NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is one of the most prominent risk factors in Crohn’s disease (CD), but the chemical mechanisms by which NOD2 mutations gives rise to CD is unclear. NOD2 is a proposed sensor of bacterial cell wall fragments that when mutated results in intestinal inflammation. However, the specific commensal bacteria that activate NOD2 and mechanism(s) by which NOD2 detects cell wall fragments at the molecular level is unknown. To elucidate how NOD2 senses gut bacteria and their cell wall fragments, we will evaluate specific commensal bacteria in mouse models of CD NOD2 mutants and determine the structure of cell wall fragments in complex with NOD2. Our collaborative studies provide a unique multi-disciplinary and synergistic approach to address the molecular mechanisms of NOD2 CD mutations. Understanding these fundamental mechanisms of NOD2 should afford new opportunities to design novel therapeutics targeted at NOD2 mutations in CD.