Succinate triggers gut dysbiosis and activates SUCNR1 to enhance inflammaging

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Abstract Inflammaging, the chronic low-grade inflammation that characterizes aging is a likely consequence of a dysfunctional relationship between the imbalanced microbiota and their metabolites with the host's immune system. Inflammaging plays an increasingly important role in the rate of aging and age-related diseases. We have shown that the elevation of succinate, an intermediate metabolite in citric cycle, was associated with aging in both human and mouse which altered the gut microbiome by increasing the relative abundance of pathobionts. Succinate elevation also activates the SUCNR1 to augment myelopoiesis and inflammation. Mechanistically we showed that succinate increased IL-1β and TNFα in the serum and bone marrow, and induced a 30-fold increase of Interleukin-1 receptor-associated kinase 1 (IRAK1) expression and a 50% increase of granulocyte macrophage progenitors in bone marrow. Our preliminary data provided new mechanistic proof that the interplay among gut microbes, altered metabolites and myelopoiesis contributes to inflammaging. We now seek to advance this project by testing the following over-arching hypothesis that targeting the gut microbiome and extracellular succinate receptor activation alleviate inflammaging. In Aim 1 we will determine the impact of succinate elevation on gut dysbiosis and host response in young and old WT C57/B6 and IRAK1 KO mice and how these alterations regulate IL-1β-IRAK1 signaling to promote inflammaging. Then we will use gnotobiotic, antibiotic treatment and Fecal Microbiota Transplantation to determine whether reprogramming the microbiome alters the course of inflammaging. In Aim 2 we will use WT and myeloid lineage-specific SUNCR1 KO mice determine whether the myeloid lineage cells are the key mediators of succinate-stimulated myelopoiesis and inflammation. Finally we will determine whether succinate- stimulated inflammation and myelopoiesis is IRAK1-dependent by conducting bone marrow transplant in WT and IRAK1 KO from young to old mice and monitor the reconstitution of myeloid and lymphoid cells. The proposed study on aging-related succinate elevation on gut dysbiosis and SUCNR1 activation will enable us to understand the causative changes in the intrinsic mechanisms of inflammaging and provide novel target to alleviate inflammaging. Impact: This project directly addresses the NIA's RFA-AG-20-030 on “Microbiome and Aging: Impact on Health and Disease” and provides information on age-related changes in the gut microbiome and how a cross-talk between the host immune system and microbiota correlates to the local and systemic immune responses.