Zip14 (Slc39a14) metal transporter dysfunction leads to <i>Akkermansia</i> dysbiosis and inflammation in intestinal epithelium via epigenetic changes

Zinc is recognized as an important component of immune function in animals, operating through many different mechanisms. Metal transporter Zip14 (Slc39a14) is up-regulated during pro-inflammatory conditions and increases zinc uptake into cells, including enterocytes. As reported here, global <i>Zip14</i> deletion in mice leads to excessive intestinal mucus accumulation and markedly increased fecal levels of the enteric microbe <i>Akkermansia muciniphila</i>. RNA sequencing showed up-regulation of a relatively small number of genes expressed in enterocytes isolated from <i>Zip14</i> knockout (KO) mice. Compared to wild-type (WT) mice. Among the most up-regulated genes were <i>St6galnac1</i> (ST6) and <i>Muc2</i>, both of which are involved in the synthesis of intestinal mucin. ATAC sequencing and ChIP assays using NF-κB antibodies demonstrated that open chromatin is the likely cause of the increased expression of these mucin-forming proteins. The differences in fecal <i>Akkermansia</i> abundance, inflammatory cytokine expression, and <i>St6</i> and <i>Muc2</i> expression were alleviated in KO mice when either orally dosed with pasteurized <i>Akkermansia</i> or provided a single oral gavage of zinc. Collectively, these experiments show that zinc delivery via Zip14 is necessary to limit chromatin accessibility for specific regulatory factors that influence mucin production and cause dysbiosis. These findings represent an example of a genome-nutrient-microbial interrelationship.