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-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.

VDR activity increased as the body upregulates 1,25-D

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)

Elevated 1,25-D for extended periods implies a partially blocked 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 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.

Effects of VDR blockage on CYP24A1, an enzyme regulating conversion of 25-D into 1,25-D

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.

Effects of VDR blockage on the PXR, a receptor which converts pre-vitamin D into 25-D

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.

Notes and comments

  • Legacy content

Not sure if this is relevant here. — Paul Albert 09.05.2010

Kidney International (2010) 78, 463–472; doi:10.1038/ki.2010.168; published online 9 June 2010

Dysregulation of renal vitamin D metabolism in the uremic rat

The progressive decline in kidney function and concomitant loss of renal 1α-hydroxylase (CYP27B1) in chronic kidney disease (CKD) are associated with a gradual loss of circulating 25-hydroxyvitamin D3 (25(OH)D3) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). However, only the decrease in 1α,25(OH)2D3 can be explained by the decline of CYP27B1, suggesting that insufficiency of both metabolites may reflect their accelerated degradation by the key catabolic enzyme 24-hydroxylase (CYP24). To determine whether CYP24 is involved in causing vitamin D insufficiency and/or resistance to vitamin D therapy in CKD, we determined the regulation of CYP24 and CYP27B1 in normal rats and rats treated with adenine to induce CKD. As expected, CYP24 decreased whereas CYP27B1 increased when normal animals were rendered vitamin D deficient. Unexpectedly, renal CYP24 mRNA and protein expression were markedly elevated, irrespective of the vitamin D status of the rats. A significant decrease in serum 1α,25(OH)2D3 levels was found in uremic rats; however, we did not find a coincident decline in CYP27B1. Analysis in human kidney biopsies confirmed the association of elevated CYP24 with kidney disease. Thus, our findings suggest that dysregulation of CYP24 may be a significant mechanism contributing to vitamin D insufficiency and resistance to vitamin D therapy in CKD.


Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism.
Schauber J, Dorschner RA, Coda AB, Büchau AS, Liu PT, Kiken D, Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, Zügel U, Bikle DD, Modlin RL, Gallo RL
J Clin Invest117p803-11(2007 Mar)
Vitamin D discovery outpaces FDA decision making.
Marshall TG
Bioessays30p173-82(2008 Feb)
Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia.
Xu Y, Hashizume T, Shuhart MC, Davis CL, Nelson WL, Sakaki T, Kalhorn TF, Watkins PB, Schuetz EG, Thummel KE
Mol Pharmacol69p56-65(2006 Jan)
Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia.
Zhou C, Assem M, Tay JC, Watkins PB, Blumberg B, Schuetz EG, Thummel KE
J Clin Invest116p1703-12(2006 Jun)
home/pathogenesis/vitamind/mechanisms.txt · Last modified: 01.03.2012 (external edit)
© 2015, Autoimmunity Research Foundation. All Rights Reserved.