. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 2007 Mar;117(3):803-11. doi: 10.1172/JCI30142. Epub 2007 Feb 8.
[PMID: 17290304] [PMCID: 1784003] [DOI: 10.1172/JCI30142]
A chronic pathogenic microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms. affects the levels of the D metabolites observed in chronic diseases in several ways. When the immune system is challenged by pathogens, the body activates CYP27B1, causing more 25-DThe vitamin D metabolite widely (and erroneously) considered best indicator of vitamin D "deficiency." Inactivates the Vitamin D Nuclear Receptor. Produced by hydroxylation of vitamin D3 in the liver. to be converted to 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol., which, of course, increases activity of the VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response..
However, just because the concentration of 1,25-D reaches high levels - sometimes extremely high values - does not mean that the hormone is successful in binding and activating all of the body's Vitamin D Receptors (VDR). In fact, a 1,25-D that is elevated for an extended period of time suggests that the activity of the VDR is at least partially blocked.
When bacterial ligands block the VDR, the Receptor is prevented from transcribing CYP24A1, a well-studied enzyme which breaks down excess 1,25-D.
A full understanding of all these mechanisms supports the conclusion that elevated 1,25-D and depressed 25-D are a result rather than a cause of the inflammatory disease process.
Given that the VDR is fundamentally a control system for the innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease., the body upregulates the Receptor's activity by increasing concentrations of 1,25-D and downregulating concentrations of 25-D.
One such mechanism is the CYP27B1 pathway.1) When the immune system is challenged by pathogens, the body activates a protein called Protein Kinase A (PKA). PKA in turn activates CYP27B1, causing more 25-D to be converted to 1,25-D, which, of course, increases activity of the VDR.2)
1α-OHase [CYP27B1] expression is upregulated in macrophages in response to bacterial infection and that 1α-OHase at the site of infection provides 1,25(OH)(2)D(3) for local regulation of vitamin D responsive genes.
C.D. Nelson 3)
Without pathogens' role in interfering with VDR activity, the innate immune response might actually succeed in transcribing the genes which fully destroy pathogenic bacteria. Under such circumstances, it's conceivable that humans may not have a chronic microbiota which drives chronic inflammatory disease.
However, just because the concentration of 1,25-D reaches high levels - sometimes extremely high values - does not mean that the hormone is successful in binding and activating all of the body's Vitamin D Receptors. In fact, a 1,25-D that is elevated for an extended period of time suggests that the activity of the VDR is at least partially blocked. After all, if the VDR were fully active and able to kill bacterial pathogens “at will,” the body would have downregulated levels of 1,25-D, at least until the next set of pathogens appeared.
It is during periods of chronic disease when the body competes with bacteria to produce substances which bind the VDR. This “arms race” between the immune system to create more 1,25-D and pathogenic bacteria to secrete more ligands is one that plays out, cell by cell, over the course of decades. But, it is one that without the intervention of the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis., the bacteria will ultimately win.
One of the reasons that neither the innate immune response nor the bacteria can fully overwhelm the other is because the VDR is relatively insensitive to changes in concentration in ligands. At some points in the binding curve, an increase by a factor of five of a ligand only increases the number of ligands bound to the receptor by 10%. (For a visual representation of olmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. competing against, 1,25-D, see Pharmacodynamics of olmesartan. In other words, it takes a substantial increase in concentration to change the activity of the receptor.
When active, the VDR transcribes CYP24A1 (sometimes referred to as CYP24), which regulates levels of 25-D and 1,25-D. CYP24A1 breaks down excess 1,25-D, ensuring that the level of 1,25-D in the body stays in the normal range.4) It is a sensible mechanism for controlling levels of the D metabolites.
[The production of CYP24A1] is the best documented of the feedback control systems used by the body to limit the concentration of 1,25-D to just that amount needed for proper transcription and activation of the VDR.
Trevor Marshall, PhD
However, an inactive VDR does not transcribe CYP24A1, and therefore levels of 1,25-D increase and values of 25-D decrease. This may be one of several ways that an inactive VDR influences levels of D metabolites.
When 1,25-D rises due to the processes described above, it also binds a receptor called the PXR. The PXR subsequently inhibits conversion of pre-vitamin D to 25-D, causing 25-D levels to drop via the CYP27A1 pathway.5) 6) PXR has also been reported to competitively downregulate the VDR-induced expression of CYP24A1, which as we saw above, breaks down excess 1,25-D.
This mechanism works well when 1,25-D is within normal ranges. But when 1,25-D becomes extremely high, as in the case of chronic diseases, 25-D is downregulated to abnormally low levels, leading some observers to erroneously conclude that vitamin D deficiency causes disease.
We evaluated whether the ability of M. leprae to induce type I IFN blocks the intrinsic activation of the vitamin D pathway, representing an escape mechanism by which the bacterium evades the host response. 7)
Vitamin D plays a crucial role in the regulation of genes central to protection against microbe invasion, such as the induction of the expression of antimicrobial peptidesBody’s naturally produced broad-spectrum antibacterials which target pathogens. (also known as host defense peptides) such as CAMP and defensin. These peptides were demonstrated to disrupt the integrity of the microbe membrane, resulting in its death (Gombart, 2009). In addition, Vitamin D regulates the immune system by managing the expression of TNFα (Golovko et al., 2005), one of the most important pro-inflammatory and pro-immune cytokinesAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system.. Therefore, downregulation of the vitamin D signaling pathway by viruses, can result in decreased production of antimicrobial peptides and cytokines and as a result, to attenuation of the immune response. Several studies have previously indicated that certain viruses can inhibit the Vitamin D signal transduction.
Our in-vitro study showed that Vitamin D does not affect the rate of HBV replication, and downregulates VDR levels in the presence of the virus, thereby attenuating vitamin D signal transduction. 8)