2型糖尿病小鼠肠道菌群宏转录组及代谢组对GLP-1类药物干预应答特征研究

GLP-1, a new type II diabetes treatment drug, has been known to slow or revert the progress of diabetes, and to interfere metabolism at multiple loci. It is also known the progress of type II diabetes closely relates to the change of microbiota in the intestine, and that intestinal microbiota and the host body co-metabolizes. Combining those evidences suggest that the intestinal microbiota are directly or indirectly affected by GLP-1 treatment and therefore influence the process of diabetes. However, the interaction between intestinal microbiota and GLP-1 has not been reported. Our previous research found GLP-1 drug changed the mice intestinal microbiota , we plan to evaluate the transcriptional response of intestinal microbiota to GLP-1 treatment in type II diabetic mice. Transcriptome of intestinal microbiota in GLP-1 treatment mice will be analyzed by testing the feces collected at a serious of post-treatment time points using Illumine Hiseq250. Metabonomics will be analyzed by testing feces, urine, and blood using NMR and GC-MS. By gathering and analyzing the transcriptome and metabonomics features, the mechanism of whether and how GLP-1 influences the intestinal microbiota will be understood theoretically, which will provide theoretical evidence for improving the treatment of GLP-1 on diabetes by targeting and regulating the intestinal microbiota, and for genetic engineering type II therapeutic intestinal microbiota.

基于GLP-1 的2型糖尿病治疗新药具有延缓和逆转糖尿病的独特优势，已知2型糖尿病病程与肠道菌群密切相关，提示肠道菌群直接或间接接受GLP-1干预，从而影响糖尿病的病程。但肠道菌群与GLP-1药效的直接关系还未有文献报道。本申请者致力于长效GLP-1药物研发，前期工作发现GLP-1药物会引起小鼠肠道菌群结构的变化，本课题拟从转录水平捕获与GLP-1药效发挥有直接关联的2型糖尿病小鼠肠道菌基因，采用Illumine Hiseq250对不同处理时间点小鼠粪便样品进行菌群宏转录组学检测，同时用NMR和GC-MS对相应小鼠粪便、尿液和血液进行代谢组学检测，通过宏转录组和代谢物组学信息关联分析，深入解析肠道菌群对GLP-1药物干预的应答性变化与药效发挥之间的关系。研究结果可为通过靶向调节肠道菌结构提高GLP-1治疗效果提供理论依据，并可将捕获的细菌功能基因用于构建防治糖尿病的重组益生菌。