Scientists found that the vitamin D supplement millions of people take is quietly lowering the only form of vitamin D that activates immune defense against viruses
Vitamin D is one of the most widely taken supplements in the world. Hundreds of millions of people buy it specifically to support their immune system, and a significant proportion of them, particularly people following vegan or plant-based diets, are taking the form their doctors and pharmacists often reach for first: vitamin D2. A study published in Nutrition Reviews by researchers at the University of Surrey, the John Innes Centre, and the Quadram Institute Bioscience has now found that vitamin D2 does something to the body that nobody knew it was doing. It actively lowers levels of vitamin D3, the form the body uses most effectively, in some cases dropping D3 below the levels seen in people taking no supplement at all.
The people taking a supplement specifically to support their health are, in a meaningful number of cases, ending up with less of the better vitamin D than if they had taken nothing.
Two Forms That Were Always Assumed to Be Equivalent
The distinction between vitamin D2 and vitamin D3 has existed in nutrition science for decades, but the clinical and public health response to that distinction has largely been to treat them as interchangeable. Both are measured together as total vitamin D in standard blood tests. Both are used in government supplementation programs. Both appear on supplement labels with the same recommended doses. Functional equivalence in their vitamin D-dependent effects on human physiology is usually assumed but has in fact not been well defined experimentally.
Vitamin D3, also called cholecalciferol, is the form the human body produces naturally when skin is exposed to sunlight. It is found in animal-based foods including oily fish, egg yolks, and liver. Vitamin D2, also called ergocalciferol, comes primarily from plant sources and fungi, particularly mushrooms exposed to ultraviolet light. It has been used in food fortification and prescription supplements for decades, partly because it can be produced without animal products, making it the default choice for vegans and for many pharmaceutical-grade formulations.
The assumption underlying this interchangeability was never rigorously tested at the level of what each form actually does inside the body once absorbed. The University of Surrey team set out to fill that gap.
What the Meta-Analysis Found
The research analyzed data from 11 randomized controlled trials covering 655 adults. Study participants who received vitamin D2 supplementation showed statistically significant reductions in serum 25-hydroxyvitamin D3 concentrations compared to controls without supplementation. The D3 reduction was not a marginal statistical effect. In some participants, D3 levels after taking D2 supplements fell below the levels measured in people who were taking no supplement whatsoever.
“We discovered that vitamin D2 supplements can actually decrease levels of vitamin D3 in the body, which is a previously unknown effect of taking these supplements,” said Dr. Emily Brown, lead researcher from the University of Surrey’s nutrition discipline. “This study suggests that, subject to personal considerations, vitamin D3 supplements may be more beneficial for most individuals over vitamin D2.”
The mechanism behind this displacement effect is not yet fully characterized. One leading hypothesis involves competition for the same metabolic enzymes in the liver and kidneys that convert both forms into their active metabolites. When D2 floods this conversion pathway, the enzymes have less capacity to process D3, and circulating D3 levels fall as a result. Another possibility involves the vitamin D binding protein, a carrier molecule in the blood that transports both forms. D2 may preferentially occupy binding sites, reducing the availability of the transport mechanism that keeps D3 circulating at functional levels.
Whatever the precise mechanism, the direction of the effect across 11 randomized controlled trials is consistent. Taking D2 suppresses D3. And that suppression matters because the two forms are not doing the same things in the immune system.
The Immune System Difference Nobody Talks About
A separate study from the same University of Surrey research group, published in Frontiers in Immunology, analyzed the blood transcriptome of people supplementing with D2 versus D3 across a 12-week winter trial. The transcriptome analysis reads which genes are being actively expressed in immune cells, providing a window into what the immune system is actually doing at the molecular level rather than just measuring circulating vitamin D concentrations.
Gene expression associated with type I and type II interferon activity, critical to the innate response to bacterial and viral infections, differed following supplementation with either vitamin D2 or vitamin D3, with only vitamin D3 having a stimulatory effect. Interferons are the immune system’s primary first-response signaling molecules against viral and bacterial threats. They are produced rapidly when the body detects a pathogen, triggering a cascade of defensive responses that slow viral replication, alert neighboring cells, and recruit immune cells to the site of infection. Type I interferons in particular are central to antiviral defense.
Vitamin D3 upregulated the genes driving this response. Vitamin D2 did not. People taking D2 were not getting the immune activation against pathogens that they were presumably taking a vitamin D supplement to support in the first place. And because D2 was simultaneously suppressing their D3, they were ending up with reduced levels of the form that would have provided that activation.
Who Is Most Affected
The people most likely to be taking D2 rather than D3 are also the people most likely to be relying on supplementation as their primary source of vitamin D. Vegans and vegetarians avoid the animal-based food sources where D3 occurs naturally, making supplementation more critical for their vitamin D status than for omnivores. Many vegan vitamin D supplements use D2 because it is plant-derived. The irony is that the population with the strongest reason to supplement carefully with vitamin D may have been taking the form that displaces the more effective version.
Older adults receiving prescription-strength vitamin D from their doctors also frequently receive D2, because high-dose D2 has historically been the pharmaceutical formulation used for clinical deficiency treatment. Patients with malabsorption conditions, those on certain medications, and people in northern latitudes during winter months, all groups where supplementation is most medically important, have regularly been given D2 without any awareness that it was suppressing their D3.
What the Label Does Not Tell You
When most people pick up a vitamin D supplement, they look at the dose in micrograms or international units and assume the form is a secondary detail. The University of Surrey research is saying that the form is not secondary. It is the primary variable that determines whether the supplement is supporting immune function or quietly undermining the very levels of vitamin D it is supposed to raise.
The standard blood test that measures vitamin D status adds another layer to this problem. Total serum vitamin D tests measure the combined levels of both 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 together. A person taking D2 supplements could show a normal or even elevated total vitamin D reading while their D3, the fraction doing the immunological work the transcriptome analysis identified, is suppressed below baseline. The test confirms the number. The number does not tell them which form they have or what their immune system is actually receiving.
The researchers’ recommendation is direct: for most people, vitamin D3 is the form that raises total vitamin D status more efficiently, preserves and builds D3 levels rather than depleting them, and activates the interferon-driven immune responses that D2 does not. Subject to individual circumstances and medical guidance, D3 is what people taking a vitamin D supplement are likely trying to get, whether or not the label tells them which form is inside the capsule.
Sources:
1. Primary meta-analysis (Nutrition Reviews, September 2025) Brown, E.I.G., Darling, A.L., Robertson, T.M., et al. Effect of Vitamin D2 Supplementation on 25-Hydroxyvitamin D3 Status: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrition Reviews, 2025. DOI: 10.1093/nutrit/nuaf166 https://pubmed.ncbi.nlm.nih.gov/40973107/
2. Transcriptome immune differences D2 vs D3 (Frontiers in Immunology, 2022) Durrant, L.R., Bucca, G., Hesketh, A., et al. Vitamins D2 and D3 Have Overlapping But Different Effects on the Human Immune System Revealed Through Analysis of the Blood Transcriptome. Frontiers in Immunology, 2022; 13: 790444. DOI: 10.3389/fimmu.2022.790444 https://pubmed.ncbi.nlm.nih.gov/35281034/
