Project Summary/Abstract The microbiome affects many aspects of human health and has been linked to diseases such as obesity, inflammatory bowel disease, diabetes, and allergy. The balance between host and commensal bacteria is well maintained in most healthy individuals. One host factor that contributes to intestinal homeostasis is antibody of the IgA subclass. Plasma cells that produce IgA are found in mucosal tissues such as the lamina propria of the gut, but they can also be found in systemic sites including the bone marrow. However, high levels of bone marrow IgA are only found in the presence of certain consortia of bacteria. Increased frequencies of bone marrow IgA-secreting plasma cells are associated with increased concentration of serum IgA that has been shown to be protective in a sepsis model of polymicrobial dissemination. The mechanisms by which bacteria induce systemic IgA responses are unknown. The main goal of this proposal is to take an unbiased approach to defining gene-level mechanisms used by commensal bacteria to induce systemic IgA. Additionally, we will examine how inter-species interactions contribute to systemic IgA specificity. Together, this proposal will provide a framework for understanding how systemic antibody responses are induced in response to commensal bacteria. This understanding could lead to novel therapies aimed at maintaining intestinal homeostasis or using commensal bacteria as a vaccine delivery system. This proposal will support the overall vision of our research program to understand the complex interplay at the interface of bacteria and host by deciphering gene-level mechanisms used by bacteria to induce IgA responses.