Prostaglandin pathways in duodenal chemosensing

Acid‐sensing pathways, which trigger mucosal defense mechanisms in response to luminal acid, involve the rapid afferent‐mediated “capsaicin pathway” and the sustained “prostaglandin ( PG ) pathway.” Luminal acid quickly increases protective PG synthesis and release from epithelia, although the mechanism by which luminal acid induces PG synthesis is still mostly unknown. Acid exposure augments purinergic ATP ‐ P 2 Y signaling by inhibition of intestinal alkaline phosphatase activity. Since P 2 Y activation increases intracellular C a 2+ , we further hypothesized that ATP ‐ P 2 Y signals increase the generation of H 2 O 2 derived from dual oxidase, a member of the nicotinamide adenine dinucleotide phosphate ( NADPH ) oxidase family activated by C a 2+ . Our recent studies suggest that acid exposure increases H 2 O 2 output, followed by phospholipase A 2 and cyclooxygenase activation, increasing PG synthesis. Released prostaglandin E 2 augments protective HCO 3 − and mucus secretion via EP 4 receptor activation. Thus, the PG pathway as a component of duodenal acid sensing consists of acid‐related intestinal alkaline phosphatase inhibition, ATP ‐ P 2 Y signals, dual oxidase 2‐derived H 2 O 2 production, phospholipase A 2 activation, prostaglandin E 2 synthesis, and EP 4 receptor activation. The PG pathway is also involved in luminal bacterial sensing in the duodenum via activation of pattern recognition receptors, including T oll‐like receptors and nucleotide‐binding oligomerization domain 2. The presence of acute mucosal responses to luminal bacteria suggests that the duodenum is important for host defenses and may reduce bacterial loading to the hindgut using H 2 O 2 , complementing gastric acidity and anti‐bacterial bile acids.