Trends in Molecular Medicine
Research FocusNOD2 mutation and mice: no Crohn's disease but many lessons to learn
Section snippets
Dr Crohn, NOD2 and Crohn's disease of the small intestine
Dr Burrill B. Crohn practiced medicine at the Mount Sinai Hospital in New York City. In the famous JAMA article from 1932, he and his colleagues reported a mysterious small-intestinal disease [1], which is now known as Crohn's disease. In industrialized countries, this chronic intestinal inflammation affects ∼1 in 500 individuals. Crohn's disease is a heterogeneous disorder with different clinical phenotypes, and the main localizations of inflammation are the small-intestinal ileum and/or the
Mice with NOD2 knockout and loss of function
Kobayashi and colleagues [8] used a sophisticated approach: they generated mice deficient in the gene encoding Nod2. Surprisingly, these mice had no readily apparent phenotype; that is, no visible intestinal signs of spontaneous inflammation after six months of observation. The authors found that macrophages from the bone marrow of normal but not those of Nod2-knockout mice detected bacterial MDP. Thus, Nod2 deficiency rendered macrophages unresponsive to MDP [8]. Taken together, these findings
Mice with NOD2-frameshift mutation and gain of function
In the paper by Maeda et al. [9], the authors have developed mice with the most common mutant form of Nod2, which is identical to that found in many patients with ileal Crohn's disease [9]. To better understand the interplay between the Nod2 mutation and intestinal bacteria, the authors provoked a colonic exposure of inflammatory cells with commensal bacteria in these mutant mice by adding a chemical to their drinking water (dextran sodium sulfate) that injured their intestinal epithelial
Crohn's disease – intestinal bacteria at the center of disease
More than 70 years ago, Dr Crohn and his colleagues stated that the etiology of this inflammatory process is unknown, but the authors speculated that there could be an infectious genesis. Crohn et al. [1] also pointed out that the healthy intestine shows a remarkable resistance to infection and inflammatory lesions. ‘…but in some instances, however, following infection or injury, resitutio ad integram [back to normal] does not occur’. Even if only a small minority of experts would have agreed
Therapy and future directions
This view of Crohn's disease might provide the necessary rationale to find new therapeutic strategies that act at the mucosal bacterial interface. The study by Maeda et al. [9] supports two alternative therapeutic approaches. Blocking the inflammatory immune response by using an IL-1β-receptor blocker represents a common theme in the modern treatment of Crohn's disease. In the second approach, provided by antibiotic therapy, the absence of bacteria also protects Nod2-mutant mice from disease [9]
Concluding remarks
The papers by Kobayashi et al. [8] and Maeda et al. [9] provide new insights into the molecular details of how this mutation leads to inflammation in Crohn's disease and will hopefully help to open more therapeutic avenues in the future. In our opinion, the lack of mucosal defensins 7, 8, 10 and increased cytokine response 9, 11 represent the sequential pathogenetic mechanism of the disease and are not mutually exclusive. Nevertheless, a caveat is necessary: Crohn's disease in the mouse has not
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