Monogenic Intestinal Epithelium Defects and the Development of Inflammatory Bowel Disease

Abstract

The incidence of inflammatory bowel disease (IBD) is increasing worldwide, most notably in young children. The development of disease is a combination of several factors, including genetics, environment, the microbiota, and immune system. Recently, next-generation sequencing has allowed for the identification of novel genetic causes for intestinal disease, including pediatric inflammatory bowel disease (IBD). These IBD genes can generally be grouped into genes causing either primary immunodeficiency or intestinal epithelial defects (the focus of this review). Most of these genes have been functionally validated with in vitro and/or animal models, and have been demonstrated to cause intestinal disease. Intestinal epithelial IBD genes are of particular interest since they are the least amenable to current therapies; therefore, further research is warranted to develop potential therapies. A number of cellular pathways are impacted with intestinal epithelial IBD genes, including intestinal epithelial cell adhesion and generation of reactive oxygen species. Here, we describe the currently known IBD risk alleles and monogenic causal intestinal epithelial genes, their putative roles in preserving intestinal epithelial cell homeostasis, and their implications for IBD pathophysiology.

FIGURE 1.

Summary of VEOIBD genes with significant roles in intestinal epithelial homeostasis. The genes affect a range of epithelial cell functions, with some shared mechanisms (e.g., NHE3 activity in SLC9A3 and GUCY2C). The broad spectrum of pathways affected in this single cell type reflects the multifactorial etiology of IBD. Red, affected genes.