Research Article: Animal Models of Inflammatory Bowel Disease at the Dawn of the New Genetics Era

Date Published: September 30, 2008

Publisher: Public Library of Science

Author(s): Ludvig M Sollid, Finn-Eirik Johansen

Abstract: None

Partial Text: Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory intestinal diseases with multifactorial etiologies. CD and UC are distinguished both by the location and by the nature of the inflammation. CD displays a transmural discontinuous inflammation, often with granulomas, in any part of the digestive system (most often ileum and/or colon). UC is almost exclusively restricted to the colon with a continuous superficial mucosal and submucosal inflammation. Both CD and UC can be further subphenotyped, suggesting that there is heterogeneity within each disorder. Despite many clinical and pathological features that distinguish CD and UC, the collective term inflammatory bowel disease (IBD) is often used for the two diseases. Clustering of IBD in families without specificity for a given form of IBD supports the notion of common genetic factors in the etiologies of the two conditions. In addition, higher concordance rates in monozygotic twins than dizygotic twins, particularly in CD, points to the importance of genes [1]. Recent advances in genetics have proven that both CD and UC are truly polygenic, but there are also strong environmental influences on IBD. This notion is first and foremost supported by the rapid increase in incidence of IBD during the past 50 years.

Many strains of mice with genetic defects in immune regulation develop colitis (Figure 1). Such genetic defects include targeted deletion of receptors for the regulatory cytokines transforming growth factor (TGF)-ß or interleukin (IL)-10, and other mutations causing a disruption of signaling from these cytokines [9]. Specific T cell involvement in dysregulation can be shown by transfer of a subpopulation of T cells (CD4+CD45RB+) to lymphopenic hosts, which leads to colitis [10]. It was early established that cotransfer of CD4+CD25+ T cells could suppress colitis development, and the concept that FoxP3+ regulatory T (Treg) cells play an important general anti-inflammatory role is now also established in human studies [11].

The understanding of the genetics of human IBD is progressing with tremendous speed. NOD2 (CARD15) was identified as a susceptibility gene in 2001 [22,23]. In 2007, genome-wide association (GWA) studies were introduced [6]. This has led to the identification of a large number of new IBD genes, and additional genes are continuously being identified (see references within [7,8]). A recent meta-analysis reported on 32 CD genes and indicated that the actual number of CD genes is substantially higher [24]. With the exception of NOD2 (CARD15) and IL-23R, which each explain 1%–2% of the total genetic variance, the odd ratios of the other loci are low (generally <1.3), and their individual contribution to the genetic variance is meager. The 32 loci were altogether estimated to account for about 10% of the overall variance in disease risk, which may be as much as a fifth of the genetic risk [6,25]. Although no extensive GWA study has been performed on UC yet, it has become clear that some of the identified genetic factors are shared between CD and UC, but also that some of the genetic factors are specific for either CD or UC (Table 1) [25,26]. In particular, it is striking that NOD2 (CARD15), which is an intracellular sensor of bacterial peptidoglycan, and ATG16L1 and IRGM, which are involved in autophagy, are genetic factors for CD, but not for UC. This indicates that there are distinct pathogenic mechanisms related to microbial processing in CD and UC. The identification of IL-23R and IL-12B as risk factors in both CD and UC points to common inflammatory pathways of the two disorders, and underscores the observations of mouse models that inflammation involving Th17 cells is important. Individuals with mutations in the NOD2 gene leading to altered NOD2 protein have increased risk for ileal-only and ileocolonic CD, but not colonic-only CD nor UC. This risk is particularly high for homozygous or compound-heterozygous individuals. NOD2 activates an NF-κB signaling pathway upon binding the peptidoglycan component muramyl dipeptide. The list of human IBD genes is continuously expanding. Some of the identified risk genes fit with pathways suggested by animal models, like the central role of Th17 cells. It will be interesting to see how many other genes will map to pathways that have been identified by animal models. Most of our current animal models have been developed without human genetics as a roadmap, but we can expect that this will change drastically. New models will be developed to understand the function of the novel IBD genes. The experience from studies of NOD2 in mice suggests that the development of adequate models will not be straightforward. Most of the novel gene polymorphisms are low-penetrance genes, and the development of suitable animal models for such genes can be particularly demanding. The intestinal physiology of the mouse and human gut are different, and the function of many genes can have species differences. Moreover, if there are gene–gene and gene–environment interactions for the risk genes, reestablishing the context into which a gene is predisposing to IBD will be difficult. A major environmental factor is the composition of the luminal bacterial community. Although there are differences between human and test animal microbiota, and the host–bug interactions likely will be different, the Human Microbiome Project (US), MetaHIT (Europe), and other big science projects aimed at determining composition of gut microflora in humans and test animals will surely be useful to IBD researchers. A further challenge will be to develop models that are representative for CD or UC or the major phenotypes within. Despite these challenges, good animal models are badly needed to bring new therapies to the clinic. Animal models of IBD should hence receive a continued interest, not least from clinicians, in the future. Source:


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