The Vitamin D–antimicrobial Peptide Pathway and Its Role in Protection against Infection

Adrian F Gombart


Future Microbiol. 2009;4(9):1151-1165. 

In This Article


Deficiency in vitamin D is associated with numerous health conditions ranging from bone health to cancer, but with the discovery of antimicrobial peptide gene regulation by the vitamin D pathway a renewed interest in its impact on the immune system has ensued. It is particularly attractive to realize that adequate serum levels (>30 ng/ml) throughout life may alleviate many of the chronic ills that befall us as we age.

During the past 30 years or so, research has demonstrated the importance of vitamin D for optimal immune function, but many pieces of the puzzle are yet to be discovered and put in place. Both cathelicidin and defensin have activities beyond killing of microbes and can act as signaling molecules to activate the immune system.[125,126] Numerous studies have established that α-defensins and cathelicidin act as chemoattractants for a variety of leukocytes, including DCs, T cells, monocytes and neutrophils.[126] In addition, these antimicrobial peptides induce the expression of numerous cytokines and chemokines.[126] This may provide another mechanism for vitamin D to exert additional effects on the adaptive immune system.

The overlap in the ligands and target genes of the VDR, FXR, PXR and CAR may reflect an important evolutionary redundancy that is critical for the detoxification and immunity of the gut. It also offers an abundance of new compounds that can be modified to produce potent ligands for the VDR. The therapeutic use of active vitamin D has been hampered by the toxic side effects of hypercalcemia. The development of synthetic analogs seeks to reduce the side effects while boosting the benefits. LCA can perform the in vivo functions of vitamin D by elevating serum calcium in rats[127] and there is an interest in developing LCA derivatives that act as selective VDR ligands without inducing hypercalcemia.[128]

The therapeutic use of vitamin D to boost immunity is an exciting possibility. While it is still not clear that we can increase the levels of cathelicidin in the blood with vitamin D or its synthetic analogs, we believe that higher levels of cathelicidin in the blood will be beneficial. We are particularly interested in testing this with the 'humanized' mouse model that we have developed.