基于肠道菌群-ImP轴探索叶黄素对二甲双胍治疗2型糖尿病疗效和初始治疗失败率的影响及机制

二甲双胍是治疗2型糖尿病（T2DM）的一线药物，如何改善其疗效和初始治疗失败率是T2DM研究领域亟待解决的热点科学问题。最新研究发现肠道菌群-咪唑丙酸（ImP）轴激活可能是二甲双胍治疗方案出现疗效降低甚至初始治疗失败的重要原因，然而目前尚无靶向调控该信号通路轴的干预措施及机制研究。血液中ImP水平与肠道菌群和膳食因素密切相关，既往研究和项目组前期实验结果提示膳食中的叶黄素可能通过肠道菌群降低血液中的ImP水平。因此我们提出了“叶黄素可通过靶向调控肠道菌群-ImP轴改善二甲双胍治疗T2DM疗效，进而降低其初始治疗失败率”的研究假说。本项目拟通过宏基因组测序、菌群移植无菌动物、UPLC-MS/MS等方法，从动物和人群两个层面对研究假说进行深入探讨。该假说的论证可为改善二甲双胍疗效和初始治疗失败率方案的制定提供新的理论依据。同时，本项目的开展对拓展了解叶黄素生理功能和增加其应用价值具有重要意义。

Metformin is the first-line oral drug for type 2 diabetes mellitus (T2DM). Improving its efficacy and initial treatment failure rate is a hot topic for the research area in T2DM. The most recent study found that activation of gut microbiota-ImP axis played a key role in causing efficacy reduction and initial treatment failure of metformin for the management of T2DM. However, the study targeting the regulation of gut microbiota-ImP axis has not been conducted. Serum ImP levels are correlated with gut microbiota and dietary factors. Previous studies and our preliminary research indicated that lutein can decrease the ImP levels by modifying the microbiota composition. As suggested by the aforementioned evidence, we hypothesized that lutein might have beneficial effects on efficacy reduction and initial treatment failure rate of metformin for the management of T2DM. The hypothesis will be tested in both human and animal studies using the techniques of metagenomic sequencing, fecal transplantation in germ-free mice and UPLC-MS/MS etc. The findings may provide a theoretical basis for physicians trying to improve efficacy and initial treatment failure rate of metformin for patients with T2DM. Meanwhile, this study is important for further clarifying the physiological function of lutein and in turn increasing its application value.