Translational control of innate barrier defense by the gut microbiota

The intestinal epithelium is protected by a mucus layer infused with antimicrobial proteins, forming a physical and chemical barrier that limits microbial access to host tissue. Mucus barrier assembly is energetically costly, yet how production of its constituent proteins is matched to demand remains unclear. Here, we show that the microbiota regulates gut barrier immunity by enhancing translation of select defense proteins, including mucin 2 and lysozyme. This occurs via induction of histone deacetylase 5 (HDAC5) in secretory epithelial cells. HDAC5 deacetylates 14-3-3, enabling it to sequester Raptor, a component of mTORC1. This releases mTOR and activates downstream signaling that promotes translation of barrier defense proteins. Our findings reveal a mechanism by which the microbiota shapes barrier immunity through translational control. Overall design: 16S rRNA sequencing analysis of fecal bacterial composition in wildtype and Hdac5-/- mice.