SCFAs/PGC-1α在肠道菌群调控追赶生长IUGR大鼠胰岛素抵抗中的作用

Intrauterine growth retardation (IUGR) has been closely linked to metabolic syndrome in adulthood, and insulin resistance is the key point. Gut microbiota plays an important role in diabetes, obesity, metabolic syndrome and other diseases, but its correlation with IUGR is rarely reported. Our previous studies have found that IUGR rats with catch-up growth (CG-IUGR) appeared insulin resistance in their early life, and compared with normal group, the composition of gut microbiota was different, futhermore, the level of short chain fatty acids (SCFAs) decreased. It is suggested that gut microbiota may have a potential therapeutic effect on the improvement of insulin resistance in CG-IUGR. On the basis of our previous study, the homeostasis of gut microbiota will be reconstructed by fecal bacteria transplantation, and taking advantage of 16S rRNA high-throughout sequencing technology, pyrosequencing assays, and gas chromatography-mass spectrometry, we explore the effect of SCFAs/epigenetic modification of PGC-1α on insulin resistance in CG-IUGR rats. It will contribute to lay the foundation of molecular mechanism of procedural change in the role of environment-epigenetics-genomics in intrauterine adverse environment leading to growth and metabolic abnormalities, and provide a new direction for therapeutic intervention .

宫内发育迟缓（IUGR）与成年期代谢综合征的发生密切相关，胰岛素抵抗是其中心环节。研究显示肠道菌群在糖尿病、肥胖、代谢综合征等疾病中发挥重要作用，但其与IUGR的联系鲜有报道。本课题组前期研究发现追赶生长IUGR（CG-IUGR）大鼠早期即出现胰岛素抵抗，肠道菌群组成改变，其代谢产物之一短链脂肪酸（SCFAs）水平降低，提示肠道菌群对改善追赶生长IUGR胰岛素抵抗有潜在的防治作用。本研究结合前期研究基础，以SCFAs/PGC-1α表观遗传修饰为切入点，通过粪菌移植重建肠道菌群稳态，借助16S rRNA高通量测序、焦磷酸测序、气相色谱-质谱联用等，探讨肠道菌群依赖的SCFAs/PGC-1α表观遗传修饰在CG-IUGR大鼠胰岛素抵抗中的调控作用，为深入研究环境-表观遗传学-基因组学在宫内不良环境导致生长发育和代谢异常的程序化改变的分子机制奠定基础，并为干预治疗提供新方向。

本课题组在前期工作基础上，以肠道菌群为新思路，通过16S-rRNA高通量测序、焦磷酸测序、气相色谱-质谱联用等技术，研究追赶生长宫内发育迟缓（CG-IUGR）大鼠肠道菌群的特征及SCFAs水平变化与肝脏、骨骼肌组织PGC-1α甲基化、糖脂代谢及胰岛素抵抗的关系，并在细胞水平及整体水平论证SCFAs/PGC-1α表观遗传调控通路对糖脂代谢网络分子及胰岛素受体后信号转导通路的影响，探讨FMT重建肠道菌群稳态可逆调控SCFAs/PGC-1α表观遗传对CG-IUGR大鼠胰岛素抵抗的作用。研究结果发现：在CG-IUGR模型中，CG-IUGR成年大鼠肠道菌群稳态失衡，相关菌群丰度发生改变；CG-IUGR大鼠结肠内SCFAs生成减少，糖脂代谢受损。粪菌移植可改善CG-IUGR大鼠胰岛素抵抗及糖脂代谢，同时结肠内SCFAs生成增加。细胞水平及整体水平研究结果均发现：与正常对照组相比，CG-IUGR组糖脂代谢紊乱，胰岛素受体后信号转导通路受损，PGC-1α的相对表达量降低，PGC-1α甲基化水平升高；SCFAs干预可改善CG-IUGR组大鼠糖脂代谢紊乱，胰岛素受体后信号转导通路受损情况并下调PGC-1α甲基化水平。说明CG-IUGR肠道菌群稳态失衡使SCFAs生成减少，SCFAs负性调控PGC-1α甲基化水平致糖脂代谢网络及胰岛素受体后信号转导通路受损。本研究揭示肠道菌群对CG-IUGR胰岛素抵抗的影响及可能调控机制，为临床改善CG-IUGR胰岛素抵抗提供新的潜在治疗方向。