The journal Frontiers in Immunology recently published a review of vitamin D₃ as an immunomodulatory agent, including discussions of its mechanisms of action, clinical evidence, and precision medicine strategies. Many studies have evaluated the associations between serum 25-hydroxyvitamin D (25(OH)D) and disease risk, as well as the effects of vitamin D supplementation in clinical trials, with mixed outcomes. This review promotes a personalized strategy, one that includes not only an assessment of baseline 25(OH)D but also of disease-specific factors and genetic polymorphisms, with this precision medicine-based approach offering the potential for improved outcomes across a variety of conditions, ranging from infectious and autoimmune diseases to metabolic diseases. Understanding the basics of vitamin D’s immunomodulatory effects helps to frame this approach, as vitamin D has a key role in both innate and adaptive immune function. (Note that this recent review only refers to vitamin D₃, not D₂).

Vitamin D3 & Immune Physiology

Well known for its role in maintaining calcium-phosphorus homeostasis and skeletal health, vitamin D is less well appreciated for orchestrating immune responses, enhancing antimicrobial defenses, and helping to impede excessive inflammatory reactions. Activated immune cells can generate active vitamin D (1,25(OH)₂D₃) locally in an autocrine manner, even at low systemic levels, highlighting the importance of vitamin D activity for optimal immune function. This is distinct from renal activation of 25(OH)D and is less subject to negative feedback regulation than renal activation. For example, renal synthesis is negatively regulated by elevated calcium levels and fibroblast growth factor 23 (FGF23), which inhibits CYP27B1 activity, the enzyme that catalyzes the final step in vitamin D activation. In contrast, immune cells lack alpha-klotho, a co-receptor for FGF23, and can synthesize large amounts of local 1,25(OH)₂D₃ without inhibition by FGF23, an indication of activated vitamin D’s importance in immune cells.

Most of vitamin D’s actions are mediated via the vitamin D receptor (VDR), which, after binding with vitamin D, forms heterodimers with the retinoid X receptor (RXR). These VDR/RXR complexes move into the nucleus and bind directly to DNA (at vitamin D response elements (VDREs), comprised of hexameric PuG/TTCA motifs known as DR3 elements), initiating gene transcription in what is known as the classical pathway. Among the immune-related genes upregulated by VDR/RXR signaling are the Cathelicidin Antimicrobial Peptide (CAMP) gene, which increases production of antimicrobial peptides, primarily cathelicidin LL-37, in natural killer cells, monocytes, neutrophils, and even epithelial cells of the respiratory tract. Vitamin D can also induce transcription of the intracellular pathogen-sensing protein NOD2/CARD15/IBD1, which detects bacterial breakdown products. In addition to upregulating antimicrobial defenses, vitamin D reins in the inflammatory response. For example, 1,25(OH)₂D₃ influences the function and phenotype of macrophages and monocytes by suppressing pro-inflammatory cytokine production (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6), and upregulating MAPK phosphatase-1 (MKP-1), which in turn also limits inflammatory cytokine production (via inhibition of LPS-induced p38 activation). Vitamin D promotes a shift toward the anti-inflammatory M2-like macrophage phenotype and enhances phagocytosis and autophagy, marking a shift toward immune tolerance and inhibition of the normal inflammatory response.

VDR/RXR signaling can also repress gene transcription via gene interactions or act independently of VDREs. Key examples of a VDRE's independent effect are protein-protein interactions with regulatory inflammatory transcription factors, including NF-κB and NFAT (nuclear factor of activated T cells). In the case of NF-κB, VDR physically interacts with IκB kinase β (IKKβ) to block NF-κB activation (an alternate mechanism than gene transcription modulation). Vitamin D’s effects on the inflammatory process are also mediated via inhibition of the NLRP3 inflammasome, a multiprotein complex that produces multiple pro-inflammatory mediators (e.g., IL-1β and IL-18), and is known to be dysregulated in multiple autoimmune diseases. VDR activation also activates nuclear factor erythroid 2-related factor 2 (Nrf2), thereby upregulating the production of multiple antioxidant enzymes (e.g., superoxide dismutase, catalase, heme oxygenase-1, and glutathione S-transferase).

Vitamin D has many adaptive immune effects as well. In addition to macrophages, vitamin D has immunomodulating effects on other white blood cell types, including B cells, dendritic cells, CD4+ and CD8+ T cells. Vitamin D’s influence on adaptive immune function generally promotes anti-inflammatory and tolerogenic responses, such as the promotion of regulatory T cell (Treg) formation. Vitamin D also has indirect adaptive effects, including the modulation of gut microbial composition and metabolite production, which may play a role in sensing and preventing bacterial overgrowth, and enhancing intestinal barrier function.

Supplementation with D3

This recent review encourages supplementation with D₃ to achieve serum 25(OH)D levels between 40-60 ng/mL, noting that each 1000 IU daily raises serum 25(OH)D by approximately 7–10 ng/mL, and that most adults may need between 1500 and 2000 IU per day. There are some exceptions they cite; for one, individuals with obesity may need 2-3 times higher dosages to achieve the same 25(OH)D levels, and 1.5 times higher for those with overweight. They suggest keeping 25(OH)D below 40–45 ng/mL among adults 75+, as well as lower doses among people with chronic kidney disease, granulomatous disease, or hyperparathyroidism, with routine checks of 25(OH)D and serum calcium.

Genotype’s Influence

One of the key takeaways from the recent review in Frontiers in Immunology is that single nucleotide polymorphisms (SNPs) in multiple genes significantly influence vitamin D status. They cite a Nature Communications genome-wide association study (GWAS), published in 2020, that reported 143 different genetic loci that influence 25(OH)D concentration, including multiple in the GC locus (the vitamin D-binding protein gene), as well as CYP2R1 (the gene encoding the hydroxylation of vitamin D to 25(OH)D), CYP27B1, VDR, and many more that may influence optimal supplementation dosing (e.g., high vs. low responders). For example, two SNPs in the GC gene were shown to increase the risk of being a low responder (defined as a 25(OH)D <50 nmol/L post-supplementation) by between 2.9 and 12.4-fold, depending on the number of minor alleles. Similarly, in the Vitamin D supplementation in Older People (VDOP) trial recently published in Frontiers in Nutrition, variants at the GC locus influenced plasma 25(OH)D levels and response to supplementation.

The recent review also cites several cross-sectional studies that find lower levels of inflammatory markers (C-reactive protein (CRP) and IL-6) among people with vitamin D sufficiency. In a small randomized clinical trial, pregnant women not only had larger increases in 25(OH)D at a dose of 2000 IU compared to 1000 IU per day, but the higher dose was also associated with a larger reduction in inflammatory signals (TNF-α in mothers and IL-6 in cord blood).

Dosing Matters

In addition to the factors above, it’s worth briefly noting (not mentioned in the review) that a number of intervention trials with vitamin D have had disappointing results, and one possible explanation for some (not all) of the trials that have not shown benefit is the use of bolus dosing. For example, in the 2021 review titled “Vitamin D: Bolus Is Bogus—A Narrative Review,” the authors point to evidence that although large doses (e.g., 100,000 IU) effectively increase 25(OH)D, this may result in the “upregulation of countervailing factors,” such as 24‐hydroxylase activity, which leads to a decrease in active vitamin D levels. Also, while the effect of boluses on antimicrobial peptides has not been examined, the increase in anti-inflammatory cytokines observed with low-dose vitamin D has not been found at higher doses; the risk of hypercalcemia is significant, there may be an increase in FGF23, etc., all factors suggesting that the effect on immune function and vitamin D activity with high and low dosing is not equivalent. The authors state, “In other words, although a large bolus produces a quick increase in 25(OH)D levels, it does so at the cost of downregulation of cellular activation and of factors of immunity.”

Also, as mentioned above, there is likely a modifying effect of body mass index (BMI) on vitamin D supplementation efficacy. This is discussed in some detail in an editorial published in JAMA Network Open, highlighting the post hoc analysis of VITAL (Vitamin D and Omega-3 Trial), which found improved outcomes with vitamin D supplementation, but only among those with a normal BMI. Overweight/obesity appears to blunt the risk reduction, which both suggests a higher dose may be warranted and helps to explain the lack of expected benefit observed in the initial analysis.

Clinical Evidence

The Frontiers in Immunology review provides a few clinical examples that give insight into their approach. Psoriasis, for example, has a very high rate of vitamin D deficiency (compared to control populations), reaching 80% in winter months. Polymorphisms in vitamin D metabolism modify risk for psoriasis, with multiple vitamin D-related mechanisms potentially improving epidermal and immunological abnormalities (e.g., inhibition of keratinocyte proliferation, promotion of Tregs, induction of cathelicidin LL-37), etc. Topical vitamin D is more effective than oral, as it drives up vitamin D levels locally at lesion sites, especially when combined with hormone or phototherapy, suggesting that systemic vitamin D levels may not always be the right biomarker.

In contrast, the authors also discuss inflammatory bowel disease (IBD), in which mean 25(OH)D is significantly lower than in controls, and in one prospective study, each 1 mcg increase in vitamin D intake was linked to an approximately 51% decrease in IBD risk (with larger benefits among women, non-smokers, and non-hypertensives). In a meta-analysis of vitamin D therapy for children and adolescents with IBD, published in the World Journal of Pediatrics, it was concluded that vitamin D supplementation significantly lowers inflammatory markers, including CRP and erythrocyte sedimentation rate (ESR), with greater effects at doses larger than 2000 IU per day. A meta-analysis conducted among adults with IBD, including 12 randomized and controlled trials (and four observational studies), found improvements in clinical and biochemical disease activity scores, including the Harvey Bradshaw Index and CRP. Additionally, in a longitudinal cohort stretching over a median of 13 years, higher levels of 25(OH)D were associated with a lower risk for bowel resection among adults with IBD, especially among those with ulcerative colitis (a 46% lower risk comparing the highest to lowest quintile). Polymorphisms in VDR have been associated with endoscopic disease activity, with the implication that higher 25(OH)D status may overcome the increased genetic susceptibility. Lastly, in one small double-blind and randomized trial, participants with Crohn’s disease (in remission) received either 2,000 IU vitamin D₃ or placebo for 3 months; supplementation was associated with maintenance of intestinal permeability and higher cathelicidin LL-37 levels, and those individuals that achieved a 25(OH)D of ≥ 75 nmol/L had significantly higher concentrations of cathelicidin LL-37 and quality of life scores, significantly lower CRP and non-significantly lower Crohn’s Disease Activity Index (CDAI), all suggesting that targeting a specific 25(OH)D level may be more effective than giving a standard dose.

Other Clinical Examples of Immunomodulation

Older Adults Immune Function

Frontiers in Immunology also published a 2026 meta-analysis of 9 randomized controlled trials evaluating micronutrient supplementation among older adults, and found an overall significant improvement in immune function with supplementation, with vitamin D specifically associated with increased immune cell activity, enhanced antioxidant status, and a positive effect on the natural inflammatory process.

Acute Respiratory Infections

In a somewhat confusing example, the Lancet Diabetes & Endocrinology published an updated 2025 systematic review and meta-analysis of vitamin D supplementation and acute respiratory infections, which included 6 new randomized and controlled trials in addition to 45 earlier ones. Although the 2021 meta-analysis of 45 trials did find a significant benefit with vitamin D supplementation, this one did not; there was a 6% nonsignificant lower risk of acute infections. Although the abstract makes no mention of it, they found a significant effect when comparing daily dosing vs. placebo, with a 16% lower risk of infection. Again, non-daily dosing may be masking the benefits of daily dosing. It’s worth noting that the 2021 meta-analysis found a 22% reduction in risk with daily dosing, vs. an 8% overall reduction (daily combined with bolus data).

Asthma

Multiple studies have found an association between 25(OH)D levels and asthma incidence and severity. The Annals of Medicine recently published a systematic review and meta-analysis of 10 controlled trials, including over 1200 children with asthma supplemented with either vitamin D or placebo. Overall, they found a 38% significant reduction in the total number of asthma exacerbations; however, when considering only daily vitamin D dosing, the reduction was 59%.

In a re-analysis of a randomized clinical trial (Vitamin D Antenatal Asthma Reduction Trial (VDAART)) published in the Journal of Nutrition, BMI was again found to modify the response to vitamin D supplementation. Pregnant women between 10-18 weeks gestation were randomized to receive either 4400 IU or 400 IU per day, and the initial results indicated a non-significant 6.1% reduction in asthma in their children by 3 years of age, though the study was thought to be underpowered. However, this re-analysis suggests that BMI may have been a mitigating factor; women with overweight and obesity had only 37 to 38% of the treatment effect (on the higher dose) on 25(OHD) levels compared to women with normal weight, and were less likely to achieve the target 25(OHD) of 75 nmol/L. Lastly, it’s worth noting that a 15 year analysis of VDAART concluded that all pregnant women should begin taking at least 4400 IU vitamin D starting at conception, and some women may require more. No adverse effects were observed at this dose, with an overall reduction in asthma/recurrent wheeze of 50% when adjusted for baseline 25(OH)D among children ages 3-6.

Multiple Sclerosis

The use of vitamin D supplementation for people with multiple sclerosis (MS) has had both positive and negative findings. A systematic review and meta-analysis, also published in Frontiers in Immunology, found a significantly higher 25(OH)D among people with relapsing-remitting MS (RRMS) compared to secondary progressive MS (SPMS), but no difference among people with primary progressive MS (PPMS), with lower levels of 25(OH)D during relapse than remission (among RRMS). Comparing the highest vs. lowest 25(OH)D, they found a negative correlation with both the incidence of MS and disease severity (but not disease activity). VDR polymorphisms were also associated with disease risk. However, overall supplementation was not associated with improvements in relapse rates or disease activity scores. Yet when assessed by dosage, higher doses (2857 to 20,400 IU per day) were associated with a significant reduction in relapse rates, while lower doses (400 to 1000 IU per day) had no effect.

Summary

Substantial data now illustrate the many biological pathways of immunomodulation by vitamin D, not limited to calcium metabolism, but closely intertwined with immune function and inflammation. Although there are still many gaps in our knowledge, consideration of dosing, including consideration of absolute dose, bolus vs. daily, genetic polymorphisms, BMI, etc., may help to explain some of the disappointing trial data, and allow practitioners to personalize vitamin D therapy for their patients.

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