FTO调控的肠道菌群介导脑肠互动调节参与肠易激综合征发生及其机制研究

Irritable Bowel syndrome (IBS) is a functional bowel disease caused by abnormal interaction of the brain and gut, and the mechanism is unclear. FTO is an obesity-related gene found in GWAS and is also associated with depression. We reported that FTO deficiency reduced anxiety and depression behaviors after stress stimulation, we also found they improved defecation, which implied that FTO may be involved in the regulation of gut-brain interaction. With regard to the gut microbiota, the abundance of Lactobacillus increased and inflammatory bacteria such as pylori decreased, which are related to IBS symptoms. In vivo, FTO plays its role through demethylation for the m6A of mRNA, m6A modification can regulate the differentiation of CD4+ T cells, which is very important for the homeostasis of gut microbiota. RNA-seq found that .RORα and RORγt significantly increased in intestine of FTO knockout mice, RORα and RORγt are important transcription factors that mediated the differentiation of TH17 cells. Therefore, we speculate that FTO regulates CD4+ T cell differentiation through transcription regulation of RORα and RORγt, then affects the homeostasis of gut microbiota and mediates the interaction of brain and gut in IBS. This study will explore the mechanism of FTO regulation of immune cell differentiation in FTO knockout mice by fecal bacteria transplantation, intestinal immune evaluation, immune cell sorting, candidate molecular verification. It is expected to reveal a new mechanism for the regulation of gut microbiota by host genes, which provides a new target for the treatment of IBS.

肠易激综合征是脑肠互动异常引起的功能性肠病，机制不清。FTO是GWAS发现的一种肥胖相关基因，也与抑郁症发生相关。我们报道了FTO敲除及杂合小鼠压力刺激后焦虑和抑郁行为减少，排便情况改善，可能参与脑肠互动调节。且乳酸杆菌增多，螺旋杆菌等炎性细菌减少，均与IBS症状相关。FTO通过mRNA的m6A去甲基化发挥功能，m6A修饰可调控CD4+T细胞分化，对肠道菌群稳态至关重要。RNA-seq发现，FTO敲除后肠道RORα、RORγt明显上调，二者是介导Th17细胞分化重要的转录因子。因此我们推测FTO通过RORα和RORγt的转录调控CD4+T细胞分化，影响肠道菌群稳态，介导IBS脑肠互动。本研究将在FTO敲除小鼠中通过粪菌移植、肠道免疫评价、免疫细胞分选、候选分子验证等探索FTO调控免疫细胞分化影响肠道菌群参与IBS调节的机制。有望揭示宿主基因调节肠道菌群的新机制，为IBS的治疗提供新的靶点。

脑肠互动异常是肠易激综合征、便秘等功能性胃肠病最重要的特征之一。肠道菌群可通过免疫信号、迷走神经、代谢产物等途径连接肠道与大脑，在脑-肠互动中发挥关键作用。宿主基因可通过调节肠道菌群组成介导脑肠互动，从而在功能性胃肠病发生发展中发挥重要作用，但其机制未明。. 本项目首先构建了一种新型的脑肠互动异常小鼠模型，可快速稳定地诱导出肠道功能及中枢神经系统功能紊乱，为后续研究提供了良好的动物模型。进而，以肠上皮特异性FTO敲除的小鼠（FTO-IKO）为模型，研究了FTO调控肠上皮干细胞自我更新及分化，引起肠道微环境改变，进而调节肠道菌群组成的作用和机制。肠道上皮-肠道菌群-肠道免疫的互作失衡是脑肠互动异常发生的关键环节，因此，我们在FTO-IKO小鼠模型中，诱导急性肠道炎症模型，探究了肠上皮FTO调控的肠道菌群通过与肠道免疫系统的相互作用，调控肠道炎症发生发展的作用和机制。本部分研究结果为肠道炎症相关疾病（肠易激综合征、炎症性肠病）的预防和治疗提供了新的特异性靶标。. 此外，我们收集了一组功能性胃肠病患者的临床特征、治疗方案及其疗效，发现了患者肠道菌群特征可预测功能性胃肠病患者使用益生菌治疗的疗效，为功能性胃肠病患者的临床治疗决策提供依据。