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Abstract：
The intestinal microbiota is an important environmental factor implicated in CRC development. Intriguingly, modulation of DNA methylation by gut microbiota has been reported in preclinical models, although the relationship between tumor-infiltrating bacteria and CIMP status is currently unexplored. In this study, we investigated tumor-associated bacteria in 203 CRC tumor cases and validated the findings using The Cancer Genome Atlas datasets. We assessed the abundance of Bacteroides fragilis, Escherichia coli, Fusobacterium nucleatum, and Klebsiella pneumoniae through qPCR analysis and observed enrichment of all four bacterial species in CRC samples. Notably, except for E. coli, all exhibited significant enrichment in cases of CIMP. This enrichment was primarily driven by a subset of cases distinguished by high levels of these bacteria, which we labeled as \"Superhigh\". The bacterial Superhigh status showed a significant association with CIMP (odds ratio 3.1, p-value = 0.013) and with MLH1 methylation (odds ratio 4.2, p-value = 0.0025). In TCGA CRC cases (393 tumor and 45 adj. normal), bacterial taxa information was extracted from non-human whole exome sequencing reads, and the bacterial Superhigh status was similarly associated with CIMP (odds ratio 2.9, p < 0.001) and MLH1 methylation (odds ratio 3.5, p < 0.001). Finally, 16S ribosomal RNA gene sequencing revealed high enrichment of Bergeyella spp. C. concisus, and F. canifelinum in CIMP-Positive tumor cases. Our findings highlight that specific bacterial taxa may influence DNA methylation, particularly in CpG islands, and contribute to the development and progression of CIMP in colorectal cancer.
摘要：
肠道微生物群是影响CRC发展的重要环境因素。有趣的是，在临床前模型中已经报道了肠道菌群对DNA甲基化的调节，尽管肿瘤浸润细菌与CIMP状态之间的关系目前尚未研究。在这项研究中,我们调查了203例CRC肿瘤病例中的肿瘤相关细菌,并使用癌症基因组图谱数据集验证了这些发现.我们评估了脆弱拟杆菌的丰度，大肠杆菌,具核梭杆菌,和肺炎克雷伯菌通过qPCR分析，并观察到CRC样品中所有四种细菌的富集。值得注意的是,除了大肠杆菌,在CIMP病例中均表现出显着富集。这种富集主要是由一组以高水平这些细菌为特征的病例驱动的，我们将其标记为“Superhigh”。细菌超高状态显示与CIMP（比值比3.1，p值=0.013）和MLH1甲基化（比值比4.2，p值=0.0025）显著相关。在TCGACRC病例中（393例肿瘤和45例。normal),细菌分类群信息是从非人全外显子组测序读取中提取的，细菌超高状态与CIMP（比值比2.9，p<0.001）和MLH1甲基化（比值比3.5，p<0.001）相似。最后,16S核糖体RNA基因测序显示高度富集的Bergeyellaspp。C.concisus,和F.canifelinuminCIMP阳性肿瘤病例。我们的发现强调特定的细菌类群可能会影响DNA甲基化，特别是在CpG群岛，并有助于大肠癌中CIMP的发生和发展。
