NOD2 Gene Mutation and Crohn's

There seems to be general consensus that Crohn's disease has some genetic component to it, so I figured it was worth learning more about it. As I discovered, studies have found that the NOD2 gene protein is somehow directly involved in a large percentage of Crohn's cases (25%). The NOD2 gene is expressed in the immune system leukocyte cells and plays a role in the body's immune response by recognizing some of the molecules (muramyl dipeptide - MDP) that are part of bacterial cell walls. In essence, they are a sensor for bacteria. And as we know, there are trillions of bacteria in the gut, so there are plenty of bacterial cell walls for them to respond to. The gene also has a connection with the NF-kB protein which regulates the immune system. Here is an excerpt from one of the articles I linked to:

Today, it is known that Nod2 expresses a protein that recognizes a building block of bacterial cell walls, called muramyl dipeptide (MDP), effectively making it a bacterial sensor. Nod2 is expressed primarily by bone-marrow-derived macrophages. In addition, the protein NOD2 appears to play a role in the activation of NF-B, a major regulator of the production of pro-inflammatory cytoines such as tumour necrosis factor- (TNF) and interleukin IL-1ß. The relation is relevant because patients with Crohn's disease overproduce NF-B and cytokines, and anti-inflammatory drugs represent the mainstays of treatment. Nevertheless, how Nod2contributes to the pathology of Crohn's disease has been an open question — one that the modelling of the disease in mice is beginning to answer.

So if everyone has the NOD2 gene, why do only Crohn's patients have problems with it? The problem arises due to mutations in the gene. The premise is that normal responses to bacterial infection should not create an overabundance of pro-inflammatory cytokines and hence should not create the inflammation associated with Crohn's disease. The mutated NOD2 genes cause the problems. But keep in mind, those genes are just responding to the environment - they don't cause it. Having a mutation in the NOD2 gene, then, doesn't necessarily cause the disease but instead makes people susceptible to it. Here's an excerpt:

The results of these studies help to explain the association between Nod2 mutations and Crohn's disease. In finding Nod2 to be an important immune mediator in the intestine, the studies also fuel the notion that bacterial infection is an important pathogenetic factor. Indeed, as Kobayashi and colleagues suggest, Nod2 mutations may not play a directly causative role but, rather, may create an environment in the gut that renders it susceptible to Crohn's disease. Further research is required to confirm this and to elucidate the link between Nod2 mutations and -defensin, one that has already been established in humans.⁶ It is hoped that the results of this research will open future therapeutic avenues.

Obvious take-aways for future research (from the perspective of managing or preventing the disease) then are to look into how to undo or prevent mutations in the NOD2 gene. The stem cell treatment previously discussed is presumably (if I'm understanding it correctly) one way to undo these mutations (i.e. by creating all immune cells from scratch using stem cells). I'm curious to learn more about alternatives like nutrigenomics, though, for example that could help prevent mutations. But more on that in another post.