A missense variant in <i>SLC39A8</i> confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity
Toru Nakata, Elizabeth A. Creasey, Motohiko Kadoki, Helen Lin, Martin K. Selig, Junmei Yao, Ariel Lefkovith, Mark J. Daly, Daniel B. Graham, Ramnik J. Xavier
Abstract
Significance SLC39A8 A391T exhibits remarkable pleiotropic effects on multiple conditions, including cardiovascular diseases, Parkinson’s disease, and Crohn’s disease. However, how this single coding variant impacts such a wide range of pathologies has not been investigated. We generated Slc39a8 A391T knockin mice and show that they exhibit severe Mn deficiency in the colon, and impaired intestinal barrier integrity due to glycoprotein barrier structure defects, leading to indolent inflammation that can prime further inflammation driven by epithelial injury. Thus, we highlight the importance of Mn in gut homeostasis, and mechanistically unravel how A391T impacts intestinal barrier integrity.