title: Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis.
abstract: 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 bacteria. 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 (HDAC3(ΔIEC) mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3(ΔIEC) mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3(ΔIEC) 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 HDAC3(ΔIEC) 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.
authors.affiliation: 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Alenghat
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Osborne
authors.forename: Steven A
authors.initials: SA
authors.lastname: Saenz
authors.forename: Dmytro
authors.initials: D
authors.lastname: Kobuley
authors.forename: Carly G K
authors.initials: CG
authors.lastname: Ziegler
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Mullican
authors.forename: Inchan
authors.initials: I
authors.lastname: Choi
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grunberg
authors.forename: Rohini
authors.initials: R
authors.lastname: Sinha
authors.forename: Meghan
authors.initials: M
authors.lastname: Wynosky-Dolfi
authors.forename: Annelise
authors.initials: A
authors.lastname: Snyder
authors.forename: Paul R
authors.initials: PR
authors.lastname: Giacomin
authors.forename: Karen L
authors.initials: KL
authors.lastname: Joyce
authors.forename: Tram B
authors.initials: TB
authors.lastname: Hoang
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Bewtra
authors.forename: Igor E
authors.initials: IE
authors.lastname: Brodsky
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Sonnenberg
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.forename: David
authors.initials: D
authors.lastname: Artis
mesh_terms: D000328:Adult; D000818:Animals; D001419:Bacteria / Q000235:genetics; D003093:Colitis, Ulcerative / Q000201:enzymology / Q000235:genetics / Q000382:microbiology; D003424:Crohn Disease / Q000201:enzymology / Q000235:genetics / Q000382:microbiology; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology; D007422:Intestines / Q000382:microbiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019879:Paneth Cells / Q000166:cytology / Q000378:metabolism; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D015398:Signal Transduction; D013559:Symbiosis; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D012336:RNA, Ribosomal, 16S; D000099186:Histone Deacetylase 3