"Nucleotide-binding domain, leucine-rich repeat-containing (NLR) proteins have emerged as central regulators of immunity and inflammation. Several NLRs form cytosolic multi-protein complexes termed inflammasomes in response to pathogen and damage- associated molecular patterns. We recently identified the NLRP6 inflammasome as a critical innate immune regulator of the intestinal microbiome, a diverse ecosystem whose poorly understood interactions with the host influence a multitude of physiological and pathological processes. We found that NLRP6 inflammasome disruption results in dramatic alterations in microbiome composition & function, in turn leading to auto-inflammation and a propensity to the development of metabolic syndrome. However, the basic mechanisms governing NLRP6 activation & regulation of host-microbiome interactions remain unknown. Using the NLRP6 system as a proof-of-principle model, and innovative robotic high-throughput modalities, gnotobiotics, metagenomics and multiple genetically altered mouse models we will decipher the codes comprising the host-microbiome communication network and factors initiating loss of homeostasis (dysbiosis). As part of our studies, we will (A) elucidate the host-derived microbiome recognition signaling pathway at its entirety, from its upstream activators to the downstream effector molecules controlling microbial ecology; (B) decipher the cell-specific mechanisms of NLRP6 regulation of the intestinal crypt niche; and (C) uncover mechanisms by which the innate immune arm regulates the composition and function of the gut commensal eco-system in health and disease. From a research perspective, deciphering the principles of NLRP6 signaling and its regulatory effects on host-microbiota interactions in health and disease will lead to a conceptual leap forward in our understanding of physiology and pathology. Concomitantly, it may generate a platform for microbiome-based personalized therapy against common idiopathic diseases."