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Vitamin B12 & Folate

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Once referred as “nature’s most beautiful cofactor”, (1) the red-colored B12 is a tetrapyrrole that occurs in several active and inactive forms (2-4). As the complex 30-step pathway for B12 biosynthesis is confined to certain bacteria, humans are completely dependent upon a dietary source of the vitamin (5).

Vitamin B12 is a water-soluble molecule that in humans, participates in ONLY two types of enzyme-catalyzed reactions (6):

  1. Methionine Synthase (aka, MS). In this reaction, Vitamin B12 works together with folate in the synthesis of DNA and red blood cells. In the process, homocysteine is converted to the amino acid methionine (7).
  2. Methylamalonyl-CoA Mutase (aka, MUT). This is an important biological pathway for extraction of energy from branched-chain amino acids and odd-chain fatty acids (6). It also participates in the production of the myelin sheath around nerves. Think of the brain and the nervous system as a big tangle of wires. Myelin is the insulation that protects those wires and helps them to conduct messages.



Here is a short summary of the complicated nature of B12 absorption: (A) Stomach acids are needed to release B12 from our food and allow it to bind with a protein called haptocorrin provided in saliva and in stomach fluids (8); (B) When leaving the stomach, enzymes released by the pancreas release B12 from haptocorrin and allow it to bind to another protein called intrinsic factor (IF), a specialized protein released by specialized stomach cells called parietal cells (9, 10). IF’s primary job is to bind together with B12 and facilitate its absorption; (C) At the very end of the small intestine (called the terminal ileum), intestinal cells have special receptor proteins that serve as glue for taking the IF-bound form of B12 out of the intestine and up into the cells (11).


Owing to the efficient enterohepatic circulation (i.e., gut to liver), as well as reuptake in the kidneys, B12 depletion can take years to become clinically evident (i.e. deficiency sets in long before obvious symptoms appear), and some of the more serious effects of B12 deficiency (such as nerve damage) are irreversible (6). So, who should you be concerned? Some people are at greater risk than others. Vitamin B12 deficiency can happen if you have certain conditions, such as:

  • Vegans and vegetarians.
  • Atrophic gastritis (thinning of the stomach lining).
  • Pernicious anemia – an autoimmune condition which makes it hard for your body to absorb vitamin B12. Affects 10 – 30% of people over 50.
  • Gastric bypass surgery or band.
  • Crohn’s, celiac disease, SIBO, or a parasite.
  • Heavy drinking.
  • Acid-reducing drugs (e.g., Tagamet, Zantac, Pepcid, Prilosec, Prevacid, Nexium).



As I mentioned above, fungi, plants, and animals are incapable of producing vitamin B12. Only bacteria and archaea have the enzymes required for its synthesis. Humans are completely dependent upon a dietary source of the vitamin (5). Vitamin B12 is found ONLY in animal products. It’s the only vitamin we can’t obtain from plants or sunlight. This explains why up to 50% of long-term vegetarians and 80% of vegans are deficient in B12 (12, 13). Therefore, all vegans and most vegetarians should supplement with B12.

fresh green spinach isolated on white background with water drops


Folates are a family of water-soluble B9 vitamins found in nature primarily as 5-methyltetrahydrofolate (5-MTHF). One of the most important folate-dependent reactions is the conversion of homocysteine to methionine, an important pathway in the generation of methyl groups (14-16). Folate functions as a co-factor in reactions involved in the synthesis of DNA, production of red blood cells and cell division.

Because of its water solubility, folate is not stored in the fat tissues of the body, meaning that any leftover will leave the body through the urine. Unlike B12 in which deficiency will take years to manifest, your blood levels will get low after only a few weeks of eating a diet low in folate.


The proximal small intestine is the major site of folate absorption. This is consistent with the presence of high levels of folate specific transporter (which is incidentally activated the presence of vitamin D3 and A) in that region. However, there is also a high level of folate transport activity in the colon, which is a rich breeding ground for ‘good’ bacteria (we’ll talk more about this later) that actively synthesize folates.

The terms “folate” and “folic acid” are often used interchangeably but they are not one and the same. Folates are members of the B vitamin family (referring to various tetrahydrofolate derivatives) naturally occurring in foods. Folic acid, on the other hand, is a fully oxidized, synthetic compound, used in dietary supplements and in food fortification.



Due to the tight link between B12 and folate, many of the underlying deficiencies are the same. Loss of appetite and weight loss can occur. Additional signs are weakness, sore tongue, headaches, heart palpitations, irritability, and behavioral disorders. In adults, anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency. In infants and children, folate deficiency can slow growth rate. Women with folate deficiency who become pregnant are more likely to give birth to low birth weight premature infants, and infants with neural tube defects (NTD). Causes of folate deficiency are:

  • Digestive system issues (celiac disease or Crohn’s disease).
  • Excessive use of alcohol.
  • Eating overcooked vegetables.
  • Hemolytic anemia.
  • Medications that interfere with absorption (e.g., antibiotics, phenytoin, sulfasalazine).
  • An unhealthy diet lacking fruits and vegetables.


Genetics & Dietary Requirements

A dietary deficiency is not the only way to impair the methionine pathway. About 85% of the general population carries a variant of the MTHFR that reduces the enzyme’s ability to produce 5-MTHF, even in the presence of folate (18). Individuals with this variant have difficulty processing folic acid that is present in most cheap supplements and added to processed foods. Low activity of MTHFR is linked with elevated homocysteine levels, a risk factor for cardiovascular disease, inflammation, birth defects, and difficult pregnancies.

A well-studied variant of the methylene tetrahydrofolate reductase (MTHFR) gene alter folate metabolism quite severely. However, risks can be virtually eliminated with increased folate intake to hide the phenotypic effects of the mutation—the concept of genetic rescue. In fact, one size doesn’t fit all when it comes to MTHFR mutations; for example, people with one form of the MTHFR allele (T allele) need a higher folate intake than do carriers of the C allele. Yet, current regulations cite an RDA (Required Daily Allowance) of 400μg per day for all ‘healthy’ adults.

Proper folate intake in maternal nutrition can permanently affect how genes are expressed and methylated in the fetus, with potentially lifelong consequences that may alter various health outcomes of the offspring.

To date, MTHFR may be the best example of a gene where variation can influence and support the concept that gene mutation modifies nutrient utilization and potentially dietary requirements.

Table 1 - Top foods rich in folate

THE B12 & FOLATE CONNECTION (A tale of Two Cycles)

The folate and the methionine cycles are two metabolic pathways that are interconnected (See figure below) through two enzymes:

  • Methionine synthase (MS) this reaction requires both B12 and 5-MTHF.
  • Methylene tetrahydrofolate reductase (MTHFR) a key enzyme for catalyzing the formation of 5-MTHF, an essential co-factor in the conversion of homocysteine to methionine by the enzyme MS.


Fig. 1. Simplified folate metabolism pathways involved in methionine recycling, DNA synthesis, purine synthesis and methylation reactions. MET = methionine; hCYS = homocysteine
Fig. 1. Simplified folate metabolism pathways involved in methionine recycling, DNA synthesis, purine synthesis and methylation reactions. MET = methionine; hCYS = homocysteine
When cells lack folate, MTHFR cannot produce 5-MTHF and the conversion of homocysteine to methionine is impaired. This leads to high blood homocysteine levels and disturbed DNA synthesis and/or DNA methylation reactions. Disturbed DNA synthesis and methylation cause DNA mutations and altered gene expression, which can lead to birth defects and various cancers. Furthermore, folate deficiency causes anemia, a condition, which occurs when there is insufficient hemoglobin in red blood cells to carry enough oxygen to cells and tissues.


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