Both human epidemiologic data and animal studies suggest that low serum vitamin D levels are associated with an increased risk for developing Inflammatory Bowel Disease (IBD). Vitamin D deficiency is increasingly prevalent worldwide, and may promote IBD in genetically susceptible individuals through changes in immune responses, gut epithelial barrier function, and/or the composition of the gut microbiome. While it is clear that diet plays a role in shaping the microbiome, the influence of individual micronutrients, such as vitamin D, remains largely unexplored. In this application I will further elucidate the mechanisms through which vitamin D modulates the intestinal environment to suppress inflammation by using a mouse model that develops IBD and colon cancer. Smad3-/- mice have dysregulated transforming growth factor ? signaling, a pathway frequently affected in human IBD and colon cancer patients, and develop colitis when infected with a gut bacteria, H. bilis. Previous work in our laboratory has demonstrated that supplementing dietary vitamin D significantly reduces colitis and subsequent inflammation-associated colon cancer in Smad3-/- mice. We hypothesize that elevated dietary vitamin D suppresses bacterial-induced colonic inflammation through its effects on adaptive immune cells (likely T lymphocytes) and/or intestinal epithelial cells during the initial stages of disease development. We will explore this hypothesis using mice lacking vitamin D receptor signaling in specific cell populations. In addition to changes in immune and epithelial cell populations, our preliminary data suggest that increased dietary vitamin D alters the gut microbiota, which likely impacts the development of IBD in our model. We will therefore characterize the changes in colonic microbiota induced by supplemental vitamin D and will evaluate potential mechanisms inducing these changes. Together these studies will provide substantial insights into the mechanisms through which vitamin D ameliorates IBD. In addition to having direct translational impacts on human health, these studies will allow me obtain cutting edge training in mucosal immunology and microbiome analysis, as well as advanced multidisciplinary bioinformatics and statistics training. I will obtan state-of-the-art knowledge in these fields of study through a mentoring team of experts in these fields and through a training program that includes didactic instruction and hands-on experiments. My career goal is to become an independent research scientist with experience in studying gastrointestinal diseases. I propose to study the interactions between diet, gut microbiota, and intestinal disease, which is an important developing area of medical research. Moreover, the training I will obtain through these studies will lay a foundation for long-term success as a research scientist. My training in veterinary lab animal research, combined with the expertise I will gain from this research project will provide me with a sound and flexible basi to continue my research career in biomedical research and will directly facilitate my transition to research independence.

Public Health Relevance

Observational studies in people and studies in animals suggest that vitamin D supplementation can ameliorate symptoms of inflammatory bowel disease, however, the mechanisms mediating these effects remain unclear. The proposed studies in this grant application: 1) will determine the role of vitamin D mediated signaling in intestinal cells known to be important in inflammatory bowel disease and colon cancer (e.g. intestinal epithelial cells, lymphocytes, macrophages, dendritic cells, NK cells, etc.) and 2) will evaluate mechanisms by which vitamin D may modulate the gut microbiome, a recently recognized component of the intestines that appears to play a central role in health and disease in the colon.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01OD021420-04
Application #
9606098
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fuchs, Bruce
Project Start
2016-01-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Hsu, Charlie C; Meeker, Stacey M; Escobar, Sabine et al. (2018) Murine norovirus inhibits B cell development in the bone marrow of STAT1-deficient mice. Virology 515:123-133
Seamons, Audrey; Treuting, Piper M; Meeker, Stacey et al. (2018) Obstructive Lymphangitis Precedes Colitis in Murine Norovirus-Infected Stat1-Deficient Mice. Am J Pathol 188:1536-1554