Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

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Abstract
This work identifies a role for intestinal epithelial cell (IEC)-intrinsic expression of histone deacetylase 3 in regulating commensal-bacteria-dependent gene expression and intestinal homeostasis; IEC-specific HDAC3 deficiency gives rise to Paneth cell abnormalities, impaired intestinal barrier function, and increased DSS-induced intestinal inflammation in commensal-bacteria-containing, but not germ-free, mice. Epigenetic mechanisms alter the transcriptional response to environmental cues and thus represent a mechanism that can link host genetic predisposition and environmental triggers in the pathogenesis of inflammatory bowel disease (IBD). This study identifies a previously unrecognized role for intestinal epithelial cell (IEC)-intrinsic expression of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3) in regulating intestinal barrier function and susceptibility to commensal-driven inflammation. IEC-specific HDAC3 deficiency in mice is shown to give rise to Paneth-cell abnormalities, rectal prolapse, increased susceptibility to dextran sodium sulphate-induced colitis and increased barrier permeability in commensal-containing but not germ-free animals. The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria1,2,3,4,5,6. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3ΔIEC mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3ΔIEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3ΔIEC mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3ΔIEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host–commensal relationships and maintain intestinal homeostasis.

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