The gastrointestinal tract hosts the microbiome, one of the highest microbial densities on earth. Diverse host-microbiome interactions influence a multitude of physiological and pathological processes, yet the basic mechanisms regulating host-microbiome interactions remain unknown. Deciphering the codes comprising the host-microbiome communication network and factors initiating loss of homeostasis (termed dysbiosis) will enable the recognition of pathways and signals critically important to initiation and progression of common immune and metabolic disorders. We recently identified the NLRP6 inflammasome as a critical innate immune regulator of colonic microbial ecology, with its disruption resulting in auto-inflammation and tumorigenesis. We will use this unique system, coupled with innovative robotic high-throughput modalities, gnotobiotics, metagenomics and multiple genetically altered mouse models to generalize our studies and decipher the critical principles governing host-microbiome interactions. We will elucidate the host-derived microbiome recognition signaling pathway at its entirety, from its upstream activators to the downstream effector molecules controlling microbial ecology; uncover the principles generating a stable microbiota composition; and develop and apply computational modelling to dissect the general mechanisms disrupting microbiome stability leading to dysbiosis. Using this innovative experimental and computational toolbox we will study the impact of dysbiosis on key components of the metabolic syndrome, and apply our findings to devise the first rational proof-of-concept approach for individualized microbiome-based treatment for these common disorders. At the basic science level, unraveling the principles of host-microbiota interactions will lead to a conceptual leap forward in our understanding of physiology and disease. Concomitantly, it may generate a platform for microbiome-based personalized therapy against common idiopathic illnesses.