Nutrigenomics of Intestinal Vitamin D Action

Project Description Vitamin D is an essential nutrient whose active hormonal form, 1,25-dihydroxyvitamin D (1,25(OH)2D), regulates vitamin D receptor (VDR)-mediated gene expression to stimulate intestinal calcium absorption, to maintain intestinal barrier function, to suppress colonic inflammation and to suppress carcinogenesis. However, intestinal resistance to vitamin D develops with advancing age. This reduces intestinal Ca absorption in rodents and in humans but it is not clear how age-associated intestinal vitamin D resistance affects other aspects of intestinal vitamin D action. Thus, there is a critical knowledge gap regarding the mechanisms for how intestinal 1,25(OH)2D action changes across the lifespan. Our long-term goal is to determine how vitamin D regulates intestinal biology across the lifespan to modulate classical (Ca absorption) and non-classical (cancer, inflammation) vitamin D endpoints. Our studies from the past grant period were the first to show the complexity of 1,25(OH)2D- regulated gene regulation across the functional compartments of the intestine (i.e. small intestine (SI) crypt, SI villus, colon). Our new preliminary data demonstrate that advanced age can suppress the intestinal induction of some, but not all, vitamin D target genes. Thus, we hypothesize that age-related intestinal resistance to 1,25(OH)2D is due to context-dependent interference of VDR transcriptional mechanisms. To address this hypothesis, we have designed three aims: Aim 1: Determine how 1,25(OH)2D genomic action is modified across the lifespan to result in age-associated intestinal vitamin D resistance. Based on our pilot data, we hypothesize that the impact of aging on vitamin D-dependent gene expression is not uniform across genes or by intestinal compartment (i.e. SI/colon, crypt/villi). We will use state-of-the-art genomic approaches to study age- and compartment-specific changes in intestinal vitamin D action. Aim 2: Determine how VDR genomic action depends upon other transcription factors and co-regulators across the lifespan. We will conduct studies to reveal the critical, VDR-interacting proteins that define compartment- and age-sensitive regulation of intestinal gene expression and functionally test their roles in organoid models. Aim 3: Test whether targeting 1,25(OH)2D to the proximal colon can enhance Ca absorption and reduce age-related bone loss. We will determine whether colon-targeted forms of 1,25(OH)2D can enhance Ca absorption in mice to prevent trabecular bone loss in adults and increased cortical porosity in old mice. Our proposed studies provide the unique opportunity to determine (a) the scope of genes and regulatory regions impacted by aging in the intestine, (b) the role of intestine-specific transcription factors and co-activators in age-associated intestinal vitamin D resistance, and (c) whether colon-targeted forms of 1,25(OH)2D can have health benefits by overcoming age-associated vitamin D resistance and Ca malabsorption. When complete, this research will serve as a scientific foundation for developing strategies to improve intestinal vitamin D action, especially in older populations at high risk for developing diseases like osteoporosis as well as colon cancer, and inflammatory bowel syndromes.