Capsaicin inhibits intestinal Cl(-) secretion and promotes Na(+) absorption by blocking TRPV4 channels in healthy and colitic mice

Although capsaicin has been studied extensively as an activator of the transient receptor potential vanilloid cation channel subtype 1 (TRPV1) channels in sensory neurons, little is known about its TRPV1-independent actions in gastrointestinal health and disease. Here, we aimed to investigate the pharmacological actions of capsaicin as a food additive and medication on intestinal ion transporters in mouse models of ulcerative colitis (UC). The short-circuit current (I(sc)) of the intestine from WT, TRPV1-, and TRPV4-KO mice were measured in Ussing chambers, and Ca(2+) imaging was performed on small intestinal epithelial cells. We also performed Western blots, immunohistochemistry, and immunofluorescence on intestinal epithelial cells and on intestinal tissues following UC induction with dextran sodium sulfate. We found that capsaicin did not affect basal intestinal I(sc) but significantly inhibited carbachol- and caffeine-induced intestinal I(sc) in WT mice. Capsaicin similarly inhibited the intestinal I(sc) in TRPV1 KO mice, but this inhibition was absent in TRPV4 KO mice. We also determined that Ca(2+) influx via TRPV4 was required for cholinergic signaling–mediated intestinal anion secretion, which was inhibited by capsaicin. Moreover, the glucose-induced jejunal I(sc)via Na(+)/glucose cotransporter was suppressed by TRPV4 activation, which could be relieved by capsaicin. Capsaicin also stimulated ouabain- and amiloride-sensitive colonic I(sc). Finally, we found that dietary capsaicin ameliorated the UC phenotype, suppressed hyperaction of TRPV4 channels, and rescued the reduced ouabain- and amiloride-sensitive I(sc). We therefore conclude that capsaicin inhibits intestinal Cl(-) secretion and promotes Na(+) absorption predominantly by blocking TRPV4 channels to exert its beneficial anti-colitic action.