Sporadic colon cancer accounts for ∼80% of CRC, with high incidence in western societies strongly linked to dietary patterns. The only mouse model for sporadic CRC results from feeding mice a purified rodent western-style diet (NWD1), establishing mouse intake of several common nutrients that mimic for each its level consumed in western populations at higher risk for colon cancer (higher fat, lower vitamin D3, calcium, methyl donors and fiber). This causes sporadic colon and small intestinal tumors at an incidence and frequency similar to that of humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts before tumors are detected. Surprisingly, feeding NWD1 decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumorigenesis, associated with extensive Lgr5hi cell transcriptional reprogramming, with nutrient levels interactive in these effects. There is a key impact of the lower vitamin D3 in NWD1 and its signaling through the Vdr. The DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, reducing accumulation of relevant somatic mutations detected by single cell exome sequencing. There are also alterations in metabolic pathways, including down-regulation of oxidative phosphorylation. In compensation for compromise of Lgr5hi cells, NWD1 also reprograms cells derived from the Bmi1+ population, defined as those cells marked in Bmi1creERT2, Rosa26tom mice following tamoxifen injection, and at least a portion of these cells then function and persist as stem-like cells in mucosal homeostasis and tumorigenesis. The data establish a key role of the nutrient environment, and vitamin D signaling, in defining contribution of at least two different stem cell populations to mucosal homeostasis and tumorigenesis. This raises significant questions regarding impact of variable human diets on which and how multiple potential intestinal stem cell populations function in the human and give rise to tumors. Moreover, genetic and epigenetic changes in long-lived stem cells have important implications for understanding the effects of vitamin D and other nutrients on intestinal homeostasis and on intervention strategies for altering probability of tumor development.

中文翻译：

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维生素D和肠道干细胞功能中的营养环境：对肿瘤发生和预防的意义。

散发性结肠癌约占CRC的80％，在西方社会中，高发病率与饮食模式密切相关。唯一的散发性CRC小鼠模型是通过给小鼠喂食纯净的啮齿动物西式饮食（NWD1）而建立的，从而建立了小鼠几种常见营养素的摄入量，这些营养素模拟了在西部人群中消耗的每种营养素水平，从而增加了罹患结肠癌的风险（脂肪含量较高，维生素D3，钙，甲基供体和纤维）。这会导致散发性结肠和小肠肿瘤，其发病率和频率与人类相似。在检测到肿瘤之前，NWD1干扰整个绒毛和结肠隐窝的肠细胞成熟和Wnt信号传导。令人惊讶的是，喂食NWD1会降低小鼠Lgr5hi肠道干细胞对体内稳态和肿瘤发生的贡献，与广泛的Lgr5hi细胞转录重编程有关，营养水平在这些作用中相互作用。NWD1中较低的维生素D3及其通过Vdr的信号传导具有关键影响。Lgr5hi细胞中的DNA错配修复途径因NWD1中较低的维生素D3和/或钙而增加，从而减少了通过单细胞外显子组测序检测到的相关体细胞突变的积累。代谢途径也有改变，包括氧化磷酸化的下调。为了补偿Lgr5hi细胞的损害，NWD1还对来自Bmi1 +群体的细胞进行了重新编程，该细胞被定义为在他莫昔芬注射后，在Bmi1creERT2，Rosa26tom小鼠中标记为Bmi1 +的那些细胞，然后这些细胞的至少一部分在干细胞中像干细胞一样发挥作用并持续存在粘膜稳态和肿瘤发生。数据确立了营养环境和维生素D信号传导在定义至少两种不同干细胞群体对粘膜稳态和肿瘤发生的作用中的关键作用。这引起了关于可变人类饮食对人类的潜在影响以及多种潜在肠道干细胞群体如何在人类中起作用并引起肿瘤的重大问题。此外，长寿干细胞的遗传和表观遗传学变化对于理解维生素D和其他营养物质对肠道稳态的影响以及改变肿瘤发生概率的干预策略具有重要意义。这引起了关于可变人类饮食对人类的潜在影响以及多种潜在肠道干细胞群体如何在人类中起作用并引起肿瘤的重大问题。此外，长寿干细胞的遗传和表观遗传学变化对于理解维生素D和其他营养物质对肠道稳态的影响以及改变肿瘤发生概率的干预策略具有重要意义。这引起了关于可变人类饮食对人类的潜在影响以及多种潜在肠道干细胞群体如何在人类中起作用并引起肿瘤的重大问题。此外，长寿命干细胞的遗传和表观遗传学变化对于理解维生素D和其他营养物质对肠道稳态的影响以及改变肿瘤发生概率的干预策略具有重要意义。