duodenum. The scheme shows our hypothesis that luminal chemicals/nutrients enhance the duodenal mucosal defenses partly via GLP-2 release. Luminal chemicals activate GPCRs expressed on the apical membrane of the enteroendocrine cell, which secretes gut hormones including GLP-2. GLP-2 may stimulate duodenal HCO₃^– secretion via vasoactive intestinal peptide (VIP) and nitric oxide (NO) pathways. Since GLP-2 is intestinotropic, the stimulated GLP-2 release may enhance mucosal repair via growth factor, such as epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1).