The eight B vitamins affect biological processes through interrelated roles and cooperative functions. Their participation as coenzymes further connects them to other vitamin and mineral cofactors. B vitamins are essential, water-soluble nutrients that function as substrates and co-enzymes in processes that:
- Break down and release energy from food
- Help form healthy red blood cells
- Regulate gene expression and DNA repair
- Support growth and nerve conduction
- Support skin and eye health
- Synthesize neurotransmitters, fatty acids, cholesterol, and ketones
Each of the B vitamins plays its own distinct role in these processes, but their complementary actions have led to their reference as the “B-Complex.” In addition to dietary sources, all of the B vitamins are synthesized by normal microorganisms in the large intestine.1 The bioavailability of bacterial sources is still being studied, but carrier-mediated mechanisms have been identified in the colon for B vitamins such as thiamin, riboflavin, pantothenic acid, vitamin B6, biotin, and folate.
Thiamin: Energy Production & Acetylcholine Synthesis
Vitamin B1 (thiamin) was the first of the B vitamins to be identified, thus its designation as “B1.” Upon entering the cell, thiamin is phosphorylated to its active form, thiamin pyrophosphate (TPP), where it then serves as a co-enzyme for three important reactions associated with energy production and the synthesis of nucleotides, amino acids, and fatty acids. Thiamin is also required for nerve conduction through both structural and functional means.
Structurally, it is found in various membranes of the neuron, and functionally it is required for the synthesis of acetylcholine, a neurotransmitter required for memory, cognition and muscle control. Magnesium is required for the conversion of thiamin to its active form and for many of thiamin’s coenzyme functions.1 Dietary thiamin is generally found in the phosphorylated form, which is de-phosphorylated prior to absorption.
Thiamin produced by microbes is absorbed in the colon, but the amount actually contributing to thiamin status is not clear.1 Thiamin absorption can be hindered by the enzyme thiaminase (found in sprouted seeds, beans, nuts, and raw fish) and by tannins (found in coffee, tea and wine). However, thiaminase can be inactivated by heat, and acidic food components such as ascorbic acid can diminish the inhibitory effect of tannins. Additionally, drinking tannin-containing products separately from meals will help maximize absorption.2
Prolonged deficiency of thiamin results in the disease known as beriberi, characterized by muscle weakness and/or paralysis, tingling in extremities, pain, mental confusion, rapid heartbeat, difficulty speaking, and involuntary eye movements. Though thiamin deficiency is assumed rare in Western culture, a diet high in unfortified, refined grains and processed foods or alcohol, and/or treatment with certain diuretics, anticonvulsants, or antiarrhythmics can lead to thiamin deficiency. Early symptoms of thiamin deficiency include short term memory loss, anorexia, and irritability. Cardiac and neurological symptoms ensue in longer term deficiency.
Riboflavin: Macronutrient Metabolism, Methylation, and Liver Detoxification
Vitamin B2 (riboflavin) is required for multiple metabolic reactions through its role as a component of the coenzymes flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). These coenzymes are electron carriers, important for the metabolism of macronutrients, by donating and accepting electrons involved in the electron transport chain of energy production. They also act as oxidation/reduction (redox) agents for the Cytochrome P450 enzyme system involved in phase I liver detoxification, and methylation reactions. FAD is also required to:
- Produce red blood cells,
- Convert tryptophan to niacin,
- Phosphorylate vitamin B6
- Reduce glutathione from its oxidized state
Dietary riboflavin is readily absorbed in the small intestine and is not inhibited by other food components. Riboflavin produced by microbes is absorbed, but the amount contributing to total riboflavin status is not known.1
Overt riboflavin deficiency is rare in the United States, but the elderly, alcoholics, and those who use birth control pills are at higher risk for deficiency. Certain medications (e.g. anticholinergics, anticonvulsants, phenothiazines, and phenytoin) will reduce absorbability of riboflavin, and riboflavin can interfere with some medications (e.g. tetracycline). Signs of riboflavin deficiency include fatigue and anemia, cracked, itching, or inflamed skin, hair loss, red and/or swollen tongue and throat, blurred vision, depression, and reproductive issues.
Niacin: ATP & Antioxidation
Vitamin B3 (niacin) is the generic term for the two forms of this B vitamin found in food – nicotinic acid and niacinamide (also known as nicotinamide). Besides being found in food, niacin can be synthesized from the amino acid tryptophan. The conversion requires 60 milligrams (mg) of tryptophan to produce one mg of niacin and is dependent upon the presence of riboflavin, vitamin B6, and iron.3 Niacin exists in two coenzyme forms:
- Nicotinamide adenine dinucleotide (NAD) – which can be reduced to NADH,
- Nicotinamide adenine dinucleotide phosphate (NADP) – which can be reduced to NADPH.
NAD and NADP are important for redox reactions, as they accept and donate electrons.4 As an acceptor of electrons (oxidizing agent), NAD is involved in catabolic reactions – primarily those involved in the breakdown of macronutrients to create cellular energy: ATP. As an electron donor, NADPH plays a role as part of the body’s total antioxidant system and acts as a coenzyme for many anabolic reactions including fatty acid synthesis, cholesterol synthesis, DNA synthesis and more. NAD is required for more than 400 total reactions, including non-redox reactions important in cell signaling pathways and genomic stability.4
Studies in the last two decades have revealed the important link between the availability of NAD and the activity of a class of enzymes involved in cell signaling, cellular homeostasis, and genetic repair: PARP enzymes and Sirtuin enzymes. These enzymes are NAD dependent and become more active as the levels of NAD increase inside the cell. NAD levels decrease with age, generally declining to half their youthful levels by middle age.5 Methods for increasing NAD levels are being studied for disease prevention and antiaging benefits.
Niacin is readily absorbed in the stomach and small intestine, but niacin that reaches the colon, or that is synthesized by the microbes, is generally retained by the cells of the colon. 1
Deficiency is rare in the United States, but over the long-term niacin deficiency may result in “pellagra,” which is characterized by the three Ds: diarrhea, dermatitis and dementia. Experimental models of cancer, cardiovascular disease, skin health, mental health, and oxidant lung injury have shown niacin supplementation to be beneficial and may point to under-recognized subclinical deficiencies.6
Pantothenic Acid: Coenzyme A & Catabolic Metabolism
Vitamin B5 (pantothenic acid) is required for the production of Coenzyme A (CoA), a mediary in the catabolic production of energy from carbohydrates, protein, and fat, and in its acetyl form, CoA is an important regulator of cell functions including mitosis, apoptosis, and autophagy.7 Coenzyme A is also required or the synthesis of fatty acids, sterols, ketones, and acetylcholine. Recent findings show CoA to be an important contributor to antioxidant defenses through a process known as “Protein CoAlation.” Protein CoAlation prevents oxidation of cellular proteins and helps regulate the activity of cellular enzymes.8
Pantothenic acid is absorbed via sodium-dependent multivitamin transporters (SMVT) present in both the small and large intestine. The pantothenic acid produced by gut microbes appears to contribute to total body need but it is not clear to what extent.1
Pantothenic acid deficiency
Deficiency symptoms are wide ranging due to the importance of CoA across multiple metabolic systems, but they have only been observed in experimental situations.9 A series of studies conducted in the 1950s found that two weeks of a diet free of pantothenic acid resulted in inability to sleep, abdominal discomfort, balance difficulties, and tingling and burning in the hands and feet.10
Vitamin B6: Amino Acid Metabolism
Vitamin B6 is the generic term for six forms of this B vitamin: pyridoxine, pyridoxal, pyridoxamine, and each of their respective phosphorylated forms. The coenzyme functions of B6 come from the phosphorylated esters: pyridoxal 5′ phosphate (PLP) and pyridoxamine 5′ phosphate (PMP). PMP is involved in over 100 enzymatic reactions of amino acid metabolism, including enzymes required for, but not limited to: 11
- The Krebs cycle
- Neurotransmitter synthesis
- Transsulfuration of homocysteine to cysteine
- The first step in heme synthesis
Approximately 75 percent of dietary B6 is absorbed, with bacterial sources contributing to nutritional needs, though the amount of contribution is not well defined. 1,11
Vitamin B6 deficiency
Traditionally, the observed signs of B6 deficiency include dermatitis, microcytic anemia, convulsions, depression, and confusion. Studies on different models of B6 depletion have shown deficiency to result in reduced levels of neurotransmitters, accumulation of tryptophan metabolites in the brain, abnormal electroencephalogram (EEG) patterns, and impaired platelet and clotting functions, possibly due to impaired conversion of homocysteine to cysteine.11
Biotin: Fatty Acid Synthesis
Vitamin B7 – Biotin – serves as a coenzyme for five carboxylase reactions required for: fatty acid synthesis, gluconeogenesis and the catabolism of specific amino acids and odd-chain fatty acids used for energy production.12 Evidence is also emerging for the role of biotin in gene expression, DNA repair, and genetic stability through biotinylating of histones.12
Dietary sources of biotin can be either:
- Protein bound: Must be released through the action of the enzyme biotinidase prior to absorption
- Free form: Efficiently absorbed via SMVTs
Absorption can be impaired by the consumption of a substance called avidin, which is found in raw egg whites. Avidin binds biotin, preventing absorption. Gut microbes also produce biotin, but the contribution to total body biotin status is unknown.
Signs of deficiency include hair loss, scaly red rash around eyes, nose, mouth and/or perineum, conjunctivitis seizures, skin infections, and neurological symptoms. However, overt deficiency has only been observed in those with genetic impairment of biotinidase activity, those who consume raw egg whites, and in cases of total parenteral nutrition (TPN) before biotin was recognized as essential.11 Sub-clinical biotin deficiency has been shown to cause birth defects in animal models and is being studied as a possible contributor to neural tube defects.12
Folate: DNA Synthesis & Amino Acid Metabolism
Vitamin B9 (folate) is the natural form of this B vitamin which is a carrier of one-carbon molecules (methyl groups) required for DNA synthesis and amino acid metabolism. Its role in the methylation cycle allows for the conversion of homocysteine to methionine – a step in the synthesis of s-adenosylmethionine (SAMe), the universal methyl donor. Folate is also required for the methylation reaction converting deoxyuridylate to thymidylate – a necessary step in the process of cell division. The role of folate in DNA synthesis and cell division necessitates higher intakes of this vitamin during phases of rapid cell growth such as early gestation. Deficiencies during this time have been associated with neural tube defects (NTD): malformations of the spine (spina bifida), skull, and/or brain (anencephaly).11
Dietary sources of folate are in the tetrahydrofolate (THF) form and are bound to one or more molecules of glutamate. The synthetic form of this vitamin is folic acid, found in fortified grains, cereals, and vitamin supplements. Naturally occurring folates are subject to degradation in the days and weeks following harvest, and their eventual absorption is limited by the availability and activity of enzymes involved in cleaving glutamate residues. Absorption is therefore diminished by 25 to 50 percent from levels in the original food source.11
Folic acid B vitamins are very stable and about 85 to 100 percent is absorbed.11 However, folic acid must be reduced to the THF form by the enzyme dihydrofolate reductase after absorption. The rate and efficiency of converting folic acid to THF is limited by the activity and availability of dihydrofolate reductase, which in cases of high levels of folic acid intake can result in unmetabolized folic acid (UMFA) in the circulation. The biological effects of unmetabolized folic acid are still being studied.13 Folate is produced by normal microflora in the gut and absorbed in the colon; however, the amount contributing to total nutritional needs is not clear.1
Once absorbed, THF receives a methyl group from the amino acid serine, forming 5, 10-methylenetetrahydrofolate which is then transformed to 5, methyltetrahydrofolate through action of the enzyme methylenetetrahydrofolate reductase (MTHFR). A genetic polymorphism in the gene encoding MTHFR can result in reduced levels of the 5-MTHF form of folate and resultant increases in homocysteine levels and neural tube defects.
Because of the varying levels of absorption between natural and synthetic forms of folate/folic acid B vitamins, intake requirements are expressed in dietary folate equivalents (DFE). Ever since the fortification of grain was mandated by the U.S. Food and Drug Administration (FDA) in January of 1998, deficiencies have been rare. Populations at risk include those with malabsorptive disorders, alcoholism, and poor diet. Megaloblastic anemia is the hallmark laboratory indicator of folate deficiency. Symptoms include large and reduced numbers of red blood cells, weakness, fatigue, difficulty concentrating, irritability, headache, heart palpitations, and shortness of breath.11
Vitamin B12: Neurological Processes, DNA Synthesis, and Red Blood Cell Formation
Vitamin B12 (cobalamin) is the collective name for a set of related compounds containing a central cobalt atom:
- Methylcobalamin (MeCbl)
- 5-deoxyadenosylcobalamin (AdoCbl)
- Hydroxycobalamin (HOCbl)
- Cyanocoabalamin (CNCbl)
All four forms are reduced to the core cobalamin molecule inside the cytosol before being converted to (or converted back to) the active coenzyme forms MeCbl and AdoCbl.14 MECbl and AdoCbl function as cofactors in the formation of red blood cells, DNA synthesis, and neurological processes. B12 is required for the synthesis of SAMe due to its action as a cofactor in the conversion of homocysteine to methionine. It is also a cofactor in fatty acid and amino acid metabolism.15
Vitamin B12 is found in animal protein and is produced by fermentation by gut bacteria; however, bacterial B12 is not absorbed. Before dietary B12 can be absorbed in the small intestine, it must be released from its food source through the action of hydrochloric acid and protease in the stomach. It also must combine with intrinsic factor, a glycoprotein secreted by the parietal cells of the stomach. 15
Vitamin B12 deficiency
Absorption is hindered in cases of low stomach acid associated with aging and acid blocking medications. The autoimmune disease pernicious anemia affects gastric secretions and results in a B12 deficiency, even when dietary intake is adequate. Intramuscular B12 injections and/or oral supplementation are required in these cases, as they bypass the need for gastric secretions and prevent the development of megaloblastic anemia and neurological symptoms such as dementia.16
Obtaining a full complement of nutrients from whole-food sources, limiting the consumption of interfering factors such as alcohol, caffeine, and tannins, and supplementing appropriately when necessary will ensure the best possible level of nutrients and their synergistic interactions for optimal enzymatic activity.