OP029 Hypoacetylation of histone-3 is a hallmark of intestinal fibrosis in Crohn's disease
Lewis A.*1, Felice C.1,2, Nihjuis A.1, Iqbal S.1, Mehta S.1, Feakins R.3, Armuzzi A.2, Silver A.1, Lindsay J.4
1Queen Mary's University London, Centre for Genomics and Child Health, Blizard Institute, London, United Kingdom 2Gemelli Hospital Catholic University Foundation, IBD Unit, Presidio Columbus, Rome, Italy 3The Royal London Hospital, Department of pathology, London, United Kingdom 4Queen Mary's University London, Centre for Immunobiology, Blizard Institute, London, United Kingdom
Recurrent cycles of intestinal inflammation and repair drive fibrosis and stricture formation in patients with Crohn's disease (CD). Histone acetylation is an important epigenetic mechanism that impacts gene transcription and is controlled by the histone deacetylase enzymes (HDACs). This pathway can be pharmacologically manipulated by HDAC inhibitors such as valproic acid (VPA), which protects against experimentally induced colitis and reduces fibrosis in non-intestinal models of disease. In this study we investigate the relationship between histone-3 acetylation levels and inflammation and fibrosis in CD and test the ability of VPA to modulate synthesis of collagen I.
Histone-3 acetylation was assessed by immunohistochemistry in FFPE tissue from healthy controls (n=12), CD patients with: quiescent (n=8); inflammatory (n=7); and fibrotic disease (n=6). The effects of VPA (5mM) on collagen I synthesis, measured by qPCR, immunofluorescence and ELISA, were tested in
Relative to healthy controls and CD patients with quiescent disease, there was a reduction in histone-3 acetylation in the mucosa overlying both inflamed and strictured gut (p=0.004, ANOVA). Histone-3 acetylation was also lower in strictured gut relative to adjacent non-strictured areas (p=0.015, n=6).
Hypoacetylation is a pathological feature of both inflammation and fibrosis in CD. Treatment with VPA increases histone acetylation and suppresses collagen expression in CD patient biopsies and models of intestinal fibrosis, demonstrating a direct link between histone acetylation and collagen production in CD. The data highlight the potential to exploit existing drugs that modulate histone acetylation in the treatment of fibrostenosing CD.