Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Department of Laboratory Medicine, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
Cell. 2014 Jul 17;158(2):288-299. doi: 10.1016/j.cell.2014.04.051.
The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APC(Min/+)MSH2(-/-) mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2(-/-) colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. PAPERCLIP:
结直肠癌（CRC）的病因与错配修复和腺瘤性结肠息肉病（APC）蛋白、饮食、炎症过程和肠道微生物群的缺陷有关。然而，微生物群与这些病因因素协同作用促进 CRC 的机制尚不清楚。我们报告称，改变微生物群组成可减少 APC(Min/+)MSH2(-/-) 小鼠的 CRC，并且碳水化合物含量降低的饮食可模拟这种效果。肠道微生物群并没有通过炎症反应或产生 DNA 诱变剂在这些小鼠中引发 CRC，而是通过提供丁酸等碳水化合物衍生的代谢物来为 MSH2(-/-) 结肠上皮细胞的过度增殖提供燃料。此外，我们提供的证据表明，错配修复途径在调节β-连环蛋白活性和调节结肠中转录扩增细胞的分化方面具有作用。这些数据因此为微生物群、饮食和错配修复缺陷在 CRC 诱导中的相互作用提供了一个解释。
