To determine the contribution of intestinal epithelial-specific SLC39A8, we generated a novel genetic model of an intestinal epithelial cell-specific Slc39a8 knockout mouse (Slc39a8-IEC KO). SLC39A8 IEC-KO mice have significantly reduced Mn levels in the intestine coupled with marked reduced Mn concentrations in blood and other organs. Despite the known ability of SLC39A8 to transport zinc and iron, tissue zinc and iron levels were not different in Slc39a8-IEC KO mice compared with levels in controls.
In experimental colitis models induced by dextran sulfate sodium, Slc39a8-IEC KO mice were highly susceptible to colitis, as manifested by markedly increased morbidity, weight loss, and colon injury, and colonic inflammation compared with controls. Without DSS treatment, Slc39a8-IEC KO mice displayed elevated intestinal permeability by impairing intestinal tight junctions.
Our unbiased transcriptomic analysis reveals that alkaline ceramidase 1 (ACER1), a lipid-generating enzyme that affects intestinal permeability, is significantly up-regulated in the intestines of Slc39a8-IEC KO mice. Based on the observations, we are currently testing whether ACER inhibitor can reduce intestinal permeability and alter the susceptibility of experimental colitis.
Together, this work suggests that intestinal epithelial Slc39a8 is required for intestinal absorption of dietary Mn, and that loss of Slc39a8 exacerbates experimental colitis likely by impairing intestinal barrier functions