The effect of NOD2 on the microbiota in Crohn's disease

Abstract

Recent advancements toward the treatment of Crohn's disease (CD) indicate great promise for long-term remission. CD patients suffer from a complex host of dysregulated interactions between their innate immune system and microbiome. The most predominant link to the onset of CD is a genetic mutation in the innate immune receptor nucleotide-binding oligomerization domain-containing 2 (NOD2). NOD2 responds to the presence of bacteria and stimulates the immune response. Mutations to NOD2 promote low diversity and dysbiosis in the microbiome, leading to impaired mucosal barrier function. Current treatments suppress the immune response rather than enhancing the function of this critical protein. New progress toward stabilizing NOD2 signaling through its interactions with chaperone proteins holds potential in the development of novel CD therapeutics.

Figure 1. NOD2 promotes the expression and secretion of α-defensins in Paneth cells

A. NOD2 activates the NF-κB pathway upon induction with MDP, resulting in the expression of α-defensins. NOD2 interacts with ATG16L, which leads to the secretion of α-defensins. Commensal bacteria remain distant from Paneth cells. B. CD mutant NOD2 has reduced activation of α-defensin expression. It is unable to recruit ATG16L, decreasing secretion of α-defensins. Harmful bacteria can invade the mucosal layer with decreased protection. C. The structure of NOD2-activating ligand MDP.