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 a target to improve alcohol-induced 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 conserved histidine as a potential alcohol-binding site in TRPV6, and its substitution for alanine in rat TRPV6 reduces ethanol-activated TRPV6 currents. Our findings reveal that TRPV6 is required for alcohol-induced gut barrier dysfunction and inflammation. Thus, molecules that decrease TRPV6 function have the potential to attenuate alcohol-associated endotoxemia and systemic inflammation.