Succinate triggers gut dysbiosis and activates SUCNR1 to enhance inflammaging

摘要 炎症，慢性低度炎症的特点老化是一个可能的后果， 不平衡的微生物群及其代谢产物与宿主免疫功能之间的功能失调关系 系统炎症在衰老和与年龄相关的疾病中起着越来越重要的作用。我们 已经表明，柠檬酸循环中的中间代谢物琥珀酸的升高与 人类和小鼠的衰老通过增加肠道微生物的相对丰度来改变肠道微生物组， 致病生物琥珀酸升高也激活SUCNR 1以增加骨髓生成和炎症。 从机制上讲，我们发现琥珀酸增加了血清和骨髓中的IL-1β和TNFα， 诱导白细胞介素1受体相关激酶1（IRAK 1）表达增加30倍， 骨髓中粒细胞巨噬细胞祖细胞增加。我们的初步数据提供了 肠道微生物、代谢物改变和骨髓生成之间的相互作用有助于 发炎我们现在试图通过测试以下过度假设来推进这个项目， 靶向肠道微生物组和细胞外琥珀酸受体活化减轻炎症。目标1 我们将确定琥珀酸升高对年轻和老年WT肠道生态失调和宿主反应的影响 C57/B6和IRAK 1 KO小鼠以及这些改变如何调节IL-1β-IRAK 1信号传导以促进 发炎然后，我们将使用gnotobiotic，抗生素治疗和粪便微生物移植， 确定重新编程微生物组是否改变了炎症过程。在目标2中，我们将使用WT 和髓系特异性SUNCR 1 KO小鼠决定髓系细胞是否是关键 琥珀酸盐刺激的骨髓生成和炎症的介质。最后，我们将确定琥珀酸- 通过在WT中进行骨髓移植，刺激的炎症和骨髓生成是IRAK 1依赖性的 和IRAK 1 KO，并监测骨髓和淋巴细胞的重建。 这项关于年龄相关琥珀酸升高对肠道生态失调和SUCNR 1激活的研究将 使我们能够理解炎症内在机制的病因变化，并提供新的 以减轻炎症为目标。 影响：本项目直接针对NIA的RFA-AG-20-030“微生物组和老化：影响” ”，并提供有关肠道微生物组中与年龄相关的变化以及 宿主免疫系统和微生物群之间的相互作用与局部和全身免疫相关。 应答

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.