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

• Published in: Cell reports (Cambridge) 2022-06, Vol.39 (11), p.110937-110937, Article 110937
• Main Authors: Meena, Avtar S., Shukla, Pradeep K., Bell, Briar, Giorgianni, Francesco, Caires, Rebeca, Fernández-Peña, Carlos, Beranova, Sarka, Aihara, Eitaro, Montrose, Marshall H., Chaib, Mehdi, Makowski, Liza, Neeli, Indira, Radic, Marko Z., Vásquez, Valeria, Jaggar, Jonathan H., Cordero-Morales, Julio F., Rao, RadhaKrishna
• Format: Article
• Language: English
• Subjects: alcohol; alcohol-binding site; calcium; CP: Cell biology; CP: Immunology; endotoxemia; intestine; liver; neuroinflammation; systemic inflammation; tight junction; TRPV
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110937

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. [Display omitted] •Ethanol and acetaldehyde elicit inward TRPV6 currents in intestinal epithelial cells•TRPV6 is required for alcohol-induced barrier dysfunction in the intestinal epithelium•TRPV6 null mice are resistant to alcohol-induced endotoxemia and systemic inflammation•H185 and R134 residues in the TRPV6 N terminus fine-tune channel response to ethanol Meena et al. show that the mechanism of alcohol-induced gut permeability, endotoxemia, and systemic inflammation requires the TRPV6 channel. They show that ethanol activates TRPV6, induces calcium influx, and disrupts intestinal epithelial tight junctions. Furthermore, specific histidine and arginine residues at the N terminus fine-tune the alcohol-induced activation of TRPV6.