Dietary Induced Dynamic Plasticity of Intestinal Stem Cells and the Mucosa in Elevating Risk for Tumor Development

NWD1, a mouse purified western diet uniquely relevant to human nutritional exposures elevating risk for human sporadic colon cancer rapidly and reversibly altered the stem cell signature and transcriptome of Lgr5hi intestinal stem cells. Down-regulated Ppargc1a expression altered mitochondrial structure and function, metabolically reprogramming Lgr5hi cells, suppressing developmental maturation of their progeny as they progress through progenitor cell compartments. This recruited Bmi1+, Ascl2 cells, remodeling the mucosa, including cell adaptation to the altered nutritional environment and elevated pathways of antigen processing and presentation, especially in mature enterocytes, a pathogenic mechanism in human Inflammatory Bowel Disease resulting in chronic low-level pro-tumorigenic inflammation. Plasticity of intestinal cells to function as stem-like cells encompasses a physiological and continual response to changing nutritional environments, supporting historic concepts of tissue homeostasis as a process of continual adaptation to the environment, with important consequences for mechanisms establishing probability for tumor development. The data emphasize importance of better reflecting human nutritional exposures in mouse models of development and disease. ### Competing Interest Statement The authors have declared no competing interest.