Harnessing the microbiome to regulate systemic innate immunity

Abstract The mechanisms used by the gastrointestinal microbiome to regulate systemic immunity remain unclear. We have identified a microbiome Bacteroidota-derived lipopeptide—L654—that is a TLR2 ligand, accesses the systemic circulation, and thus potentially links the microbiome and 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 TLR2 interactions that maintain “normal” levels of innate immune signaling feedback inhibitors; 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 responses and attenuates murine autoimmunity. In the present study, our goal was to document the converse effect, i.e., that decreasing microbiome L654 production enhances systemic innate immune responses. Using wild-type C57BL/6 mice, we report that decreasing microbiome Bacteroidota using specific non-absorbable oral antibiotics reduces fecal and serum L654 levels and significantly enhances innate immune responses. Moreover, the intravenous administration of L654 to antibiotic-treated mice prevents this innate immune enhancement. Overall, our results suggest that L654 is: 1) used by the microbiome to regulate systemic innate immunity; and 2) a manipulatable target capable of enhancing or decreasing innate immunity in the context of infectious, malignant, or autoimmune diseases. UConn Health Center Academic Advancement Fund