Dynamic intestinal stem cell and mucosal remodeling by a mouse diet uniquely relevant to human risk and tumorigenesis

Background and Aims NWD1 is a purified rodent diet unique in establishing mouse exposure to key nutrients recapitulating levels in the human that increase risk for intestinal cancer and supporting its unique relevance, NWD1 is the only rodent diet that causes sporadic intestinal and colon tumors in the mouse. The aim was to understand mechanisms of the dietary remodeling of stem cells and the mucosa in establishing the higher risk phenotype; Methods Deconvolution of complex reprogramming and remodeling was by bulk and scRNAseq, scATACseq, functional genomics and imaging. Results NWD1 extensively, rapidly, and reversibly reprogrammed Lgr5hi stem cells, with epigenetic down-regulated Ppargc1a expression altering mitochondrial structure and function, suppressing Oxphos and the TCA cycle. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated pathways of antigen processing and presentation, especially in mature enterocytes, leading to chronic low-level inflammation. Conclusions Aspects of the reprogramming and remodeling of stem cells and mucosa parallel pathogenic mechanisms in human inflammatory bowel disease, also pro- tumorigenic, and the adaptive mucosal response determining which stem cells function is similar to recent data that human colon tumors are comprised of both Lgr5 positive and negative stem cells with the balance determined by the environment. Stem cell and mucosal plasticity in response to nutrient intake supports historic concepts of homeostasis as a continual process of tissue adaptation to its environment, with the human mucosa therefore likely in constant flux. Moreover, although oncogenic mutations provide a competitive advantage to intestinal stem cells in tumorigenesis, the competition takes place on a playing field sculpted by the nutritional environment, with a major influence on which cells dominate in mucosal maintenance and tumorigenesis.