A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner.
A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner.
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gnotobiotic小鼠模型表明，饮食纤维以微生物群和丁酸酯依赖性方式预防结肠直肠肿瘤发生。
DOI：
10.1158/2159-8290.cd-14-0501
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发表时间：
2014-12
期刊：
影响因子：
28.2
通讯作者：
Bultman SJ
中科院分区：
文献类型：
--
作者：
Donohoe DR;Holley D;Collins LB;Montgomery SA;Whitmore AC;Hillhouse A;Curry KP;Renner SW;Greenwalt A;Ryan EP;Godfrey V;Heise MT;Threadgill DS;Han A;Swenberg JA;Threadgill DW;Bultman SJ
由于人类流行病学研究的结果相互矛盾，膳食纤维是否能预防结直肠癌仍存在争议。然而，这些研究和结直肠癌小鼠模型并没有控制肠道微生物群的组成，这些微生物群将纤维发酵成短链脂肪酸，如丁酸盐。丁酸是值得注意的，因为它在结肠细胞中具有能量和表观遗传功能，并且在结肠直肠癌细胞系中具有肿瘤抑制特性。我们利用定殖有产丁酸盐细菌的野生型或突变株的gnotobiotic小鼠模型来证明纤维确实具有有效的肿瘤抑制作用，但以微生物群和丁酸盐依赖的方式。此外，由于瓦尔堡效应，丁酸盐在肿瘤中代谢较少，在肿瘤中积累并作为HDAC抑制剂发挥作用，以刺激组蛋白乙酰化并影响凋亡和细胞增殖。为了支持这一机制在人类癌症中的相关性，我们证明了丁酸和组蛋白乙酰化水平在结直肠腺癌中与正常结肠组织相比升高。
It is controversial whether dietary fiber protects against colorectal cancer because of conflicting results from human epidemiologic studies. However, these studies and mouse models of colorectal cancer have not controlled the composition of gut microbiota, which ferment fiber into short-chain fatty acids such as butyrate. Butyrate is noteworthy because it has energetic and epigenetic functions in colonocytes and tumorsuppressive properties in colorectal-cancer cell lines. We utilized gnotobiotic mouse models colonized with wild-type or mutant strains of a butyrate-producing bacterium to demonstrate that fiber does have a potent tumor-suppressive effect but in a microbiota- and butyrate-dependent manner. Furthermore, due to the Warburg effect, butyrate was metabolized less in tumors where it accumulated and functioned as an HDAC inhibitor to stimulate histone acetylation and affect apoptosis and cell proliferation. To support the relevance of this mechanism in human cancer, we demonstrate that butyrate and histone-acetylation levels are elevated in colorectal adenocarcinomas compared to normal colonic tissues.