NWD1是纯净饮食，使小鼠暴露于关键营养素，重现了增加人类肠癌风险的水平，可重复导致小鼠散发性肠道和结肠肿瘤，反映出人类病因、发病率、频率和发展年龄。通过批量和单细胞RNA测序、单细胞ATAC测序、功能基因组学和成像技术，对NWD1复杂的干细胞和谱系重编程进行了解析。NWD1广泛地、迅速地、可逆地重编程Lgr5hi干细胞，通过表观遗传学下调Ppargc1a表达、改变线粒体结构和功能，抑制Lgr5hi干细胞功能和Lgr5hi细胞后代的发育成熟，当细胞通过祖细胞区域时，通过体内Lgr5hi细胞的Ppargc1a基因失活来重现。激活的Bmi1+、Ascl2hi细胞，适应营养环境，提高特别是在成熟肠上皮细胞中的抗原处理和呈递通路，导致慢性、促进肿瘤的低水平炎症。NWD1重塑干细胞和谱系的多个相似之处表明，这与人类炎症性肠病的病因机制有着多重共通之处，也是促进肿瘤的。此外，干细胞转向另一种干细胞的趋势表明，Lgr5阳性和阴性干细胞在支持人类结肠肿瘤方面的平衡是由环境影响决定的。对营养素的干细胞和谱系的可塑性支持了关于稳态是对环境不断适应的历史概念，人类黏膜可能在不断被营养物质的改变所影响。启示：虽然致癌突变在克隆扩展中为肠道上皮细胞提供了竞争优势，但竞争发生在营养环境动态塑造的平台上，影响着哪些细胞在黏膜维护和肿瘤发生过程中占据主导地位。

NWD1, a purified diet establishing mouse exposure to key nutrients recapitulating levels that increase human risk for intestinal cancer, reproducibly causes mouse sporadic intestinal and colonic tumors reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 stem cell and lineage reprogramming was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly, reprogrammed Lgr5hi stem cells, epigenetically down-regulating Ppargc1a expression, altering mitochondrial structure and function. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments, recapitulated by Ppargc1a genetic inactivation in Lgr5hi cells in vivo. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lgr5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. Implications: Although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.