Antiphospholipid syndrome (APS) is a potentially lethal autoimmune clotting disorder that is frequently associated with lupus. The triggers that induce the adaptive immune response against the main autoantigen are unknown. We have evidence in the (NZWxBXSB)F1 hybrid, a spontaneous model for APS, that specific members of the gut microbiota sustain pathogenic autoantibodies and mortality. The phenotype is also reversed by caloric restriction in this model. Since dietary interventions are known to affect the gut microbiota, we hypothesize that caloric restriction prevents APS via suppression of pathobionts or outgrowth of protective symbionts. We will define the microbial community composition of antibiotic-treated as well as calorically restricted mice. Key candidates that emerge from these comparative studies will be cultured and introduced into commensal-ablated animals to demonstrate functionally induction of APS. We plan to dissect also if the pathobionts induce not only autoantibodies but also helper T cell subsets and autoantigen-specific T cell proliferation. These studies will therefore link specific gut commensals to pathogenic adaptive immune responses in APS and uncover entirely novel aspects of this syndrome. We plan to translate our studies to human APS and lupus with the potential to develop new therapeutic avenues aimed at gut commensals.