Editorial: Understanding Crohn’s Disease: Immunity, Genes and Microbes

Crohn's disease (CD) is a chronic debilitating syndrome, associated with considerable morbidity and resulting in elevated public health costs every year. CD and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD), which has long been characterized as an exacerbated inflammatory response to common antigenic stimuli in the gut due to immune dysregulation. Although both CD and UC share some common patterns, they are distinct diseases. In fact, while UC is characterized by a diffuse mucosal inflammation involving mainly the rectum and adjacent colonic tissue, CD is a transmural inflammatory disease that may involve any part of the gastrointestinal tract, from the mouth to the anus, although in most cases the terminal ileum is affected. Etiology of IBD, particularly CD, has been long debated and is likely to involve the contribution of multiple factors, making its study challenging. Among those contributing factors are genetic inheritance, epigenetic mechanisms, infection with particular pathobionts, and the gut microbiota in general. This topic aimed at bringing together contributions covering aspects related primarily to CD etiol-ogy and immunopathology, helping to drive forward a more comprehensive understanding of this challenging syndrome. Genetic inheritance is an important predisposing factor for IBD. In a comprehensive review, Loddo and Romano point out the importance of genetic traits in susceptibility to IBD. The authors discuss the success of next-generation sequencing in the investigation of rare monogenic susceptibility variants, implicated in early-onset and very early-onset IBD. They also address the importance of epigenetic mechanisms, such as DNA methylation, in linking environmental stress and gene expression and discuss the use of microRNAs as biomarkers and therapeutical targets in IBD. The first genetic variant conferring susceptibility to ileal CD was located in the nucleotide oligomerization domain 2 (NOD2) gene (1), a gene implicated in recognition of bacterial muramyl dipeptide. Sidiq et al. highlight the role played by epithelial cell NOD2 expression in maintaining gut homeostasis and regulating ileal microbiota composition and address the consequences of a deficient NOD2 variant in gut dysregulation. As described in an original research article, Parkhouse and Monie tested whether loss-of-function NOD2 variants conferring susceptibility to CD (R702W, G908R, and L1007fsincC) exhibited deficient binding to receptor-interacting protein kinase 2, an adaptor protein implicated in NOD2 signaling. They found that impairment of NOD2 signaling shown by variants containing CD-susceptibility polymorphisms did not correlate with deficient RIP2 binding, concluding that the causes for impairment are multifactorial. A …