TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response

Abstract

Intestinal epithelial tight junction disruption is a primary contributing factor in alcohol-associated endotoxemia, systemic inflammation, and multiple organ damage. Ethanol and acetaldehyde disrupt tight junctions by elevating intracellular Ca²⁺. Here we identify TRPV6, a Ca²⁺-permeable channel, as responsible for alcohol-induced elevation of intracellular Ca²⁺, intestinal barrier dysfunction, and systemic inflammation. Ethanol and acetaldehyde elicit TRPV6 ionic currents in Caco-2 cells. Studies in Caco-2 cell monolayers and mouse intestinal organoids show that TRPV6 deficiency or inhibition attenuates ethanol- and acetaldehyde-induced Ca²⁺ influx, tight junction disruption, and barrier dysfunction. Moreover, Trpv6^-/- mice are resistant to alcohol-induced intestinal barrier dysfunction. Photoaffinity labeling of 3-azibutanol identifies a histidine as a potential alcohol-binding site in TRPV6. The substitution of this histidine, and a nearby arginine, reduces ethanol-activated currents. Our findings reveal that TRPV6 is required for alcohol-induced gut barrier dysfunction and inflammation. Molecules that decrease TRPV6 function have the potential to attenuate alcohol-associated tissue injury.

Keywords: CP: Cell biology; CP: Immunology; TRPV; alcohol; alcohol-binding site; calcium; endotoxemia; intestine; liver; neuroinflammation; systemic inflammation; tight junction.