Vitamin D discovery outpaces FDA decision making

Abstract

The US FDA currently encourages the addition of vitamin D to milk and cereals, with the aim of reducing rickets in children and osteoporosis in adults. However, vitamin D not only regulates the expression of genes associated with calcium homeostasis, but also genes associated with cancers, autoimmune disease, and infection. It does this by controlling the activation of the vitamin D receptor (VDR), a type 1 nuclear receptor and DNA transcription factor. Molecular biology is rapidly coming to an understanding of the multiplicity of roles played by the VDR, but clinical medicine is having difficulty keeping up with the pace of change. For example, the FDA recently proposed a rule change that will encourage high levels of vitamin D to be added to even more foods, so that the manufacturers can claim those foods "reduce the risk of osteoporosis". The FDA docket does not review one single paper detailing the transcriptional activity of vitamin D, even though, on average, one new paper a day is being published on that topic. Nor do they review whether widespread supplementation with vitamin D, an immunomodulatory secosteroid, might predispose the population to immune dysfunction. This BioEssay explores how lifelong supplementation of the food chain with vitamin D might well be contributing to the current epidemics of obesity and chronic disease.

The paradoxical effects of vitamin D on type 1 mediated immunity

“…One group (TG Marshall, Autoimmunity Research Foundation, Thousand Oaks, CA) has recommended and continues to recommend lowering vitamin D status to treat a number of chronic inflammatory conditions (Marshall 2008). The basis for this recommendation are the reports of production of 1,25(OH) 2 D 3 by the immune system during disease pathology and the possibility that this induction of 1,25(OH) 2 D 3 may be contributing to diseases from obesity to other chronic diseases including those mediated by Th1 cells like sarcoidosis and Crohn's disease (Marshall et al 2004;Marshall 2008).…”

“…The basis for this recommendation are the reports of production of 1,25(OH) 2 D 3 by the immune system during disease pathology and the possibility that this induction of 1,25(OH) 2 D 3 may be contributing to diseases from obesity to other chronic diseases including those mediated by Th1 cells like sarcoidosis and Crohn's disease (Marshall et al 2004;Marshall 2008). The argument is that the hormone activity of 1,25(OH) 2 D 3 induces transcription of a large number of genes that somehow cause these diseases and that 1,25(OH) 2 D 3 should be measured because it is the biologically active form of vitamin D that binds the receptor (Marshall 2008). Current assays for 25(OH)D3 that are used to assess vitamin D levels in the general population are inaccurate and lack standards (Glendenning et al 2006).…”

Immunostimulation in the era of the metagenome

“…38 This work suggested that microbes may be able to directly alter VDR ligand binding pocket occupancy, and subsequently VDR expression, in order to gain a survival advantage.…”

“…However, this drug has a unique affinity for the VDR nuclear receptor, for which it is most probably a partial agonist. 38,77 In order to be effective in this targeting, the dosing has to be more frequent as the VDR's half-life is only 4-6 h before it is broken apart by caspase-3, and protease activity. 78 Thus, when dosed at 4-to 8-h intervals, VDR stimulation persists between doses.…”

“…As expression of CYP24A1 diminishes, 1,25-D levels rise. When the hormone/secosteroid rises above a normal range, it may downregulate, via the nuclear receptor pregnane X receptor, the amount of pre-vitamin D converted into 25-D. 38 The result is that 25-D levels drop.…”