Vitamin D (calciferol) strengthens immunity and maintains a healthy microbiota. Vitamin D is also a potential helper in the fight against cancer. Research shows that vitamin D may slow the growth of cancer cells and help kill them, as well as reduce the proliferation of blood vessels that feed tumors and suppress the activity of tumor-associated fibroblasts, specialized cells that surround tumors and promote their growth and development. However, the question of how much vitamin D may influence cancer development and whether the immune system or microbiota is involved in this process remains open.
Vitamin D: Forms and Metabolism
Vitamin D is available in D2 (ergocalciferol) and D3 (cholecalciferol). Vitamin D3 is obtained from animal sources or synthesized in the skin under ultraviolet radiation, while D2 comes from plants and fungi.
Both forms of vitamin D are converted in the liver to 25-hydroxyvitamin D (25-OHD), the primary vitamin D metabolite in the blood. In the kidneys, 25-OHD is converted into the active form, 1,25-dihydroxyvitamin D. This active form binds to vitamin D receptors in different tissues, regulating gene expression.
Vitamin D and its metabolites, 25-OHD and 1,25-(OH)2D bind to the vitamin D-binding protein, Gc-globulin, in the blood. Gc serves as a reservoir for vitamin D in the blood, sequestering it from tissues and thus regulating its availability to the body. Gc binds more strongly to 25-OHD and less strongly to 1,25-(OH)2D.
Interestingly, mice and rare patients with a genetic Gc deficiency have reduced blood vitamin D levels but not the bone anomalies typical of vitamin D deficiency. The absence of Gc in animals leads to a more rapid and robust tissue response to vitamin D.
The Role of Vitamin D in Anticancer Immunity
In the fight against cancer, dendritic cells play a crucial role by detecting tumor cells and activating immune cells to destroy cancer. One key component of this process is the DNGR-1 receptor on dendritic cells, which recognizes dying cells by the F-actin protein. The tumor-secreted protein gelsolin interferes with this process by degrading F-actin, which reduces the ability of dendritic cells to activate an anticancer response.
Gc-globulin binds to F-actin, protecting it from degradation. The binding of Gc-globulin to F-actin affects the availability of vitamin D. Increasing vitamin D levels promotes the interaction of intestinal epithelial cells with the microbiota, enhancing the anticancer response.
An experiment on mice without microbiota showed that vitamin D-dependent resistance to cancer could be restored by fecal transplantation or oral administration of Bacteroides fragilis bacteria, provided that vitamin D intake from food is maintained.
In humans, high vitamin D levels are associated with a lower prevalence of cancer and the activity of the vitamin D receptor is associated with better cancer treatment outcomes and enhanced effectiveness of immunotherapy.
Mice without Gc Are More Resistant to Cancer. Resistance Depends on the Microbiota
An experiment on mice with melanoma demonstrated that the absence of Gc enhances the immune system’s ability to fight cancer by increasing the number of active T cells. Additionally, cancer treatment with immunotherapy was more effective in mice without Gc.
The resistance to cancer was transferred to other mice from the same lineage, indicating a potential influence of the microbiota. Fecal transplantation from mice without Gc to regular mice enhanced their ability to control tumor growth. Conversely, antibiotic treatment diminished this capability.
The Resistance to Cancer in Mice without Gc Depends On Vitamin D
These mice exhibited lower levels of vitamin D3 and 25-OHD3 in the blood, indicating a redistribution of vitamin D in tissues. Mice without Gc receiving adequate vitamin D were highly resistant to tumors. Conversely, a 4-week diet deficient in vitamin D3 depleted the vitamin D stores and completely suppressed these mice’s ability to resist tumors.
The opposite experiment, where regular mice were fed a diet rich in vitamin D3, resulted in increased overall vitamin D levels in the serum and reduced tumor growth to such an extent that regular mice became comparable to mice without Gc fed a standard diet with vitamin D. Anticancer immunity was transferred to other mice through fecal transplantation if the recipient’s diet was also rich in vitamin D.
Increasing Vitamin D Levels Enhances Microbiota Development, Which Boosts Anticancer Immunity
The ability of mice without Gc to transmit tumor resistance through the microbiota depends on the presence of vitamin D in the diet. A diet high in vitamin D3 induced changes in gene activity in the colons of regular mice. These findings suggest that vitamin D acts through intestinal epithelial cells, promoting the formation of intestinal microbiota that enhances cancer immune control.
Vitamin D increased the abundance of B. fragilis bacteria and reduced the abundance of P. brevis. Three rounds of oral administration of B. fragilis were sufficient to induce increased cancer resistance. Deficiency in vitamin D3 suppressed this resistance. Conclusion: vitamin D is necessary to maintain a niche where B. fragilis can thrive.
In contrast, oral administration of P. brevis did not increase cancer resistance; in a diet deficient in vitamin D3, it even slightly decreased it.
Human Vitamin D Levels Are Linked to Cancer Resistance
Some genes involved in vitamin D metabolism may influence cancer risk. Vitamin D obtained from food or synthesized in the skin under ultraviolet radiation affects the activity of various genes.
Analysis of cancer patient data revealed that low activity of genes regulated by the vitamin D receptor is associated with poorer disease outcomes. These results are supported by analysis of a large cohort from Denmark: low vitamin D levels in the blood are associated with an increased risk of developing cancer within 10 years after measurement.
Conclusion
Adequate vitamin D levels reduce cancer risk and improve the response to immunotherapy. Vitamin D regulates intestinal microbiota balance, increasing the abundance of B. fragilis bacteria, which enhances the immune response against cancer.
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Reference
Vitamin D regulates microbiome-dependent cancer immunity
