Inflammatory bowel disease is a chronic disorder that accompanies patients throughout their lives. Two main forms can be distinguished, namely Crohn’s disease and ulcerative colitis. Whereas the treatment options have dramatically improved over the last decade, in particular because of the introduction of anti–tumor necrosis factor (TNF)-α strategies (infliximab and adalimumab), a relevant subset of patients still exists in whom satisfactory therapy is required.
To identify novel therapeutic targets, we must focus on the pathogenesis of the disease first. The genome-wide association studies of the last years have contributed significantly to the understanding of the pathogenesis of inflammatory bowel disease (IBD) (1
). The results obtained from the genome-wide association studies not only confirmed the relevance of earlier characterized pathways, but equally opened novel avenues. If one must suggest a hypothesis on the etiology of IBD, one could simply say that the mucosal immune system is hyperresponsive to luminal antigens (for example, dietary factors, commensal bacteria) in genetically predisposed individuals (2
A critical long-term complication of chronic inflammation (in particular, of the colon) is the development of colorectal cancer. The risk increases significantly with duration as well as with extension of disease; thus, a chronically active pan-colitis is associated with the highest risk (3
). Historically, the idea that a chronic inflammatory condition represents a predisposing factor for developing cancer is well known, and other examples are chronic hepatitis, pancreatitis and esophagitis (4
In the example of colorectal cancer, the mechanism by which inflammation induces cancer development has not been elucidated; however, it is clear that the sequence differs from the pathway activated in “non-inflammatory” colorectal cancer (5
). Several lines of evidence, experimental as well as clinical data, suggest that antiinflammatory strategies and, as a consequence, mucosal healing contribute to preventing colorectal cancer. Thus, the identification of novel therapeutic strategies that exert antiinflammatory and possibly antiproliferative properties is desirable.
In addition to the identification of genetic polymorphisms associated with either Crohn’s disease or ulcerative colitis, this review will serve to shed light on a novel way of regulation that might result in a relevant impact in chronic intestinal inflammation, (namely epigenetic modifications and in particular changes driven by histone deacetylases [HDACs]).
Our own in vivo
data from models of acute and chronic intestinal inflammation in mice as well as inflammation-driven tumorigenesis strongly indicate that inhibition of HDAC represents a highly effective therapeutic option. Recent human data (6
) provide solid evidence that the novel HDAC inhibitor ITF2357 can be administered in doses sufficient to exert this antiinflammatory capacity; thus, it seems that these compounds might in fact provide a future pharmacological strategy for patients suffering from IBD.