结直肠癌(CRC),全世界的恶性肿瘤,与肠道微生物群有关。肠道微生物源代谢产物对CRC的影响已引起广泛关注。然而,由共生微生物来源的代谢产物介导的免疫在CRC肿瘤发生中的作用尚未得到深入研究。在这里,我们监测了没有饮食和药物干预的CRC小鼠模型(ApcMin/+模型)中的肠道微生物菌群失调,随后表征了在CRC模型小鼠中富集的代谢物。在肠道疾病期间观察到肠道微生物组(细菌组)的深刻变化。代谢组学分析表明胍丁胺,来自肠道细菌,即Blautia,Odoribacter,Alistipes和Paraprevotella,可以与Rnf128相互作用以抑制Rnf128介导的β-catenin的泛素化,从而进一步上调β-catenin的下游靶标,包括CyclinD1,Lgr5,CD44和C-myc,从而激活Wnt信号。激活的Wnt信号通路通过诱导促炎细胞因子(IL-6和TNF-α)的上调和抗炎细胞因子(IL-10)的下调,促进肠细胞的异型增生和淋巴细胞的炎性浸润。从而促进结直肠癌的发生。因此,我们的研究为肠道菌群在CRC发病机制中的作用和机制提供了新的见解.
Colorectal cancer (CRC), a malignant tumor worldwide, is associated with gut microbiota. The influence of gut microbe-derived metabolites on CRC has attracted a lot of attention. However, the role of immunity mediated by commensal microbiota-derived metabolites in tumorigenesis of CRC is not intensively explored. Here we monitored the gut microbial dysbiosis in CRC mouse model (ApcMin/+ model) without dietary and pharmacological intervention, followed by characterized of metabolites enriched in CRC model mice. Profound changes of gut microbiome (bacteriome) were observed during intestinal disorders. Metabolomic profiling indicated that agmatine, derived from the gut bacteria i.e. Blautia, Odoribacter, Alistipes and Paraprevotella, could interact with Rnf128 to suppress the Rnf128-mediated ubiquitination of β-catenin to further upregulate the downstream targets of β-catenin including Cyclin D1, Lgr5, CD44 and C-myc, thus activating Wnt signaling. The activated Wnt signaling pathway promoted dysplasia of intestinal cells and inflammatory infiltration of lymphocytes via inducing the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) and downregulation of anti-inflammatory cytokine (IL-10), thereby contributing to colorectal carcinogenesis. Therefore, our study presented novel insights into the roles and mechanisms of gut microbiota in pathogenesis of CRC.