P022 Histone deacetylases in inflammatory mucosa distinguish Crohn's disease from ulcerative colitis
J. de Bruyn*1, C. Wichers2, T. Radstake2, J. Broen2, G. D'Haens1
1Academic Medical Center, Gastroenterology & Hepatology, Amsterdam, Netherlands, 2Wilhelmina Children's Hospital-Utrecht Medical Center, Translational Immunology, Utrecht, Netherlands
Inflammatory bowel disease (IBD) creates a high burden of both patient disability and health care costs. There is a high unmet need to better understand the pathophysiology of IBD, leading the way to novel therapeutic targets. Histone deacetylation (HDAC) regulates chromatin remodeling and influences inflammatory gene transcription. Sirtuin(SIRT)1, SIRT6 and HDAC9 are members of the HDAC superfamily that exert proinflammatory properties. Interestingly, murine research suggested a critical role for HDAC9 in breaching immune homeostasis in experimental colitis. Considering the advent of a new generation of HDAC inhibitors we aimed to explore the role of HDACs in IBD.
We collected colon resection tissue from Crohn's disease (CD) patients and ulcerative colitis (UC) patients operated on for therapy refractory disease. From each patient both macroscopically inflamed and non-inflamed areas were collected, and for CD patients stenotic lesions were collected as well. For RNA isolation the lamina propria was separated from the muscularis externa, and a micro array was performed for HDAC and SIRT mRNA expression.
Baseline characteristics were comparable for 15 CD (47% male) and 9 UC (66% male) patients with mean age at operation of 34 +/- 10 years in CD and 37 +/- 10 years in UC pts. Of the CD patients, 53% had ileal and 47% ileocolonic disease, of the UC patients had 44% left sided colitis and 56% pancolitis. Serum CRP levels immediately before surgery averaged 18 mg/L in both cohorts. Expression of HDAC9 was at average 3.81 fold higher in the inflamed mucosa in CD patients compared to the inflamed mucosa of UC patients (p=0.002), in the uninflamed mucosa the expression of HDAC did not differ significantly. Moreover, in the inflamed mucosa of CD patients SIRT6 was significantly upregulated in comparison to UC patients (p=0.003), whereas in the inflamed muscularis mucosa the expression of SIRT1 was higher in CD than in UC patients (p=0.04). Intriguingly, the increased levels of HDAC9, SIRT1 and SIRT6 were only present in inflamed tissue and were found to be the same compared to UC in stenotic or non-inflamed lesions.
Our findings show an increased expression of HDAC9 and SIRT6 in the mucosa of inflamed CD colon compared to inflamed UC colon. Therefore, histone deacetylases expression has the potential to serve as an additional marker to distinguish CD from UC in tissue biopsies. Further research is necessary to investigate the functional properties of histone deacetylation in CD pathogenesis, which could grant opportunities for therapeutical action.