Genetic and microbial regulation of NOD2 signaling in homeostasis and disease

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a key intracellular pattern recognition receptor that senses bacterial peptidoglycan-conserved motifs, and has long been implicated in initiating immune responses. Loss-of-function mutations in NOD2 have been identified as the strongest genetic risk factor for Crohn's disease (CD), a primary subtype of inflammatory bowel disease (IBD), underscoring its significance in the gut homeostasis. Recent advancements extend our understanding of NOD2, revealing how gut microbiota variation impacts NOD2 signaling and broadening its pathological significance far beyond CD. This review highlights the transition from focusing on genetic mutations in NOD2 to examining its dynamic regulation by the gut microbiome. This new perspective not only deepens our understanding of NOD2 in diverse health contexts, but also paves the way for innovative therapeutic strategies targeting the gut microbiota-NOD2 axis.