Inflammasomes are multi-protein complexes that control the activity of the cysteine protease caspase-1. Inflammasomes are assembled around one of several different sensor proteins, which enable inflammasome activation after sensing of diverse microbial and endogenous damage-associated molecules. Recently, I discovered a novel role for the NLRP6 inflammasome in regulation of the intestinal microbiota of mice. In its absence an altered microbiota, called dysbiosis, develops that increases the severity of experimentally-induced colitis. Strikingly, transfer of the altered microbiota to WT mice resulted in exacerbated colitis in these mice compared to normal WT mice. These findings highlight two important features of the interplay of host and microbiota. First, that deficiencies in the immune system may lead to pathologic aberrations in the commensal microbiota. In this proposal I will address how the NLRP6 inflammasome regulates the microbiota using newly generated gene-deficient mouse strains as well as germfree mouse models. The second implication is that the microbiota has a large effect on mucosal inflammatory processes that are largely regulated by its specific composition. Dysbiosis is observed in many human individuals with immune-mediated diseases, but its impact on other aspects of immunity is less well characterized. Hence, I intend to study the effects of the microbiota, specifically dysbiosis, on orchestrating anti-microbial immune responses, as well as the impact in host response to vaccination. Specifically, I will study vaccination and challenge models of bacterial and viral pathogens that enter through mucosal routes, i.e. Salmonella enterica and influenza virus. The knowledge emerging from this work is expected to expand our understanding of innate and adaptive immune responses to infection and pave the road for the development of new therapies and immune interventions against microbial pathogens.