大肠癌（CRC）发病率高，肠道菌群紊乱、染色质修饰异常、细胞糖代谢重编程和增殖相关信号通路活化参与其发生中。我们曾发现肠菌异常致黏膜丁酸盐减少、组蛋白乙酰化降低和ERK-MAPK与STAT通路活化；HIF-1α诱导的组蛋白去甲基化酶JMJD2B通过STAT3通路而促进增殖，低糖时JMJD2B增高、与p-ERK1/2在胞内共定位且通路活化；CRC细胞中抑制ERK通路则降低JMJD2B而减少细胞摄取葡萄糖；抑制肿瘤血管形成则CRC细胞线粒体受抑而糖酵解增强。以下问题亟待解决①肠菌影响肠黏膜细胞组蛋白修饰和信号通路变化的详细机制是何？②肠菌怎样影响细胞糖代谢重编程？③其间的网络调控如何参与大肠癌的发生发展？我们将在临床标本分析和体内外实验中，通过ChIP- seq结合GO注释和pathway分析、定量质谱、基因敲除与导入等研究，阐释上述网络关系，探讨通过调节肠菌而预防CRC的可行性及其机制。

Colorectal cancer (CRC) is one of higher morbidity cancers worldwide. Its progression involves in gut flora dysbiosis, activation of proliferation pathways, abnormal chromatin modification and reprogrammed cell glucose metabolism. In our previous studies, we found disturbances of gut bacterial communities suppressed the production of butyrate, decreased histone acetylation and activated ERK-MAPK and STAT pathways. The histone demethylmethylase JMJD2B, which was induced by HIF-1α, promoted cell proliferation through STAT3 pathway. In low glucose environment, JMJD2B expression was significantly elevated and it exhibited colocalization with phosphorylated ERK1/2, leading to ERK-MAPK pathway activation. Conversely, inhibition of ERK-MAPK pathway decreased JMJD2B expression and impaired glucose uptake in CRC cells. Meanwhile, tumor anti-angiogenesis therapy resulted in inhibition of mitochondria respiratory function and enhanced activity of glycolysis. However, it remains to be clarified the mechanism of how gut flora impact on histone modifications and pathways activations in intestinal mucosal cells. In another aspect, whether and how do gut bacterial communities influence reprogramming of cell glucose metabolism? Herein lies the problem of how these regulatory networks function in CRC development and progression. In the present study, we will identify these regulatory networks both in vivo and ex vivo, by the approaches of ChIP-sequence in combination with GO annotation, pathway analysis, quantitative mass spectrometry, gene knockdown or knockup and so on. We will also establish whether and how manipulation of gut microbial dysbiosis may be used as a potential therapeutic approach in the treatment of human CRC.