W221 - Harnessing the Microbiome to Regulate Systemic Innate Immunity

Frank Nichols – Department of Periodontology, School of Dental Medicine – University of Connecticut Health Center; Anthony Provatas – Center for Environmental Sciences and Engineering, Institute of the Environment – University of Connecticut; Christopher Blesso – Department of Nutritional Sciences – University of Connecticut; Robert Clark – Department of Immunology; Department of Medicine – University of Connecticut Health Center

Abstract Text: While many studies have correlated changes in the gastrointestinal microbiome with systemic immune-based diseases, the mechanisms underlying the crosstalk between the microbiome and the systemic immune system are poorly understood. We have now identified a microbiome Bacteroidota-derived lipodipeptide—L654—a TLR2/TLR6 ligand that accesses the systemic circulation, as a microbiome-derived regulator of systemic innate immunity. We previously documented that Multiple Sclerosis patients have significantly lower serum L654 levels than healthy controls, leading us to postulate that: 1) L654 regulates systemic innate immunity by entering the systemic circulation and mediating weak TLR2-signaling that maintains “normal” levels of innate immune signaling feedback inhibitors (e.g., A20); and 2) inadequate systemic L654 levels result in poorly regulated, enhanced innate immune responses. In prior proof-of-concept studies, we reported that increasing systemic L654 levels by administering exogenous L654 intravenously significantly diminishes systemic innate immune pro-inflammatory responses and attenuates murine autoimmunity. In the present study, our goal is to directly study the role of the microbiome in this mode of immunoregulation. Using wild-type C57BL/6 mice, we now report that decreasing microbiome Bacteroidota using a specific protocol of oral antibiotics reduces fecal and serum L654 levels and significantly enhances innate immune pro-inflammatory responses. Moreover, replenishing levels of L654 in antibiotic-treated mice reverses this innate immune enhancement. Overall, our results suggest that: 1) L654 is a microbiome-derived mediator of systemic innate immune regulation and; 2) our approach now allows the microbiome to be harnessed therapeutically for enhancing or diminishing immunity in the context of infectious, malignant, or autoimmune disease.