Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis.

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.

An optimized patient-reported ulcerative colitis disease activity measure derived from the Mayo score and the simple clinical colitis activity index.

BACKGROUND: There is a need for simple, noninvasive patient-driven disease assessment instruments in ulcerative colitis (UC). We sought to further assess and refine the previous described 6-point Mayo score. METHODS: A cross-sectional study of 282 UC patients was conducted assessing the correlation of the 2 patient-reported Mayo score components (6-point Mayo score) with the simple clinical colitis activity index (SCCAI) and a single Likert scale of patient-reported disease activity. Spearman's correlation, sensitivity, specificity, and area under the receiver operating curves (AUC) were calculated. A separate validation study in 59 UC patients was also conducted. RESULTS: Participants predominantly had long-standing disease (83%) and were in self-reported remission (63%). The 6-point Mayo score correlated well with the SCCAI (rho = 0.71; P < 0.0001) and patient-reported disease activity (rho = 0.65; P < 0.0001). Using a cutpoint of 1.5, the 6-point Mayo score had 83% sensitivity and 72% specificity for patient-defined remission, and 89% sensitivity and 67% specificity for SCCAI-defined remission (score, <2.5). The 6-point Mayo score and SCCAI had similar accuracy of predicting patient-defined remission (AUC = 0.84 and 0.87, respectively). Addition of the SCCAI general well-being question to the 6-point Mayo improved the predictive ability for patient-defined remission; and a new weighted score had an AUC of 0.89 in the development cohort and 0.93 in the validation cohort. The optimal cutpoint was 1.6. CONCLUSIONS: The patient-reported UC severity index that includes stool frequency, bleeding, and general well-being accurately measures clinical disease activity without requiring direct physician contact.