EA7375 (EC2M3 Research Team), Université Paris Est, Créteil 94000, France;
Service de Gastroenterologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil 94000, France.
Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24285-24295. doi: 10.1073/pnas.1912129116. Epub 2019 Nov 11.
Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls' microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study ( = 266), the blood methylation levels of 3 genes (, , and ) were shown closely associated with CRC dysbiosis. In a validation study ( = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC.
散发性结直肠癌（CRC）是宿主与其环境之间复杂相互作用的结果。环境应激源通过引起宿主细胞 DNA 改变而导致癌症的发生。在这里，我们研究了与 CRC 相关的肠道菌群失调作为宿主 DNA 改变的原因的应激源能力。在人类和小鼠中研究了这些改变的表观遗传性质。接受来自接受正常结肠镜检查或 CRC 患者的粪便样本的无菌小鼠，接受 7 或 14 周的监测。在接受人类粪便转移后，监测异常隐窝病灶、管腔微生物群和 DNA 改变（结肠外显子组测序和甲基化模式）。与健康对照的微生物群接受者相比，CRC 相关的微生物群在小鼠结肠黏膜中诱导了更高数量的高甲基化基因。在 CRC 中但不在正常组织或粪便供体的流出物中发现了几个基因启动子（包括 SFRP1、2、3、PENK、NPY、ALX4、SEPT9 和 WIF1 启动子）的高甲基化。在一项初步研究（= 266）中，3 个基因（、和）的血液甲基化水平与 CRC 菌群失调密切相关。在一项验证研究（= 1000）中，这些基因的累积甲基化指数（CMI）在 CRC 中明显高于对照组。此外，多元分析表明，CMI 作为 CRC 诊断的独立危险因素，该分析包括粪便免疫化学血液测试。因此，通过全宏基因组分析鉴定了血液中 CMI 较高的个体中的粪便细菌种类。因此，与 CRC 相关的菌群失调诱导宿主基因的甲基化，相应的 CMI 以及相关细菌是 CRC 的潜在生物标志物。
