Vitamin D and the nutritional environment in functions of intestinal stem cells: Implications for tumorigenesis and prevention

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 Lgr5^hi intestinal stem cell contribution to homeostasis and tumorigenesis, associated with extensive Lgr5^hi 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 Lgr5^hi 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 Lgr5^hi cells, NWD1 also reprograms cells derived from the Bmi1+ population, defined as those cells marked in Bmi1^creERT2, Rosa26^tom 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.