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Vitamin D Receptor, the gut, the immune system, and the Middle East – May 2019

Vitamin D Deficiency in the Gulf Cooperation Council: Exploring the Triad of Genetic Predisposition, the Gut Microbiome and the Immune System

Front. Immunol., 10 May 2019 | https://doi.org/10.3389/fimmu.2019.01042
Parul Singh, Manoj Kumar and Souhaila Al Khodor*
Research Department, Sidra Medicine, Doha, Qatar

  • The risk of 40 diseases at least double with poor Vitamin D Receptor as of July 2019
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85% have <20 ng of Vitamin D

Caption:    The proposed role of Vitamin D mediated signaling in epithelial cell barrier function, Gut microbial hemostasis and modulation of Innate and adaptive immune responses. VDR regulates the level of tight junction proteins ZO1, ZO2 via claudin2 and 12 (39, 118) and helps maintain the structural integrity of epithelial barrier. Vitamin D deficiency have also been shown to disrupt gut homeostasis leading to systemic inflammation (119). Effects of Vitamin D on different players of the innate and adaptive immune system. In response to an antigenic challenge, macrophages, dendritic cells, and lymphocytes express the Vitamin D receptor (VDR), thereby becoming targets for the active Vitamin D metabolite, 1,25(OH)2D (120). Macrophages and dendritic cells also express the CYP27B1 that synthesizes 1,25(OH)2D leading to intra and paracrine responses such as stimulates enhancing the phagocytotic responses of macrophages and production of antimicrobial proteins such as cathelicidin (49, 121,122). Active Vitamin D also modulates adaptive immunity. At the level of the APCs (like DCs), 1,25(OH)2D inhibits the surface expression of MHC-II-complexed antigen. In addition, 1,25(OH)2D directly affects T cell responses, by inhibiting the production of Th1 cytokines (IL-2 and IFN-y), Th17 cytokines (IL-17 and IL-21), and by stimulating Th2 cytokine production (IL-4) and Treg cell development (123-129). Finally, 1,25(OH)2D blocks plasma-cell differentiation, IgG and IgM production and B-cell proliferation (130). The above factors can trigger inflammatory immune responses such as TNF-a and IFN-y leading to intestinal permeability and susceptibility to pathogenic infections, microbial dysbiosis and manifestation of immune related inflammatory diseases (19).
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Vitamin D is a fat soluble secosteroid that is primarily synthesized in the skin upon exposure to Ultraviolet B (UVB) sun rays. Vitamin D is essential for the growth and development of bones and helps in reducing inflammation by strengthening muscles and the immune system. Despite the endless supply of sunlight in the Gulf Cooperation Council (GCC) countries which includes United Arab Emirates, Qatar, Kuwait, Bahrain, Saudi Arabia, and Oman, Vitamin D deficiency in the (GCC) general population at various age groups remains alarmingly high. In parallel runs the increasing prevalence of acute and chronic illnesses including, autoimmune diseases, cancer, type 1 diabetes mellitus, cardiovascular disease and Inflammatory bowel disease in the adult as well as the pediatric population of these countries. The exact association between Vitamin D deficiency and chronic disease conditions remains unclear; however, studies have focused on the mechanism of Vitamin D regulation by assessing the role of the Vitamin D associated genes/proteins such as VDR (Vitamin D receptor), VDBP (Vitamin D Binding protein), CYP27B1 as these are integral parts of the Vitamin D signaling pathway. VDR is known to regulate the expression of more than 200 genes across a wide array of tissues in the human body and may play a role in controlling the Vitamin D levels. Moreover, reduced Vitamin D level and downregulation of VDR have been linked to gut dysbiosis, highlighting an intriguing role for the gut microbiome in the Vitamin D metabolism. However, this role is not fully described yet. In this review, we aim to expand our understanding of the causes of Vitamin D deficiency in the GCC countries and explore the potential relationship between the genetic predisposition, Vitamin D levels, immune system and the gut microbiome composition. Trying to unravel this complex interaction may aid in understanding the mechanism by which Vitamin D contributes to various disease conditions and will pave the way toward new therapeutics treatments for Vitamin D deficiency and its associated outcomes.

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