Vitamin D deficiency is associated with cancer, cardiovascular disease, and osteoporosis, but clinical trials of vitamin D supplements have yielded mixed results. A new study that found links between the active form of the vitamin and gut bacteria may help explain why.

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Vitamin D is essential for strong immunity and maintaining healthy bones and teeth.

Several studies have found that low levels of vitamin D in the blood correlate with a wide range of illnesses, including cancer, cardiovascular disease, diabetes, and osteoporosis.

A few studies have even hinted that low vitamin D levels are associated with severe COVID-19, although the research is inconclusive.

Despite these associations, evidence for the benefits of widespread vitamin D supplementation to prevent disease in otherwise healthy people has been mixed.

For example, a large clinical trial found no evidence that a vitamin D supplement prevented cardiovascular disease and cancer in older adults. Another trial found no evidence that taking a supplement improved bone health.

This apparent lack of health benefits from widespread vitamin D supplementation has baffled medical researchers.

Scientists at the University of California (UC) San Diego in La Jolla have now discovered a possible explanation. Their findings appear in Nature Communications.

The paper suggests that gut bacteria may play a vital role in converting inactive vitamin D into its active, health-promoting form.

When healthcare professionals and medical researchers want to determine an individual’s vitamin D status, they measure serum levels of the inactive precursor, because this reflects how much vitamin D the body stores.

However, the crucial factor may be how the vitamin is metabolized rather than how much of it is stored.

When measuring how much active vitamin D older males had in their blood, the UC San Diego researchers found that its levels correlated with the diversity of the community of bacteria living in their gut, or gut microbiome.

Levels of active vitamin D also correlated with the number of “friendly” bacteria in their gut.

By contrast, there was not a strong association between the inactive, precursor form of the vitamin and bacterial diversity or friendly bacteria.

“We were surprised to find that microbiome diversity — the variety of bacteria types in a person’s gut — was closely associated with active vitamin D but not the precursor form,” says senior author of the study Dr. Deborah Kado, director of the Osteoporosis Clinic at UC San Diego Health.

“Greater gut microbiome diversity is thought to be associated with better health in general,” she adds.

The correlation between microbial diversity and active vitamin D remained even after adjusting for factors known to determine microbial diversity. These included the participants’ age, where in the United States they lived, their ethnic background, and their antibiotic use.

In fact, the participants’ levels of active vitamin D correlated much more strongly with microbiome diversity than any of these other factors.

This is particularly remarkable given that people who live in sunnier places, such as California, are able to synthesize more of their own vitamin D through the action of ultraviolet light on their skin.

“It seems like it does not matter how much vitamin D you get through sunlight or supplementation, nor how much your body can store.”

– Dr. Deborah Kado

“It matters how well your body is able to metabolize that into active vitamin D, and maybe that is what clinical trials need to measure in order to get a more accurate picture of the vitamin’s role in health,” Dr. Kado explains.

The researchers say more studies are needed to investigate the role of bacteria in vitamin D metabolism. They speculate that changing patients’ microbiota could augment existing treatments for improving bone density, and possibly other health outcomes.

The team analyzed stool and blood samples from 567 men living in six U.S. cities who were taking part in a study called the Osteoporotic Fractures in Men Study (MrOS).

The mean age of the participants was 84 years, and most of them reported being in good or excellent health.

To identify and quantify bacteria in the stool samples, the researchers sequenced copies of a bacterial gene that delineates different species.

They also measured the amounts of three vitamin D metabolites — the precursor, the active vitamin, and a breakdown product — in the blood samples.

Reporting their results, the authors write:

“The significant correlation between amplified vitamin D activation and greater individual stool microbial diversity supports the idea that increased microbial diversity reflects a healthy state.”

Not only did males with the highest levels of active vitamin D in their blood have the greatest microbiome diversity, but also their gut harbored more friendly bacterial species that produce butyrate.

This short-chain fatty acid, which some types of bacteria in the colon generate when they digest fiber, has a wide range of potential health benefits. Research suggests that butyrate helps prevent colon cancer, lower blood cholesterol, and combat insulin resistance, for example.

The authors stress that their study was unable to determine whether high levels of active vitamin D allow butyrate-producing bacteria to thrive or whether these bacteria promote the conversion of the vitamin to its active form.

By the same token, the study could not prove that having a more diverse gut microbiome leads to better vitamin D metabolism. It only found an association between the two.

Another limitation of the study was that the participants were predominantly older white males.

In addition, around 75% of them reported that they were taking some form of vitamin D supplement. Only 7% of all the participants met the standard definition of vitamin D deficiency.

The findings of the study may therefore not hold true for other populations, for people who do not take the supplement, or for those who are classified as being deficient in the vitamin.