Folic Acid Is Not the Same Thing as Folate

Air pollution contributes to an estimated seven million early deaths every year around the world. Exposure to even just a few hours of diesel exhaust can modulate the methylation of thousands of sites on our DNA, which may contribute to the inflammation that leads to such a burden of disease. This involves mostly demethylation thought perhaps due to the shunting of part of the methyl donor machinery to the production of glutathione, an antioxidant our body makes to detoxify a variety of chemical exposures. Give people B vitamins like folic acid, though, and this demethylation can be blocked. Does any of this translate into clinical benefits? 
 
Folic acid is best known for preventing neural tube defects, severe birth defects of the brain and spine. The first clue came in the 1960s, when researchers noticed that women who conceived in the winter when there was a lack of green vegetables were struck with higher rates. With mandatory folic acid fortification policies now in place in 80 countries, there’s been a dramatic drop in neural tube defects. All women of reproductive age are encouraged to supplement, but what about later in life? 
 
A review of more than a hundred meta-analyses of population studies show that those who get more folate in their diet tend to live longer and are protected against cardiovascular disease, several cancers, and a wide range of other chronic diseases. But since folate is found in beans and greens, this should not be surprising. The only way to know if it’s the folate itself, is to put it to the test. 
 
Since DNA hypomethylation had been reported in colorectal cancer tissue, and folic acid supplementation could increase DNA methylation and potentially even prevent the recurrence of colon polyps, the National Cancer Institute funded a study which randomized more than a thousand polyp patients to folic acid or placebo to see if colon cancer could be prevented. It didn’t work. In fact, the study had to be stopped prematurely because there were even more of a certain type of advanced polyp in the folic acid group. Those study subjects may have gotten off lucky. In 2019 a trial of more than 2,000 older men and women was published showing those randomized to supplemental folic acid every day for a few years suffered a 77% increased risk of developing colorectal cancer. 
 
Other randomized controlled trials of folic acid supplementation have not found an increased colorectal cancer risk, but they have consistently found increased prostate cancer risk. Wait, why would folate intake from foods be associated with lower cancer risk, but supplementation with folic acid increase risk? The mystery may have been solved when scientists figured out we’re not rats. 
 
See, natural folate isn’t shelf-stable, but there’s an enzyme in our liver that can convert the stable synthetic folic acid in supplements into an active form of folate in our body. The original experiments were done on rats, though, and it turns out rat livers are 50 times more efficient at this conversion than human livers. So when we take more than 200 µg of folic acid at a time (most supplements have 400 or 800) we end up with unmetabolized folic acid circulating throughout our body. And why is that a problem? 
 
Because blood levels of unmetabolized folic acid were found to be associated with decreased natural killer cell function. Natural killer cells are one of our first lines of immune defense against viruses and rogue cancer cells. You can’t prove cause and effect until you put it to the test, which researchers in Brazil finally did and published in 2017. Within weeks of folic acid supplementation study subjects suffered a significant drop in the number and function of their natural killer cells. The researchers used a massive dose, though (5,000 µg a day), and there was no control group to compare them to, so the body of evidence to conclusively support human adverse effects from folic acid supplementation is considered “insufficient.” 
 
Yes, randomized controlled trials show folic acid supplementation can increase prostate cancer risk, but also decreases stroke risk by 10%, or potentially twice that in those with low baseline folate levels. We can presumably get the best of both worlds by getting folate from natural sources, though women capable of getting pregnant (who don’t need to worry about prostates) are still advised to take folic acid supplements given their proven efficacy for reducing birth defects.  
 
The third way to improve your folate status—beyond food and supplements—is to contract out some of the production to your microbiome. There’s a folate transporter in our colon that appears specially designed to absorb folate produced by good bacteria like Bifidobacterium when we feed them with fiber.