ABSTRACT The discovery of innate immune receptors has revolutionized the field of innate immunity. An unexpected finding is that innate immune receptor are not only located on the cell membrane, but a majority of these are found intracellularly. This allows cells to detect intracellular perturbation from pathogen-associated molecular patterns (PAMPs) or from damage-associated molecular patterns (DAMPs). Our studies have revealed a novel roles of intracellular innate immune receptor in attenuating inflammation and shaping the microbiome during inflammatory bowel disease (IBD). The central hypothesis is that the bi-directional interplay of inhibitory intracellular innate receptors with the microbiome is a major contributing factor in IBD. Our proposal focuses on the intracellular NLR (nucleotide-binding domain, leucine-rich repeat containing protein, or NOD-like receptor) proteins. While NOD2 remains the most prominent in Crohns’ disease, we have focused on the role of other NLRs in colitis. We have data to show that several inhibitory NLR proteins strongly mitigate intestinal inflammation by reducing the activation of immune signaling pathway thus preventing an inflammatory cytokine response that is integral to colitis. This in turn can affect both innate and adaptive immune cells, as well as colon epithelial cells. We have also shown that these inhibitory NLRs affect the microbiome, partly by maintaining bacteria that can contain a pro-inflammatory response. Thus the first goal is to understand the bidirectional interaction of inhibitory NLR and the gut microbiota in mitigating gut inflammation in mice by working with Projects 2, 4 and the Animal Models Core A. Another over-arching goal is to assess the translational relevance of results obtained in mice to humans. Working with Project 3 and the Human Tissue and Genomics Core B, we will analyze patient-derived material to verify the significance of our findings in mice to inflammatory bowel disease patient samples.