肿瘤细胞耐药频繁发生已成为威胁中晚期结直肠癌患者生存质量的重要危险因素，肠道菌群可通过调节细胞局部反应，进而影响化疗效果。申请者前期证实具核梭杆菌可能通过激活自噬促进结直肠癌化疗耐药，但是产肠毒素脆弱拟杆菌（ETBF）对结直肠癌化疗的潜在影响未有相关研究。根据前期实验数据，申请者证实结直肠癌细胞感染ETBF后能抵抗化疗药物奥沙利铂诱导的细胞杀伤，其机制可能是ETBF上调lncRNA CACClnc的表达后，促进DNA损伤修复关键基因转录表达，增强肿瘤细胞DNA的损伤修复能力，最终导致结直肠癌细胞化疗耐药。因此我们将在临床标本、体内外实验中通过RNA pull down、ChIP seq生物信息分析、基因编辑等手段阐释上述网络关系，探讨ETBF诱导结直肠癌细胞化疗耐药的机制并寻找潜在干预靶点。这一研究可为我们深入理解肠道菌群参与结直肠癌耐药发生的机理及研发有效干预措施提供理论基础。

Chemotherapy resistance has become an important risk factor threatening the survival of patients with advanced colorectal cancer. The intestinal microbiota may modulate local intestinal responses and in turn affect chemotherapy. Our team has confirmed that Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. However, it is not clear whether other pathogenic bacteria, such as Enterotoxigenic Bacteroides fragili (ETBF), which is involved in the tumorgenesis of colorectal cancer (CRC), may participate in the chemotherapeutic process of CRC patients. According to our previous data, we have proved that ETBF may promote chemoresistance to CRC cells in vitro and in vivo conditions. It is possible that ETBF may up-regulate lncRNA CACClnc expression, which recruits KAT2A protein to the promoter regions of those genes, which is closely correlated with repair of DNA damage, and activates these genes expression. The activation of repair of DNA damage correlated genes will lead to the enhancement of DNA homologous recombination repair ability in CRC cells, and finally induce chemoresistance in CRC cells in response to Oxaliplatin treatment. Therefore, we will verify our hypothesis in clinical samples; animals and cell models by employing RNA pull down, ChIP seq bioinformatica analysis, gene editing and other methods. We will also establish whether and how manipulation of gut microbial dysbiosis may be used as a potential therapeutic approach in the treatment and block of human CRC chemoresistant progression.