The microbes that flourish within our guts are central to many aspects of human health. Which microbes are present can dictate susceptibility to a number of acute and chronic diseases, including IBD. This proposal will use a mouse model with a defined and stable set of bacteria to probe how mice interact with specific members of their microbiota in health and during disease. First, each microbe will be tested for its ability to elicit an immune response in healthy mice. Once we have established the baseline response in normal healthy mice, we will use chemicals to disrupt the gut lining to elicit an inflammatory response, or we will disrupt genes known to limit intestinal inflammation. We will then investigate how immune recognition of the microbiota changes under these altered conditions. This system will enable us to track responses to the microbiota with unprecedented precision and will provide clues regarding which microbes drive immune activation during dysregulated responses to the microbiota. Such studies will pave the way for future work aimed at manipulating responses to key members of the microbiota responsible for inflammatory diseases of the gut.