Thomas Jacob

Background: Inflammatory Bowel Disease (IBD) is a condition that affects 7-16% of the US population. IBD is a group of conditions, namely Crohn’s Disease and Ulcerative Colitis, that mainly impacts the digestive tract. The genetic component of IBD is still vastly unknown, but great strides have been made in uncovering this component. In particular, the NOD2 gene has been shown to greatly influence IBD, particularly Crohn’s Disease pathogenesis.

Objective: In this review, we look into the mechanisms and role of NOD2 in IBD pathogenesis (namely Crohn’s Disease)

Search Methods: The search was conducted through PubMED database with articles from the years 2018-2023. The following keywords were used: “ulcerative colitis”, “nod2”, “inflammatory bowel disease”. “inflammatory bowel syndrome”, and “genetic”.

Results: The NOD2 gene encodes an antipathogenic intracellular receptor that is heavily involved in the innate immunity of the human body. The receptor looks at pathogen-associated molecular patterns (PAMPS) and initiates an immune response when it finds a matching foreign body. In addition, the NOD2 protein has a role in autophagy within intestinal epithelial and reticuloendothelial cells. The autophagy mechanism is heavily involved in IBD pathogenesis. Autophagy is a major mechanism for the maintenance of the epithelial cell border. Essentially, it is a way for the cell to replace the old, dysfunctional parts of the cell and replace it with new, functional ones. The primary protein involved in autophagy is the ATG16L1 protein. However, for the ATG16L1 protein to do its job, the NOD2 gene needs to recruit it to the cell membrane. Therefore, if there is a dysfunction in the NOD2 gene, there would be dysfunction in autophagy, which would inevitably lead to increased bacterial load. With increased bacterial load, the gut would be more prone to inflammation. NOD2 is also important in the production of lysozyme in immune cells, therefore if there is a dysfunction of NOD2, there would be a decreased ability for immune cells to clear bacteria. NOD2 cross-talks with other IBD-linked genes, namely ELMO1 and the complex that they form is responsible for proper macrophage function, such as secreting reactive oxygen species (ROS). Moreover, the NOD2 signaling pathway has a lot of moving parts, and dysfunction of any of the proteins involved could lead to IBD pathogenesis.

Conclusions: Studies have found that NOD2 is linked with several signaling pathways involved in IBD pathogenesis, such as the autophagy-regulating pathway through ATG16L1. It also crosstalks with other genes linked to IBD pathogenesis, such as ELMO1. All in all, the NOD2 gene plays an important role in IBD pathogenesis and can be an important pathway for the potential treatment of Crohn’s Disease.

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