A growing body of research reveals that vitamin D signaling is shaped by genetics and environment, while modulating transcriptional and epigenetic programs in target cells. Within this framework, vitamin D is best understood as a hormone-like signaling molecule, translating sunlight exposure and dietary intake into coordinated gene regulatory activity.
Marked interindividual variability—often observed despite similar circulating 25-hydroxyvitamin D (25-OHD) levels—suggests that serum concentrations alone may not fully capture functional vitamin D activity. A 2022 review published in Nutrients characterized vitamin D as a nutri-epigenetic modulator, linking it to DNA methylation and chromatin processes that orchestrate gene expression, particularly in immune and inflammatory pathways.
Epigenetic processes, including DNA methylation, histone modifications, and chromatin remodeling, govern transcriptional accessibility without altering the DNA sequence, allowing environmental signals to dynamically shape gene expression. These mechanisms form a critical regulatory interface through which diet, sunlight, circadian cues, and microbial signals converge to shape immune, metabolic, and neuroendocrine programs.
Within this context, vitamin D acts as a regulatory signal that directly modulates chromatin state and transcriptional potential, translating environmental inputs into coordinated gene network activity that support systemic balance.
Vitamin D is synthesized in the skin via ultraviolet B exposure or obtained from dietary sources, then converted to its active form, 1,25-dihydroxyvitamin D (calcitriol). Calcitriol binds the vitamin D receptor (VDR), which heterodimerizes with the retinoid X receptor (RXR) and interacts with vitamin D response elements (VDREs) across the genome.
A 2022 systematic review and meta-analysis reported consistent associations between vitamin D exposure, VDR activation, and locus-specific chromatin remodeling in immune and metabolic tissues. Ligand-activated VDR–RXR complexes recruit chromatin-modifying enzymes, including histone acetyltransferases and other epigenetic cofactors, producing context-dependent changes in chromatin accessibility. These interactions modulate transcriptional programs regulating immunity, inflammation, metabolism, and neuroimmune communication.
Genome-wide analyses published in Molecular and Cellular Endocrinology demonstrate that VDR binds broadly across transcriptionally active regions of the genome. Ligand activation promotes RXR heterodimerization and cofactor recruitment, producing locus-specific changes enriched at active sites, thus highlighting vitamin D’s role in coordinating gene networks rather than functioning as a simple on/off switch.
Human longitudinal data reinforce these mechanistic insights. In a 2022 quasi-interventional study of 1,036 older adults from the BASE-II and GendAge cohorts, individuals who were vitamin D-deficient at baseline and initiated supplementation exhibited significantly lower DNA methylation age acceleration (DNAmAA) compared with untreated deficient participants. Supplementation was associated with a 2.6-year reduction in 7-CpG DNAmAA and a 1.3-year reduction in Horvath DNAmAA, effectively restoring epigenetic aging trajectories to levels comparable with non-deficient controls.
Aligned with these findings, a 2024 human epigenomic study demonstrated locus-specific chromatin remodeling in immune cells following vitamin D exposure, consistent with adaptive, context-dependent transcriptional regulation.
Cutaneous vitamin D synthesis varies with pigmentation, age, latitude, season, sun exposure, and lifestyle. Dietary intake and supplementation can enhance endogenous production; however, absorption, transport, metabolic activation, and receptor responsiveness often vary substantially.
Genetic variants in VDR, CYP2R1, and GC influence enzyme activity, receptor function, and transport efficiency, affecting transcriptional output downstream of vitamin D signaling and may help explain why similar 25-OHD levels do not uniformly predict biological response. Vitamin D status is therefore best interpreted through a bioindividuality framework rather than fixed thresholds.
The gastrointestinal tract is a key site of absorption and immune–microbial interaction influencing vitamin D responsiveness. Vitamin D signaling and gut microbiota composition interact bidirectionally. Adequate vitamin D status is associated with greater abundance of commensal taxa such as Bifidobacterium and Lactobacillus, supporting immune and inflammatory regulation. VDR signaling maintains intestinal barrier integrity, modulates antimicrobial peptide expression, and promotes mucosal immune balance through transcriptional and epigenetic mechanisms.
A 2025 integrative analysis in Cureus examined genetic variation in vitamin D metabolism alongside epigenetic regulation and gut microbiota composition, proposing a phenotype-to-genotype framework in which vitamin D-related polymorphisms shape microbial ecology and immune-metabolic interactions.
Genetic and epigenetic variability shapes metabolic responses to vitamin D interventions. A 2025 precision nutrition trial found that vitamin D₃ supplementation combined with genotype-informed dietary optimization improved insulin resistance, inflammatory markers and parathyroid hormone regulation. Individuals with certain GC and CYP2R1 variants exhibited lower functional vitamin D activity despite similar serum levels, highlighting genetic constraints on absorption, activation, and transcriptional responsiveness. These findings underscore the importance of interpreting vitamin D status in a genetic and epigenetic context.
Vitamin D exerts immunomodulatory effects through coordinated, context-dependent transcriptional regulation that shapes immune tone and responsiveness. Ligand-activated VDR signaling attenuates pro-inflammatory cytokine expression, modulates antigen presentation, promotes anti-inflammatory macrophage phenotypes, and enhances antimicrobial peptide production, influencing neuroimmune communication.
Circadian rhythms—epigenetically regulated and entrained by the light–dark cycle—intersect with vitamin D synthesis, metabolism, immune signaling, and endocrine function, linking environmental light exposure to circadian patterning of immune-related gene expression and signaling. Mechanistic evidence from a 2025 study demonstrates that multiple vitamin D target genes in immune cells exhibit circadian expression and form transcription-factor–driven regulatory networks, with notable interindividual variability in responsiveness.
Complementing these findings, a 2024 epidemiologic review reported that sunlight exposure is associated with reduced all-cause mortality independent of supplementation, suggesting systemic benefits that extend beyond circulating vitamin D levels. Low vitamin D status, therefore, may reflect limited sunlight exposure or circadian disruption rather than dietary insufficiency alone.
Vitamin D functions as a hormone-like epigenetic signal, influencing gene expression and downstream metabolic and neuroimmune pathways in a context-dependent manner. Genetic and environmental factors shape how this signal translates into biological outcomes, offering a nuanced framework for understanding variability and guiding personalized, systems-informed strategies.
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