菊粉型果聚糖通过调节肠道微生物稳态改善小鼠糖尿病肾病的机制研究

Diabetic nephropathy is one of the most serious chronic complications of diabetes mellitus and the main cause of end-stage renal disease. There is still a lack of effective treatment for diabetic nephropathy. Previous studies have found that inulin-type fructans participates in the occurrence and development of various metabolic related diseases. However, little research has been done on whether inulin-type fructans can improve diabetic nephropathy. In this study, we constructed a model of diabetic nephropathy in mice, using 16S microbial diversity sequencing, fecal transplantation and a variety of biological means to explore the protective effect of inulin-type fructose on diabetic nephropathy, and further explore the role of intestinal microorganisms and their metabolite acetate in it. At the same time, this project intends to explore the regulation of acetate on the number and function of glomerular mitochondria and the specific molecular mechanism of reducing the accumulation of toxic metabolites of glucose through animal and cell experiments. In this study, we tried to explore the effects of inulin-type fructose on intestinal microorganisms and their metabolites in mice, and elaborated the specific mechanism of acetate as a link molecule of intestinal-renal axis to protect diabetic nephropathy.

糖尿病肾病是糖尿病最严重的慢性并发症之一，是导致终末期肾脏疾病的主要原因，目前仍缺乏糖尿病肾病的有效治疗方法。既往研究发现，菊粉型果聚糖参与机体多种代谢相关疾病的发生发展，然而关于其能否改善糖尿病肾病至今却鲜有研究。本研究中，我们构建了小鼠糖尿病肾病的模型，利用16S微生物多样性测序、粪便移植及多种生物学手段，探究菊粉型果聚糖对糖尿病肾病的保护作用，并进一步探讨肠道微生物及其代谢产物乙酸盐在其中发挥的作用。与此同时，本项目拟通过动物及细胞实验探究乙酸盐对肾小球线粒体数量及功能的调节，以及减少葡萄糖毒性代谢产物累积的具体分子机制。本课题力图探究菊粉型果聚糖对小鼠肠道微生物及其代谢产物的影响，阐述乙酸盐作为肠-肾轴的联系分子发挥保护糖尿病肾病的作用及具体机制。

糖尿病肾病是终末期肾病最常见的原因，然而目前没有有效预防肾功能进行性丧失的治疗措施。研究表明，摄入膳食纤维很可能通过短链脂肪酸改善肾脏疾病和代谢相关疾病。本研究通过16S rRNA基因测序、气相色谱质谱分析和粪便菌群移植实验，研究了菊粉型果聚糖（ITFs）对糖尿病肾病的保护作用。结果表明，补充ITFs通过调节db/db小鼠肠道微生物的组成保护其肾脏损伤。抗生素预处理和粪便菌群移植实验进一步证实了肠道微生物在介导ITFs肾脏保护作用方面的关键作用。ITFs诱导的肠道菌群变化导致了产短链脂肪酸菌群的富集，尤其是Akkermansia和Candidatus Saccharimonas菌属，这增加了粪便和血清种乙酸盐浓度。同时，补充乙酸盐通过改善线粒体功能障碍和降低糖毒性代谢产物水平来改善肾小球损伤和肾脏纤维化。综上所述，ITFs通过调节肠道微生物组成和增加乙酸盐的产生发挥肾脏保护作用，其中乙酸盐通过调节糖代谢、降低糖毒性产物水平和改善线粒体功能介导肾脏保护作用。