- Water-soluble biotin is an essential cofactor to enzymes in intermediary metabolism and a key regulator of gene expression. (More information)
- Both parenteral nutrition devoid of biotin and prolonged consumption of raw egg white have been associated with symptoms of frank biotin deficiency, including hair loss, dermatitis, and skin rash, ataxia, seizures, and other neurologic dysfunctions. (More information)
- Biotinidase deficiency is a rare hereditary disorder that impairs biotin absorption and recycling, resulting in secondary biotin deficiency. (More information)
- The recommended adequate intake (AI) of biotin is set at 30 micrograms (mcg)/day in adults. Biotin requirements are likely increased during pregnancy and breast-feeding. (More information)
- Animal studies have shown that biotin sufficiency is essential for normal fetal development. Whether marginal biotin deficiency during pregnancy increases the risk for congenital anomalies in humans is currently an area of concern and investigation. (More information)
- Biotin is used in the treatment of an inherited disorder of thiamin transport, called biotin-responsive basal ganglia disease, and is currently being tested in trials to limit or reverse functional disabilities in individuals with multiple sclerosis. (More information)
- Definitive evidence that establishes whether biotin supplementation improves glucose and lipid homeostasis in individuals with type 2 diabetes mellitus is currently lacking, but suggestive observations have been published. (More information)
- Biotin cannot be synthesized by mammalian cells and must be obtained from exogenous sources. Biotin is widely found in food, and good dietary sources include egg yolk, liver, whole-grain cereal, and some vegetables. (More information)
- Long-term anticonvulsant (anti-seizure) therapy may increase the dietary requirement for biotin because anticonvulsants can interfere with the intestinal absorption and renal re-absorption of biotin and likely also increase degradation of biotin to inactive metabolites. (More information)
Biotin is a water-soluble vitamin that is generally classified as a B-complex vitamin. After its initial discovery in 1927, 40 years of additional research was required to unequivocally establish biotin as a vitamin (1). Biotin is required by all organisms but can be synthesized by some strains of bacteria, yeast, mold, algae, and some plant species (2).
Biotin functions as a covalently bound cofactor required for the biological activity of the five known mammalian biotin-dependent carboxylases (see below). Such a non-protein cofactor is known as a "prosthetic group." The covalent attachment of biotin to the apocarboxylase (i.e., catalytically inactive carboxylase) is catalyzed by the enzyme, holocarboxylase synthetase (HCS). The term "biotinylation" refers to the covalent addition of biotin to any molecules, including apocarboxylases and histones. HCS catalyzes the post-translational biotinylation of the epsilon amino group of a lysine residue at the active site of each apocarboxylase, converting the inactive apocarboxylase into a fully active holocarboxylase (Figure 1a). Particular lysine residues within the N-terminal tail of specific histones, which help package DNA in eukaryotic nuclei, can also be biotinylated (3). Biotinidase is the enzyme that catalyzes the release of biotin from biotinylated histones and from the peptide products of holocarboxylase breakdown (Figure 1b).
Five mammalian carboxylases that catalyze essential metabolic reactions:
• Both acetyl-Coenzyme A (CoA) carboxylase 1 (ACC1) and acetyl-CoA carboxylase 2 (ACC2) catalyze the conversion of acetyl-CoA to malonyl-CoA using bicarbonate and ATP; malonyl CoA generated via ACC1 is a rate-limiting substrate for the synthesis of fatty acids in the cytosol, and malonyl CoA generated via ACC2 inhibits CPT1, an outer mitochondrial membrane enzyme important in fatty acid oxidation (Figure 2). ACC1 is found in all tissues and is particularly active in lipogenic tissues (i.e., liver, white adipose tissue, and mammary gland), heart, and pancreatic islets. ACC2 is especially abundant in skeletal muscle and heart (4).
• Pyruvate carboxylase is a critical enzyme in gluconeogenesis — the formation of glucose from sources other than carbohydrates, such as pyruvate, lactate, glycerol, and the glucogenic amino acids. Pyruvate carboxylase catalyzes the ATP-dependent incorporation of bicarbonate into pyruvate, producing oxaloacetate; hence, pyruvate carboxylase is anaplerotic for the citric acid cycle (Figure 3). Oxaloacetate can then be converted to phosphoenolpyruvate and eventually to glucose.
• Methylcrotonyl-CoA carboxylase catalyzes an essential step in the catabolism of leucine, an essential branched-chain amino acid. This biotin-containing enzyme catalyzes the production of 3-methylglutaconyl-CoA from methylcrotonyl-CoA (Figure 4a).
• Propionyl-CoA carboxylase produces D-malonylmalonyl-CoA from propionyl-CoA, a by-product in the β-oxidation of fatty acids with an odd number of carbon atoms (Figure 4a). The conversion of propionyl-CoA to D-malonylmalonyl-CoA is also required in the catabolic pathways of two branched-chain amino acids (isoleucine and valine), methionine, threonine, and the side chain of cholesterol (Figure 4a and 4b).
Regulation of chromatin structure and gene expression
In eukaryotic nuclei, DNA is packaged into compact structures to form nucleosomes — fundamental units of chromatin. Each nucleosome is composed of 147 base pairs of DNA wrapped around eight histones (paired histones: H2A, H2B, H3, and H4). Another histone, called H1 linker, is located at the outer surface of each nucleosome and serves as an anchor to fix the DNA around the histone core. The compact packaging of chromatin must be relaxed from time to time to allow biological processes, such as DNA replication and transcription to occur. Chemical modifications of DNA and histones affect the folding of chromatin, increasing or reducing DNA accessibility to factors involved in the above-mentioned processes. Together with DNA methylation, a number of chemical modifications within the N-terminal tail of core histones modify their electric charge and structure, thereby changing chromatin conformation and transcriptional activity of genes.
The various modifications of histone tails, including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, carbonylation, deimination, hydroxylation, and biotinylation, have different regulatory functions. Several sites of biotinylation have been identified in histones H2A, H3, and H4 (5). Amongst them, histone H4 biotinylation at lysine (K) 12 (noted H4K12bio) appears to be enriched in heterochromatin, a tightly condensed chromatin associated with repeat regions in (peri)centromeres and telomeres, and with transposable elements known as long terminal repeats (3). In addition, biotinylation marks co-localize with well-known gene repression marks like methylated lysine 9 in histone H3 (H3K9me) in transcriptionally competent chromatin (6). For example, H4K12bio can be found at the promoter of the gene SLC5A6 that codes for the transporter mediating biotin uptake into cells, the human sodium-dependent multivitamin transporter (hSMVT). When biotin is abundant, HCS can biotinylate histones H4 in the SLC5A6 promoter, which halts hSMVT synthesis and reduces biotin uptake. Conversely, in biotin-deficient cells, biotinylation marks in the SLC5A6 promoter are removed such that gene expression can occur, enabling the synthesis of hSMVT and subsequently increasing the uptake of biotin (7).
Although overt biotin deficiency is very rare, the human requirement for dietary biotin has been demonstrated in three different situations: prolonged intravenous feeding (parenteral) without biotin supplementation, infants fed an elemental formula devoid of biotin, and consumption of raw egg white for a prolonged period (many weeks to years) (8). Raw egg white contains an antimicrobial protein known as avidin that can bind biotin and prevent its absorption. Cooking egg white denatures avidin, rendering it susceptible to digestion and therefore unable to prevent the absorption of dietary biotin (5).
Signs and symptoms of biotin deficiency
Signs of overt biotin deficiency include hair loss (alopecia) and a scaly red rash around the eyes, nose, mouth, and genital area. Neurologic symptoms in adults have included depression, lethargy, hallucinations, numbness and tingling of the extremities, ataxia, and seizures. The characteristic facial rash, together with unusual facial fat distribution, has been termed the "biotin deficient facies" by some investigators (1). Individuals with hereditary disorders of biotin metabolism (see Inborn metabolic disorders) resulting in functional biotin deficiency often have similar physical findings, as well as seizures and evidence of impaired immune system function and increased susceptibility to bacterial and fungal infections (9, 10).
Risk factors for biotin deficiency
Aside from prolonged consumption of raw egg white or total intravenous nutritional support lacking biotin, other conditions may increase the risk of biotin depletion. Smoking has been associated with increased biotin catabolism (11). The rapidly dividing cells of the developing fetus require biotin for synthesis of essential carboxylases and histone biotinylation; hence, the biotin requirement is likely increased during pregnancy. Research suggests that a substantial number of women develop marginal or subclinical biotin deficiency during normal pregnancy (see also Disease Prevention) (8, 12, 13). Additionally, certain types of liver disease may decrease biotinidase activity and theoretically increase the requirement for biotin. A study of 62 children with chronic liver disease and 27 healthy controls found serum biotinidase activity to be abnormally low in those with severely impaired liver function due to cirrhosis (14). However, this study did not provide evidence of biotin deficiency. Further, anticonvulsant medications, used to prevent seizures in individuals with epilepsy, increase the risk of biotin depletion (for more information on biotin and anticonvulsants, see Drug interactions).
Inborn metabolic disorders
There are several ways in which the hereditary disorder, biotinidase deficiency, leads to secondary biotin deficiency. Intestinal absorption is decreased because a lack of biotinidase prevents the release of biotin from dietary protein (15). Recycling of one's own biotin bound to carboxylases and histones is also impaired, and urinary loss of biocytin (N-biotinyl-lysine) and biotin is increased (see Figure 1 above) (5). Biotinidase deficiency uniformly responds to supplemental biotin. Oral supplementation with as much as 5 to 10 milligrams (mg) of biotin daily is sometimes required, although smaller doses are often sufficient (reviewed in 16).
Holocarboxylase synthetase (HCS) deficiency
Some forms of HCS deficiency respond to supplementation with pharmacologic doses of biotin. HCS deficiency results in decreased formation of all holocarboxylases at physiological blood biotin concentrations; thus, high-dose biotin supplementation (10-80 mg of biotin daily) is required (10).
The prognosis of these two disorders is usually good if biotin therapy is introduced early (infancy or childhood) and continued for life (10).
Biotin transport deficiency
There has been one case report of a child with biotin transport deficiency who responded to high-dose biotin supplementation (17). Of note, the presence of a defective human sodium-dependent multivitamin transporter (hSMVT) was ruled out as a cause of biotin transport deficiency.
Abnormally elevated concentrations of the amino acid, phenylalanine, in the blood of PKU-affected individuals may inhibit the activity of biotinidase. Schulpis et al. speculated that the seborrheic dermatitis associated with low biotinidase activity in these patients would resolve upon compliance with a special low-protein diet but not with biotin supplementation (18).
Markers of biotin status
Four measures of marginal biotin deficiency have been validated as indicators of biotin status: (1) reduced urinary excretion of biotin and some of its catabolites; (2) high urinary excretion of an organic acid, 3-hydroxyisovaleric acid, and its derivative, carnityl-3-hydroxyisovaleric acid, both of which reflect decreased activity of biotin-dependent methylcrotonyl-CoA carboxylase; (3) reduced propionyl-CoA carboxylase activity in peripheral blood lymphocytes (5); and (4) reduced levels of holo-methylcrotonyl-CoA carboxylase and holo-propionyl-CoA carboxylase in lymphocytes — the most reliable indicators of biotin status (19). These markers have been only validated in men and nonpregnant women, and they may not accurately reflect biotin status in pregnant and breast-feeding women (12).
The Adequate Intake (AI)
Sufficient scientific evidence is lacking to estimate the dietary requirement for biotin; thus, no Recommended Dietary Allowance (RDA) for biotin has been established. Instead, the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) set recommendations for an Adequate Intake (AI; Table 1). The AI for adults (30 micrograms [mcg]/day) was extrapolated from the AI for infants exclusively fed human milk and is expected to overestimate the dietary requirement for biotin in adults. Dietary intakes of generally healthy adults have been estimated to be 40-60 mcg/day of biotin (1). The requirement for biotin in pregnancy may be increased (20).
Table 1. Adequate Intake (AI) for Biotin
||19 years and older
Current research indicates that at least one-third of women develop marginal biotin deficiency during pregnancy (8). Small observational studies in pregnant women have reported an abnormally high urinary excretion of 3-hydroxyisovaleric acid in both early and late pregnancy, suggesting decreased activity of biotin-dependent methylcrotonyl-CoA carboxylase (21, 22). In a randomized, single-blinded intervention study in 26 pregnant women, supplementation with 300 mcg/day of biotin for two weeks limited the excretion of 3-hydroxyisovaleric acid compared to placebo, confirming that increased 3-hydroxyisovaleric acid excretion indeed reflected marginal biotin deficiency in pregnancy (23). A small cross-sectional study in 22 pregnant women reported an incidence of low lymphocyte propionyl-CoA carboxylase activity (another marker of biotin deficiency) greater than 80% (13). Although the level of biotin deficiency is not associated with overt signs of deficiency in pregnant women, such observations are sources of concern because subclinical biotin deficiency has been shown to cause cleft palate and limb hypoplasia in several animal species (reviewed in 13). In addition, biotin depletion has been found to suppress the expression of biotin-dependent carboxylases, remove biotin marks from histones, and decrease the proliferation in human embryonic palatal mesenchymal cells in culture (24). Impaired carboxylase activity may result in alterations in lipid metabolism, which have been linked to cleft palate and skeletal abnormalities in animals. Further, biotin deficiency leading to reduced histone biotinylation at specific genomic loci may increase genomic instability and result in chromosome anomalies and fetal malformations (13).
While pregnant women are advised to consume supplemental folic acid prior to and during pregnancy to prevent neural tube defects (see Folate), it would also be prudent to ensure adequate biotin intake throughout pregnancy. The current AI for pregnant women is 30 mcg/day of biotin, and no toxicity has ever been reported at this level of intake (see Safety).
Biotin-responsive basal ganglia disease
Biotin-responsive basal ganglia disease, also called thiamin metabolism dysfunction syndrome-2, is caused by mutations in the gene coding for thiamin transporter-2 (THTR-2). The clinical features appear around three to four years of age and include sub-acute encephalopathy (confusion, drowsiness, and altered level of consciousness), ataxia, and seizures. A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia was recently conducted. The data showed that biotin monotherapy (5-10 mg/kg/day) efficiently abolished the clinical manifestations of the disease, although one-third of the patients suffered from recurrent acute crises. Often associated with poor outcomes, acute crises were not observed after thiamin supplementation started (300-400 mg/day) and during a five-year follow-up period. Early diagnostic and immediate treatment with biotin and thiamin led to positive outcomes (25). The mechanism for the beneficial effect of biotin supplementation has yet to be elucidated.
Multiple sclerosis (MS) is an autoimmune disease characterized by progressive damages to the myelin sheath surrounding nerve fibers (axons) and neuronal loss in the brain and spinal cord of affected individuals. The progression of neurologic disabilities in MS patients is often assessed by the Expanded Disability Status Scale (EDSS) with scores from 1 to 10, from minimal signs of motor dysfunction (score of 1) to death by MS (score of 10). ATP deficiency due to mitochondrial dysfunction and increased oxidative stress may be partly responsible for the progressive degeneration of neurons in MS (26). Given its role in intermediary metabolism and fatty acid synthesis (required for myelin formation) (see Function), it has been hypothesized that biotin might exert beneficial effects that would limit or reverse MS-associated functional impairments (26).
A nonrandomized, uncontrolled pilot study in 23 patients with progressive MS found high doses of biotin (100-600 mg/day) to be associated with sustained clinical improvements in 5 (out of 5) patients with progressive visual loss and 16 (out of 18) patients with partial paralysis of the limbs after a mean three months following treatment onset (27). In addition, the preliminary results from a multicenter, randomized, placebo-controlled trial in 154 subjects with progressive MS indicated that 13 out of 103 patients randomized to receive daily oral biotin (300 mg) for 48 weeks achieved a composite functional endpoint that included a decrease in EDSS scores. In comparison, none of the 51 patients randomized to the placebo group showed significant clinical improvements (28). Two ongoing trials are evaluating the effect of high-dose biotin supplementation in the treatment of MS (see trials NCT02220933 and NCT02220244 at www.clinicaltrials.gov).
Overt biotin deficiency has been shown to impair glucose utilization in mice (29) and cause fatal hypoglycemia in chickens. Overt biotin deficiency likely also causes abnormalities in glucose regulation in humans (see Function). One early human study reported lower serum biotin concentrations in 43 patients with type 2 diabetes mellitus compared to 64 non-diabetic control subjects, as well as an inverse relationship between fasting blood glucose and biotin concentrations (30). In a small, randomized, placebo-controlled intervention study in 28 patients with type 2 diabetes, daily supplementation with 9 milligrams (mg) of biotin for one month resulted in a mean 45% decrease in fasting blood glucose concentrations (30). Yet, another small study in 10 patients with type 2 diabetes and 7 nondiabetic controls found no effect of biotin supplementation (15 mg/day) for 28 days on fasting blood glucose concentrations in either group (31). A more recent double-blind, placebo-controlled study by the same research group showed that the same biotin regimen lowered plasma triglyceride concentrations in both diabetic and nondiabetic patients with hypertriglyceridemia (32). In this study, biotin administration did not affect blood glucose concentrations in either patient group. Additionally, a few studies have shown that co-supplementation with biotin and chromium picolinate may be a beneficial adjunct therapy in patients with type 2 diabetes (33-36). However, administration of chromium picolinate alone has been shown to improve glycemic control in diabetic subjects (see the article on Chromium) (37).
As a cofactor of carboxylases required for fatty acid synthesis, biotin may increase the utilization of glucose for fat synthesis. Biotin has been found to stimulate glucokinase, a liver enzyme that increases synthesis of glycogen, the storage form of glucose. Biotin also appeared to trigger the secretion of insulin in the pancreas of rats and improve glucose homeostasis (38). Yet, reduced activity of ACC1 and ACC2 would be expected to reduce fatty acid synthesis and increase fatty acid oxidation, respectively. Not surprisingly, it is currently unclear whether pharmacologic doses of biotin could benefit the management of hyperglycemia in patients with impaired glucose tolerance. Moreover, whether supplemental biotin lowers the risk of cardiovascular complications in diabetic patients by reducing serum triglycerides and LDL-cholesterol remains to be proven (32-34).
Brittle fingernails (onychorrhexis)
The finding that biotin supplements were effective in treating hoof abnormalities in hoofed animals suggested that biotin might also be helpful in strengthening brittle fingernails in humans (39-41). Three uncontrolled trials examining the effects of biotin supplementation (2.5 mg/day for several months) in women with brittle fingernails have been published (42-44). In two of the trials, subjective evidence of clinical improvement was reported in 67%-91% of the participants available for follow-up at the end of the treatment period (42, 43). One trial that used scanning electron microscopy to assess fingernail brittleness reported less fingernail splitting and a 25% increase in the thickness of the nail plate in patients supplemented with biotin for 6 to 15 months (44). Biotin supplementation (5 mg/day) was also found to be effective in controlling unruly hair and splitting nails in two toddlers with inherited uncombable hair syndrome (45). Although preliminary evidence suggests that supplemental biotin may help strengthen fragile nails, larger placebo-controlled trials are needed to assess the efficacy of high-dose biotin supplementation for the treatment of brittle fingernails.
Hair loss (alopecia)
Biotin administration was found to reverse alopecia in children treated with the anticonvulsant, valproic acid (see Drug interactions). Yet, although hair loss is a symptom of severe biotin deficiency (see Deficiency), there are no published scientific studies that support the claim that high-dose biotin supplements are effective in preventing or treating hair loss in men or women (46).
Biotin is found in many foods, either as the free form that is directly taken up by enterocytes or as biotin bound to dietary proteins. Egg yolk, liver, and yeast are rich sources of biotin. Estimates of average daily intakes of biotin from small studies ranged between 40 and 60 micrograms (mcg) per day in adults (1). However, US national nutritional surveys have not yet been able to estimate biotin intake due to the scarcity and unreliability of data regarding biotin content of food. Food composition tables for biotin are incomplete such that dietary intakes cannot be reliably estimated in humans. A study by Staggs et al. (47) employed a high-performance liquid chromatography method rather than bioassays (48) and reported relatively different biotin content for some selected foods. Table 2 lists some food sources of biotin, along with their content in mcg.
Table 2. Some Food Sources of Biotin (47, 48)
||1 packet (7 grams)
|*A three-ounce serving of meat is about the size of a deck of cards.
A majority of bacteria that normally colonize the small and large intestine (colon) synthesize biotin (49). Whether the biotin is released and absorbed by humans in meaningful amounts remains unknown. The uptake of free biotin into intestinal cells via the human sodium-dependent multivitamin transporter (hSMVT) has been identified in cultured cells derived from the lining of the small intestine and colon (50), suggesting that humans may be able to absorb biotin produced by enteric bacteria — a phenomenon documented in swine.
Biotin is available as a single-nutrient supplement in various doses and is often included in B-complex and multivitamin-mineral (MVM) supplements. Many MVM supplements contain 30 mcg of biotin (51).
Biotin is not known to be toxic. In people without disorders of biotin metabolism, doses of up to 5 mg/day for two years were not associated with adverse effects (52). Oral biotin supplementation has been well tolerated in doses up to 200 mg/day (nearly 7,000 times the AI) in people with hereditary disorders of biotin metabolism (1). Daily supplementation with a highly concentrated formulation of biotin (100-600 mg) for several months was also found to be well tolerated in individuals with progressive multiple sclerosis (27, 28). However, there is one case report of life-threatening eosinophilic pleuropericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid (vitamin B5) for two months (53). Because reports of adverse events were lacking when the Dietary Reference Intakes (DRI) for biotin were established in 1998, the Institute of Medicine did not establish a tolerable upper intake level (UL) for biotin (1).
Large doses of pantothenic acid (vitamin B5) have the potential to compete with biotin for intestinal and cellular uptake by the human sodium-dependent multivitamin transporter (hSMVT) (54, 55). Biotin also shares the hSMVT with α-lipoic acid (56). Pharmacologic (very high) doses of α-lipoic acid have been found to decrease the activity of biotin-dependent carboxylases in rats, but such an effect has not been demonstrated in humans (57).
Individuals on long-term anticonvulsant (anti-seizure) therapy reportedly have reduced blood biotin concentrations, as well as an increased urinary excretion of organic acids (e.g., 3-hydroxyisovaleric acid) that indicate decreased carboxylase activity (see Markers of biotin status) (5). Potential mechanisms of biotin depletion by the anticonvulsants, primidone (Mysoline), phenytoin (Dilantin), and carbamazepine (Carbatrol, Tegretol), include inhibition of biotin intestinal absorption and renal reabsorption, as well as increased biotin catabolism (51). Use of the anticonvulsant valproic acid in children has resulted in hair loss reversed by biotin supplementation (58-61). Long-term treatment with antibacterial sulfonamide (sulfa) drugs or other antibiotics may decrease bacterial synthesis of biotin. Yet, given that the extent to which bacterial synthesis contributes to biotin intake in humans is not known, effects of antimicrobial drugs on biotin nutritional status remain uncertain (51).
Linus Pauling Institute Recommendation
Little is known regarding the amount of dietary biotin required to promote optimal health or prevent chronic disease. The Linus Pauling Institute supports the recommendation made by the Institute of Medicine, which is 30 micrograms (mcg) of biotin per day for adults. A varied diet should provide enough biotin for most people. However, following the Linus Pauling Institute recommendation to take a daily multivitamin-mineral supplement will generally provide an intake of at least 30 mcg/day of biotin.
Older adults (>50 years)
Presently, there is no indication that older adults have an increased requirement for biotin. If dietary biotin intake is not sufficient, a daily multivitamin-mineral supplement will generally provide an intake of at least 30 mcg of biotin per day.
Authors and Reviewers
Originally written in 2000 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in June 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in August 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in July 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in September 2015 by:
Donald Mock, M.D., Ph.D.
Departments of Biochemistry and Molecular Biology and Pediatrics
University of Arkansas for Medical Sciences
Copyright 2000-2015 Linus Pauling Institute
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