(revised) The vitamin D hypothesis proposes that vitamin D regulates gastrointestinal homeostasis by multiple mechanisms and that changes in vitamin D status affect the composition of the microbiota, the development of the immune response, clearance of gastrointestinal infections and the ability to reinstate homeostasis following injury or infection. During the last grant cycle we determined several novel mechanisms by which vitamin D regulated T cells to control homeostasis in the gut. Our new preliminary data demonstrate that disruptions in the microbiota would inhibit vitamin D regulation of immune function and the metabolism of vitamin D by the host. These novel areas of investigation serve as the focus of the present application. The gastrointestinal immune system is a population of heterogeneous cells whose role is to maintain ignorance of the large number of antigens present in food as well as the microbiota. The microbiota in turn shapes the immune response. Germfree mice have reduced B cell IgG1, IgG2a and IgA responses, but hyper-IgE antibodies. Hyper-IgE is a symptom of dysbiosis and a failure of homeostasis. Vitamin D deficient and vitamin D receptor knockout mice have hyper-IgE and dysbiosis of the microbiota. In addition, following injury vitamin D regulates the T and B cell response in part through regulation of the microbiota. Perturbations of homeostasis, following gastrointestinal infection, of vitamin D deficient mice was severe and associated with the reduced production of antigen specific antibody responses. Not only was there an effect of vitamin D on the microbiota but the microbiota affected vitamin D metabolism. This proposal will focus on the effects of vitamin D on B cells and the microbial interactions that control the B cell response and microbial regulated tissue vitamin D metabolism. Our novel central hypothesis is that ?Vitamin D and the microbiota cooperate to regulate B cells and the vitamin D responsiveness of the host.? The three aims are:
Aim 1 : Determine the direct and indirect targets of vitamin D on B cells in vivo that are important for maintaining homeostasis, induction of antibody responses, and protection from GI infection.
Aim 2 : Determine which of the effects of vitamin D depend on the microbiota.
Aim 3 : Determine the role of the microbiota in the induction of 24,25(OH)2D by B cells.

Public Health Relevance

These studies will be critical to understand the mechanisms by which vitamin D regulates mucosal immunity and the microbiome to maintain gastrointestinal homeostasis. Understanding the mechanisms underlying the effects of vitamin D is needed to provide the evidence to council the public on nutritional interventions and to move vitamin D supplementation into mainstream medicine.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
2R01AT005378-06A1
Application #
9174557
Study Section
Special Emphasis Panel (ZRG1-EMNR-F (02)M)
Program Officer
Pontzer, Carol H
Project Start
2009-08-01
Project End
2021-05-31
Budget Start
2016-09-06
Budget End
2017-05-31
Support Year
6
Fiscal Year
2016
Total Cost
$300,000
Indirect Cost
$109,160
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Bora, Stephanie A; Kennett, Mary J; Smith, Philip B et al. (2018) Regulation of vitamin D metabolism following disruption of the microbiota using broad spectrum antibiotics. J Nutr Biochem 56:65-73
Tian, Yuan; Nichols, Robert G; Cai, Jingwei et al. (2018) Vitamin A deficiency in mice alters host and gut microbial metabolism leading to altered energy homeostasis. J Nutr Biochem 54:28-34
Bora, Stephanie A; Kennett, Mary J; Smith, Philip B et al. (2018) The Gut Microbiota Regulates Endocrine Vitamin D Metabolism through Fibroblast Growth Factor 23. Front Immunol 9:408
James, Jamaal; Weaver, Veronika; Cantorna, Margherita T (2017) Control of Circulating IgE by the Vitamin D Receptor In Vivo Involves B Cell Intrinsic and Extrinsic Mechanisms. J Immunol 198:1164-1171
Bora, Stephanie; Cantorna, Margherita T (2017) The role of UVR and vitamin D on T cells and inflammatory bowel disease. Photochem Photobiol Sci 16:347-353
Chen, J; Waddell, A; Lin, Y-D et al. (2015) Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells. Mucosal Immunol 8:618-26
Cantorna, Margherita T; Snyder, Lindsay; Lin, Yang-Ding et al. (2015) Vitamin D and 1,25(OH)2D regulation of T cells. Nutrients 7:3011-21
Waddell, Amanda; Zhao, Jun; Cantorna, Margherita T (2015) NKT cells can help mediate the protective effects of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis in mice. Int Immunol 27:237-44
McDaniel, Kaitlin L; Restori, Katherine H; Dodds, Jeffery W et al. (2015) Vitamin A-Deficient Hosts Become Nonsymptomatic Reservoirs of Escherichia coli-Like Enteric Infections. Infect Immun 83:2984-91
Chen, Jing; Bruce, Danny; Cantorna, Margherita T (2014) Vitamin D receptor expression controls proliferation of naïve CD8+ T cells and development of CD8 mediated gastrointestinal inflammation. BMC Immunol 15:6

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