非那雄胺抑制ESRD肠道微生物驱动的TMAO/IL-12/CCR9+/CXCR3+/CD4+T淋巴细胞对心血管损伤的机制探讨

TMAO由肠道微生物分解含胆碱食物生成前体，再经肝脏FMO3催化而成，由肾脏排出体外。TMAO是心血管疾病的高危因素之一，ESRD患者TMAO高于正常人群。我们前期研究发现：血透患者TMAO升高伴显著差异，与内瘘失功密切相关；高脂饮食诱发小鼠血浆TMAO升高伴动脉粥样硬化；FMO3抑制剂非那雄胺通过调节小鼠肠道菌群，下调TMAO，并缓解心血管损伤；高脂小鼠的外周血CCR9+CXCR3+CD4+T淋巴细胞及CD4+/IL-12+细胞还显著升高。为验证非那雄胺通过抑制特定肠道微生物产生TMAO，降低IL-12驱动的CCR9+/CXCR3+/CD4+T淋巴细胞对CKD小鼠心血管的浸润和损伤的具体效应，本项目拟构建ApoE-/-/IL-12-/-双敲除小鼠行5/6肾大切，明确非那雄胺调控TMAO/IL-12/CCR9+/CXCR3+/CD4+T信号轴的机制，为ESRD心血管疾病治疗提供新方案。

TMAO is produced by intestinal microbes decomposing choline-containing foods to produce precursors, which are catalyzed by liver FMO3 and eventually excreted by the kidneys. TMAO is one of the risk factors for cardiovascular disease, and the TMAO of ESRD patients is higher than that of the normal population. Our previous study found that: TMAO increased in hemodialysis patients was significantly different, which was closely related to internal fistula failure; high-fat diet induced plasma TMAO increased with atherosclerosis; finasteride can regulate the intestinal flora of mice The microenvironment inhibits the generation of TMAO and alleviates cardiovascular damage; and causes peripheral blood CCR9 + CXCR3 + CD4 + T lymphocytes and CD4 + / IL-12 + cells to be significantly higher than the control group. We speculate that finasteride can inhibit the production of TMAO by specific intestinal microorganisms and weaken the cardiovascular infiltration and damage of IL-12-driven CCR9 + / CXCR3 + / CD4 + T lymphocytes. In order to verify this speculation, this project intends to construct ApoE-/-/ IL-12-/-double knockout mice for 5/6 nephrectomy and explore the regulation of finasteride by TMAO / IL-12 / CCR9 + / CXCR3 + / CD4 + The mechanism of the signal axis provides more targets for ESRD cardiovascular disease treatment.