比利时VIB炎症研究中心Lars Vereecke等合作发现，大肠杆菌素驱动的结肠癌需要黏附素介导的上皮结合。该研究于2024年11月6日发表于国际一流学术期刊《自然》杂志上。

据介绍，多种细菌可能促进结直肠癌（CRC）的发生，包括携带pks⁺的大肠杆菌，这种细菌会产生基因毒素大肠杆菌素，能够在宿主上皮细胞中引发特征性的突变标记。然而，目前尚不清楚这种高度不稳定的大肠杆菌素，是如何进入宿主上皮细胞并对其造成伤害的。

通过利用微生物依赖的ZEB2转基因侵袭性结直肠癌的小鼠模型，该团队证明了pks⁺大肠杆菌的致癌潜力，严重依赖于细菌对宿主上皮细胞的粘附，由1型绒毛粘附素FimH和F9绒毛粘附素FmlH介导。使用阻断细菌粘附的药理学FimH抑制剂，可减轻大肠杆菌素介导的遗传毒性和结直肠癌恶化。

研究人员还发现，FimH的等位基因开关强烈影响pks⁺大肠杆菌的基因毒性潜能，并能诱导益生菌菌株Nissle 1917的基因毒性功能获得。粘附素介导的上皮结合随后允许，在宿主上皮细胞附近产生基因毒素大肠杆菌素，从而促进DNA损伤并驱动结直肠癌的发展。

这些发现为开发抗粘附疗法提供了有希望的治疗途径，旨在减轻大肠杆菌素诱导的DNA损伤，抑制结直肠癌的发生和进展，尤其是针对具有结直肠癌风险的个体。

附：英文原文

Title: Colibactin-driven colon cancer requires adhesin-mediated epithelial binding

Author: Jans, Maude, Kolata, Magdalena, Blancke, Gillian, DHondt, Aline, Grf, Claudia, Ciers, Maarten, Sze, Mozes, Thiran, Alexandra, Petta, Ioanna, Andries, Vanessa, Verbandt, Sara, Shokry, Engy, Sumpton, David, Vande Voorde, Johan, Berx, Geert, Tejpar, Sabine, van Loo, Geert, Iliev, Iliyan D., Remaut, Han, Vereecke, Lars

Issue&Volume: 2024-11-06

Abstract: Various bacteria are suggested to contribute to colorectal cancer (CRC) development1,2,3,4,5, including pks+ Escherichia coli, which produces the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells6. However, it remains unclear how the highly unstable colibactin molecule is able to access host epithelial cells to cause harm. Here, using the microbiota-dependent ZEB2-transgenic mouse model of invasive CRC7, we demonstrate that the oncogenic potential of pks+ E. coli critically depends on bacterial adhesion to host epithelial cells, mediated by the type 1 pilus adhesin FimH and the F9 pilus adhesin FmlH. Blocking bacterial adhesion using a pharmacological FimH inhibitor attenuates colibactin-mediated genotoxicity and CRC exacerbation. We also show that allelic switching of FimH strongly influences the genotoxic potential of pks+ E. coli and can induce a genotoxic gain-of-function in the probiotic strain Nissle 1917. Adhesin-mediated epithelial binding subsequently allows the production of the genotoxin colibactin in close proximity to host epithelial cells, which promotes DNA damage and drives CRC development. These findings present promising therapeutic routes for the development of anti-adhesive therapies aimed at mitigating colibactin-induced DNA damage and inhibiting the initiation and progression of CRC, particularly in individuals at risk for developing CRC.

DOI: 10.1038/s41586-024-08135-z

Source: https://www.nature.com/articles/s41586-024-08135-z