Folate Absorption and Digestion

Folate Absorption and Digestion

The digestion/absorption process of folate is complicated. Many foods contain folate, but in different forms, some of which cannot be absorbed until they are broken down by intestinal enzymes. Even under the best circumstances, the absorption rate of ingested food folate is only about 50%. On the other hand, many Americans eat a diet that is heavy in folate-depleted processed foods. As a result, folate deficiency is a widespread problem.

Absorption of folate is much more effective in the form of folic acid in fortified foods and supplements than when folate is found in food naturally. However, individual differences are another important determinant. The bioavailability of folate not only varies with the form the folate is in, but can also be dependent on genetic factors, the person’s health status, and interactions between folate and other substances or medications the person is ingesting. Because absorption of folate can vary so much, requirements are often expressed as dietary folate equivalents (DFE).

One reason why the folate that exists naturally in certain foods is absorbed less efficiently than the folic acid taken on an empty stomach is that the food folate is in the polyglutamine form, requiring the presence of intestinal enzymes to separate out the excess glutamates. However, folic acid supplements are in the monoglutamate form, ready to be absorbed.

Typically, folic acid in supplement form is almost 100% bioavailable (especially if taken on an empty stomach) while the folic acid in fortified food has about 85% bioavailability. This is in contrast to folate from a mixed diet that averages about 50% bioavailability though it can vary from that figure considerably and in some individuals be much less.

Dietary folate contains glutamate that needs to be cleaved for absorption to take place. However, compounds contained in various foods (such as lentils, cabbage, and oranges) inhibit this process, thereby contributing further to the decreased bioavailability of folate. After folate is taken up by the intestinal cells, with the addition of hydrogen, it is converted into tetrahydrofolate (THF), the active form of folate. Then a methyl group is added, which in turn results in the production of 5-methyltetrahydrofolate (5-methyl THF), which is released into the blood and transported to the liver, where a limited amount of folate is stored (enough for the body to use if necessary over the next 6-9 months).

These activities rely on a carrier system called protein-coupled folate transporter (PCFT) located in the duodenum and upper jejunum. PCFT detects associated with hereditary folate malabsorption and severe folate deficiency.

Folate in the form of THF acts as a coenzyme for many chemical reactions, all involving a single carbon transfer from one molecule to another. One very important type of chemical reaction is the metabolism of amino acids. A notable example is the conversion of homocysteine to the amino acid methionine. More specifically, 5-methyl THF transfers the methyl group –CH3 to homocysteine to produce a combination of THF (the active form of folate) and methionine. However, for this reaction to take place, another chemical reaction must take place simultaneously in which the methyl group -CH3 is first transformed from 5-methyl THF to vitamin B 12. Afterward, vitamin B12 facilitates the transfer of the methyl group –CH3 to homocysteine to form methionine. 

In summary, the conversion of homocysteine to methionine requires the dual presence of both folate and vitamin B 12 working together in the following two-step process:  

  1. 5-methyltetrahydrofolate (an inactive form of folate) transfers the methyl group known as -CH3 to vitamin B 12.

  2. Then vitamin B12 transfers the methyl group -CH3 to homocysteine to form methionine.

Since adequate amounts of both folate and vitamin B 12 are needed, a deficiency in either vitamin causes homocysteine levels to build up in the blood.  As already mentioned, high levels of homocysteine are directly associated with increased risk of heart disease. There is also evidence that high concentrations of homocysteine are related to memory loss and difficulty with abstract thinking. Therefore, there may be a relationship between impaired folate metabolism and Alzheimer’s disease.

The synergistic relationship between folate and vitamin B12 is sometimes called the methyl-folate trap. The term refers to the fact that without vitamin B12, the methyl group from 5-methyl THF cannot be transferred, and not only is the synthesis of methionine impossible, but metabolically useless 5-methyl THF accumulates and THF cannot be regenerated. As a result, the folate that exists in the cells is “trapped” and not in a form that can be used for DNA synthesis.

As long as there is a sufficient amount of both folate and vitamin B12 without undue interference from other factors that might inhibit folate absorption, the process takes place the way it is supposed to in the small intestine.  After the polyglutamates are hydrolyzed into monoglutamates and reduced to dihydrofolate and THF in the epithelial cells (enterocytes) of the small intestine, they are ready to enter into circulation. There they are bound to protein and transported as methyltetrahydrofolate to the tissues of the body.

Metabolism and Excretion 

Folate that is not going to be used by the body is excreted in both the urine and the feces. However, folate-binding proteins in the kidneys along with tubular reabsorption mechanisms allow some needed folate to be retained.

Most of the folate that winds up being secreted by the liver into the bile is likewise reabsorbed, so in a healthy individual, the amount of folate lost via the feces is minimal.