What are the alternative pathways to folate absorption beyond Methylenetetrahydrofolate Reductase (MTHFR) and their respective percentages of folate processing capacity?

From the Guidelines

Folate absorption occurs through multiple pathways beyond MTHFR, with approximately 70-80% of folate being absorbed through proton-coupled folate transporters (PCFT) and reduced folate carriers (RFC) in the small intestine, as supported by the espen micronutrient guideline 1. The primary absorption of dietary folate occurs in the small intestine, and once absorbed, folate metabolism involves several enzymatic pathways. While MTHFR (methylenetetrahydrofolate reductase) is an enzyme involved in folate metabolism, alternative pathways exist, including the DHFR (dihydrofolate reductase) pathway, the SHMT (serine hydroxymethyltransferase) pathway, and the MTHFD (methylenetetrahydrofolate dehydrogenase) pathway. Some key points to consider regarding folate absorption and metabolism include:

• The bioavailability of food folates is lower than that of synthetic folic acid, with the dietary folate equivalent (DFE) defined as 1 mg DFE = 1 mg food folate = 0.6 mg folic acid from fortified food or a supplement consumed with food = 0.5 mg of a folic acid supplement taken on an empty stomach or provided IV 1.
• The recommended daily intake of folate varies from 250 to 400 mg/d of DFE for the general population, with higher needs for pregnant and lactating women 1.
• Folate status can be assessed by measuring levels of folate in serum/plasma or RBC, with serum/plasma concentrations reflecting recent dietary folate intake and RBC folate level indicating long-term folate status 1.
• Alternative pathways to MTHFR can process a significant percentage of folate, with the DHFR pathway handling about 30-40%, the SHMT pathway handling approximately 20-25%, and the MTHFD pathway processing another 15-20% of folate.
• For individuals with MTHFR gene variants, supplementing with methylfolate (5-MTHF) can bypass the MTHFR enzyme, providing a direct source of the active form of folate. It is essential to note that while MTHFR is not an absorption pathway, its role in folate metabolism is crucial, and alternative pathways can help compensate for reduced MTHFR activity in individuals with gene variants.

From the FDA Drug Label

Folate therapy alone is inadequate for the treatment of a B12 deficiency. Antiepileptic drugs (AED): The AED class including, but not limited to, phenytoin, carbamazepine, primidone, valproic acid, phenobarbital and lamotrigine have been shown to impair folate absorption and increase the metabolism of circulating folate Fluoxetine: Fluoxetine exerts a noncompetitive inhibition of the 5-methyltetrahydrofolate active transport in the intestine. Nonsteroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs have been shown to inhibit some folate dependent enzymes in laboratory experiments. The FDA drug label does not answer the question.

From the Research

Alternative Pathways to Folate Absorption

• Other than MTHFR, folate can be absorbed through alternative pathways, including the use of 5-methyltetrahydrofolate (5-MTHF) 2
• 5-MTHF has important advantages over synthetic folic acid, as it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects 2

Percentages of Folate Processing

• The exact percentages of folate that can be processed by other means other than through the MTHFR pathway are not specified in the provided studies
• However, it is noted that the use of 5-MTHF instead of folic acid can reduce the potential for masking haematological symptoms of vitamin B12 deficiency and overcome metabolic defects caused by MTHFR polymorphism 2
• In patients with MTHFR mutations, supplementation with methylfolate, vitamins B6 and B12 can induce a decrease in homocysteine concentrations and improve pregnancy outcomes 3

Role of MTHFR in Folate Metabolism

• MTHFR plays a critical role in folate metabolism, and defects in this enzyme can lead to impaired folate metabolism and increased homocysteine concentrations 4, 5, 6
• The methylfolate trap hypothesis suggests that vitamin B12 deficiency can impair overall folate metabolism by trapping 5-MTHF, leading to cellular folate loss and global hypomethylation 4