肠道菌群代谢物丁酸激活FFAR3上调SIRT4表达改善线粒体稳态延缓血管衰老

肠道菌群与宿主疾病关系是当前研究热点，丁酸是重要肠道菌群代谢物，与衰老关系研究正兴起，但与血管衰老关系尚未知。我们预实验发现老年小鼠产丁酸Roseburia菌属丰度减少；丁酸减轻老化期人脐静脉内皮细胞衰老并上调SIRT4表达；转录组测序分析发现丁酸调控线粒体稳态相关基因转录，但不影响HDACs；生物信息学分析发现人主动脉游离脂肪酸受体（FFAR3）高低表达组的差异通路与丁酸干预HUVECs均富集在PI3K/AKT通路。据此提出假说：丁酸通过结合FFAR3激活PI3K/AKT信号通路，上调SIRT4表达，改善线粒体稳态，延缓血管衰老。拟行小鼠血管衰老与肠道菌群、血浆丁酸相关关系；证明丁酸延缓血管衰老；其机制是通过结合FFAR3而激活PI3K/AKT信号并上调SIRT4表达、改善线粒体稳态等研究以证明假说。本项目以肠道菌群代谢物丁酸这新视点研究血管衰老及其机制，为防治血管衰老提供新策略新靶点。

The relationship between intestinal flora and host disease is the focus of current medical research. As an important metabolite of intestinal flora, butyrate is being studied on its relationship with aging, but whether it is related to vascular aging is not yet known. Our previous experiments found that the abundance of butyrate-producing genus Roseburia decreased in old mice compared to the young mice; butyrate could alleviate the senescence and upregulate the expression level of sirtuin 4(SIRT4) in senescent human umbilical vein endothelial cells(HUVECs); transcriptome sequencing analysis suggested that butyrate could regulate the transcription level of mitochondrial homeostasis related genes, but did not change the transcription level of histone deacetylases(HDACs); Bioinformatics analysis showed that the differential signaling pathway between the high and low expression groups of human aortic free fatty acid receptor (FFAR3) and between the butyrate-treating and control groups were both enriched in the PI3K/AKT signaling pathway. Based on the above results, we propose the hypothesis that butyrate activates the PI3K/AKT signaling pathway by combining with FFAR3, upregulates SIRT4 expression, improves mitochondrial homeostasis to delay vascular aging. To prove the hypothesis, the association among vascular aging, intestinal flora and plasma butyric acid in mice will be evaluated; the effect of butyrate on delaying vascular aging and the mechanism which butyrate combined with FFAR3 activates the PI3K / AKT signaling pathway, up-regulates SIRT4 expression and improves mitochondrial homeostasis will be tested. This project investigates vascular aging and its mechanisms from the new perspective of intestinal flora metabolite butyrate, and provides new strategies and targets for the prevention and treatment of vascular aging.