Mechanisms by which bacteria affect levels of vitamin D

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-D to be converted to 1,25-D, which, of course, increases activity of the VDR.

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 response, 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.

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 Protocol, 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.² 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.^{3 4} 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.