Secretory cell specific HDAC5 coordinates microbiota-dependent intestinal barrier synthesis and integrity

The secretory cells of the gut epithelium are essential for intestinal homeostasis by producing and secreting mucosal defense proteins. However, how these processes are regulated intrinsically remains undefined. Here, we show that the intestinal microbiota programs the synthesis of mucosal defense proteins and regulates barrier integrity through secretory cell specific histone deacetylase 5 (HDAC5). HDAC5 is highly expressed in goblet cells and Paneth cells and its expression is induced by microbiota. Disruption of HDAC5 reduces the abundance of mucosal defense proteins and impairs mucosal barrier functions in the presence of microbiota. Mechanistically, HDAC5 is localized in the cytoplasm and activates mTOR signaling, which promotes the translation of mucosal defense proteins. Our findings reveal that HDAC5 is a secretory cell specific regulator that integrates gut microbial signals to control the synthesis of mucosal defense proteins and maintain barrier integrity.