Vitamin D has become a hot topic in recent years, largely because failure to get enough of it is associated with multiple diseases, and because much of the general population is deficient in this micronutrient.

Since 1930, when its chemical structure was first identified, significant advances have been made in research into vitamin D’s functions in the body. Initially, studies focused on the role of this compound and its metabolites in calcium homeostasis and bone metabolism.

Later, with the discovery of the metabolised forms of 25-hydroxyvitamin D (25(OH)D) in 1968 and then 1,25-hydroxyvitamin D (1,25 (OH)2D), research expanded and focused on the role it plays in the onset of immunological diseases, infections and cancer, as well as chronic non-communicable diseases such as cardiovascular conditions, obesity and type 2 diabetes.

Currently, there is no doubt that vitamin D plays a role in regulating the immune system; vitamin D deficiency is actually associated with a worse prognosis for COVID-19 infection.

A growing deficiency

Epidemiological data from 2020 shows that 40 per cent of Europe’s population are not getting enough vitamin D. In the US, 24 per cent of people are lacking it, as are 37 per cent of Canadians. These high figures are cause for alarm. The population groups most at risk are pregnant women, children, the elderly, obese people, individuals with darker skin tones, and those with little exposure to sunlight.

Humans can meet part of their vitamin D requirements through skin synthesis from cholesterol, provided they are exposed to sufficient sunlight. However, it is difficult to specify the minimum recommended amount of time, as it depends on a range of factors, including the season, time of day, geographical latitude, age, and skin type.

An expert panel from the Spanish Society for Bone and Mineral Metabolism Research recommends that light-skinned people expose their face and arms to the sun for 15 minutes every day between March and October.

For elderly people and patients with osteoporosis, the recommendation is to extend this to 30 minutes. In both cases, sunblock with an SPF between 15 and 30 should be used, depending on the latitude and intensity of UV (ultraviolet) radiation.

Dietary intake is also necessary. Good dietary sources of vitamin D include oily fish (especially salmon and trout), full-fat dairy products, margarines and fortified vegetable drinks.

Some common health choices may be behind the growing vitamin D deficiency. These include the increasingly frequent use of sunscreen and the reduced consumption of fatty foods.

Supplements: when should we take them?

Currently, vitamin D levels are assessed by determining the serum concentration of 25(OH)D, though results can vary depending on the analytical method used.

In general, values above 20 nanograms per millilitre (ng/mL) are considered optimal for the general population. They should be above 30 ng/mL for people over 65 years of age, patients with bone conditions, or those undergoing chronic drug treatments such as corticosteroids or anticonvulsants.

Values between 12 and 20 ng/mL are considered insufficient, and anything below 12 ng/mL is considered a deficiency. There is also concern about the risks of too much vitamin D, known as hypervitaminosis D, which occurs at 25(OH)D levels above 100 ng/mL.

For people with adequate 25(OH)D serum levels, there is debate over whether vitamin D supplements should be prescribed in order to improve their immune response.

To address this question, a 2022 meta-analysis evaluated the effects of supplements of 1,000-2,000 international units (IU) per day in healthy individuals. The analysis concluded that the supplements did not lead to significant improvements in immune system function, nor did they help prevent illnesses such as acute respiratory diseases, influenza, or COVID-19 infection.

However, other authors have observed positive effects of this intervention in individuals with respiratory diseases, especially in those with vitamin D deficiency. There are also conflicting results regarding its benefits in patients with metabolic diseases and neurodegenerative conditions.

Too much vitamin D?

The intake of vitamin D from food is unlikely to cause problems. However, indiscriminate use of supplements in people who are not deficient can lead to chronic toxicity. For example, the administration of vitamin D supplements in doses exceeding 4,000 IU/day for prolonged periods can raise serum 25 (OH)D concentrations to values above 50 ng/ml. This leads to a risk of excessive levels in the body, known as hypervitaminosis.

The most common manifestation of hypervitaminosis D is hypercalcaemia. This is characterised by gastrointestinal symptoms (anorexia, nausea, vomiting and constipation) alongside weakness and fatigue. In the most severe cases, it can cause polyuria (excessive urine production), polydipsia (abnormal increase in thirst), renal failure, ectopic calcifications (outside the normal areas), depression, confusion, bone pain, fractures, and kidney stones.

Due to increased consumption of supplements, cases of toxicity have risen significantly in recent years. A 2016 report from the US National Toxicology Data System indicates that this overexposure to vitamin D has led to a sharp increase in the number of hypervitaminosis cases – the annual average in the period 2000-2005 was 196, but this rose to 4,535 in the following five-year period.

Supplements: Use with caution

Interest in vitamin D has increased significantly due to its association with multiple diseases and a possible, though perhaps not well-established, deficiency in the general population. However, research into the effects of vitamin D supplements in people who do not have a deficiency is by no means conclusive.

There is evidence that they can help reduce the severity of respiratory diseases in people with deficiencies, but hypervitaminosis D, resulting from improper supplementation, is also a real risk, potentially leading to hypercalcaemia and other health problems.

It is therefore essential to approach this issue with caution, always acting on the basis of scientific evidence and exercising prudence when taking or recommending a vitamin D supplement.

One thing is clear, though: the myth of vitamin D as a “supervitamin” does not stack up against current scientific evidence. The truth is that there is still a lot that we don’t understand, and more research is needed.

The challenge: addressing a critical nutrient deficiency

Climate change and agricultural intensification have increasingly deprived honeybees of the floral diversity they need to thrive. Pollen, the major component of their diet, contains specific lipids called sterols necessary for their development. Increasingly, beekeepers are feeding artificial pollen substitutes to their bees due to insufficient natural pollen. However, these commercial supplements — made of protein flour, sugars, and oils — lack the right sterol compounds, making them nutritionally incomplete.

In the new study, the research team succeeded in engineering the yeast Yarrowia lipolytica to produce a precise mixture of six key sterols that bees need. This was then incorporated into diets fed to bee colonies during three-month feeding trials. These took place in enclosed glasshouses to ensure the bees only fed on the treatment diets.

Key findings:

• By the end of the study period, colonies fed with the sterol-enriched yeast had reared up to 15 times more larvae to the viable pupal stage, compared with colonies fed control diets.
• Colonies fed with the enriched diet were more likely to continue rearing brood up to the end of the three-month period, whereas colonies on sterol-deficient diets ceased brood production after 90 days.
• Notably, the sterol profile of larvae in colonies fed the engineered yeast matched that found in naturally foraged colonies, suggesting that bees selectively transfer only the most biologically important sterols to their young.

Senior author Professor Geraldine Wright (Department of Biology, University of Oxford), said: “Our study demonstrates how we can harness synthetic biology to solve real-world ecological challenges. Most of the pollen sterols used by bees are not available naturally in quantities that could be harvested on a commercial scale, making it otherwise impossible to create a nutritionally complete feed that is a substitute for pollen.”

Lead author Dr Elynor Moore (Department of Biology, University of Oxford at the time of the study, now Delft University of Technology) added: “For bees, the difference between the sterol-enriched diet and conventional bee feeds would be comparable to the difference for humans between eating balanced, nutritionally complete meals and eating meals missing essential nutrients like essential fatty acids. Using precision fermentation, we are now able to provide bees with a tailor-made feed that is nutritionally complete at the molecular level.”

From pollen to precision nutrition: Identifying and producing key bee sterols

Before this work, it was unclear which of the diverse sterols in pollen were critical for bee health. To answer this, the researchers chemically assessed the sterol composition of tissue samples harvested from pupae and adult bees. This required some extraordinarily delicate work; for instance, dissecting individual nurse bees to separate the guts. The analysis identified six sterol compounds that consistently made up the majority in bee tissues: 24-methylenecholesterol, campesterol, isofucosterol, β-sitosterol, cholesterol, and desmosterol.

Using CRISPR-Cas9 gene editing, the researchers then engineered the yeast Yarrowia lipolytica to produce these sterols in a sustainable and affordable way. Y. lipolytica was selected since this yeast has a high lipid content, has been demonstrated as food-safe, and is already used to supplement aquaculture feeds. To produce the sterol-enriched supplement, engineered yeast biomass was cultured in bioreactors, harvested, then dried into a powder.

Co-author Professor Irina Borodina (The NNF Center for Biosustainability, Technical University of Denmark) said: “We chose oleaginous yeast Yarrowia lipolytica as the cell factory because it is excellent at making compounds derived from acetyl-CoA, such as lipids and sterols, and because this yeast is safe and easy to scale up. It is used industrially to produce enzymes, omega-3 fatty acids, steviol glycosides as calorie-free sweeteners, pheromones for pest control, and other products.”

Benefits for agriculture and biodiversity

Pollinators like honeybees contribute to the production of over 70% of leading global crops. Severe declines — caused by a combination of nutrient deficiencies, climate change, mite infestations, viral diseases, and pesticide exposure — poses a significant threat to food security and biodiversity. For instance, over the past decade, annual commercial honey bee colony losses in the U.S have typically ranged between 40 and 50%, and could reach 60 to 70% in 2025. This new engineered supplement offers a practical means to enhance colony resilience without further depleting natural floral resources. Since the yeast biomass also contains beneficial proteins and lipids, it could potentially be expanded into a comprehensive bee feed.

Co-author Professor Phil Stevenson (RBG Kew and Natural Resources Institute, University of Greenwich) added: “Honey bees are critically important pollinators for the production of crops such as almonds, apples, and cherries and so are present in some crop locations in very large numbers, which can put pressure on limited wildflowers. Our engineered supplement could therefore benefit wild bee species by reducing competition for limited pollen supplies.”

Danielle Downey (Executive Director of honeybee research nonprofit Project Apis m., not affiliated with the study) said: “We rely on honey bees to pollinate one in three bites of our food, yet bees face many stressors. Good nutrition is one way to improve their resilience to these threats, and in landscapes with dwindling natural forage for bees, a more complete diet supplement could be a game changer. This breakthrough discovery of key phytonutrients that, when included in feed supplements, allow sustained honey bee brood rearing has immense potential to improve outcomes for colony survival, and in turn the beekeeping businesses we rely on for our food production.”

Next steps and future applications

Whilst these initial results are promising, further large-scale field trials are needed to assess long-term impacts on colony health and pollination efficacy. Potentially, the supplement could be available to farmers within two years.

This new technology could also be used to develop dietary supplements for other pollinators or farmed insects, opening new avenues for sustainable agriculture.