Consumption of a low-carbohydrate and high-fat diet (the ketogenic diet) exaggerates biotin deficiency in mice

Abstract

Objective

Biotin is a water-soluble vitamin that acts as a cofactor for several carboxylases. The ketogenic diet, a low-carbohydrate, high-fat diet, is used to treat drug-resistant epilepsy and promote weight loss. In Japan, the infant version of the ketogenic diet is known as the “ketone formula.” However, as the special infant formulas used in Japan, including the ketone formula, do not contain sufficient amounts of biotin, biotin deficiency can develop in infants who consume the ketone formula. Therefore, the aim of this study was to evaluate the effects of the ketogenic diet on biotin status in mice.

Methods

Male mice (N = 32) were divided into the following groups: control diet group, biotin-deficient (BD) diet group, ketogenic control diet group, and ketogenic biotin-deficient (KBD) diet group. Eight mice were used in each group.

Results

At 9 wk, the typical symptoms of biotin deficiency such as hair loss and dermatitis had only developed in the KBD diet group. The total protein expression level of biotin-dependent carboxylases and the total tissue biotin content were significantly decreased in the KBD and BD diet groups. However, these changes were more severe in the KBD diet group.

Conclusion

These findings demonstrated that the ketogenic diet increases biotin bioavailability and consumption, and hence, promotes energy production by gluconeogenesis and branched-chain amino acid metabolism, which results in exaggerated biotin deficiency in biotin-deficient mice. Therefore, biotin supplementation is important for mice that consume the ketogenic diet. It is suggested that individuals that consume the ketogenic diet have an increased biotin requirement.

Introduction

Biotin is a water-soluble vitamin that acts a cofactor for several of the carboxylases involved in fatty acid synthesis, gluconeogenesis, and branched-chain amino acid (BCAA) metabolism. Various biotin-dependent carboxylases such as β-methylcrotonyl-coenzyme A (CoA) carboxylase (MCC), propionyl-CoA carboxylase (PCC), pyruvate carboxylase (PC), and acetyl CoA carboxylase (ACC) are known to exist [1]. Biotin deficiency can be induced by consuming large amounts of raw egg white [2], [3] or anticonvulsants [4], [5] and also can be caused by congenital metabolic disorders (e.g., holocarboxylase synthetase deficiency [6] and biotinidase deficiency [7]). In humans, lymphocyte PCC activity is decreased by the consumption of raw egg white [8]. Moreover, the consumption of a biotin-deficient diet results in the increased urinary excretion of 3-hydroxyisovaleric acid (3-HIA) because of the inhibition of MCC, which is involved in leucine catabolism [9]. In experimental animals, biotin deficiency was demonstrated to induce teratogenic effects in mice [10], [11], [12] and decrease the total protein expression level of PC and PCC in the rat liver [13]. Biotin deficiency is characterized by dermatitis, hair loss, and neuropathy in humans and rodents. Biotin deficiency is very rare in humans because biotin is abundant in various foods [14], [15. However, as biotin is not registered as a food additive in Japan, the biotin content of special infant formulas is not sufficient to maintain normal growth and development. Thus, biotin deficiency often develops in infants who are taking special infant formulas in Japan [16], [17], and hence, Japanese infant formulas should be supplemented with biotin.

Low-carbohydrate, high-fat diets are used for the treatment of drug-resistant epilepsy or to promote weight loss [18]. In adult cases of drug-resistant epilepsy, the ketogenic diet is prescribed [19]. In Japan, the version of this diet given to infants with drug-resistant epilepsy is called the ketone formula. However, we determined that the biotin content of the ketone formula is 0.07 μg/100 kcal (unpublished data, Masahiro Yuasa, M.Y.), which is lower than the recommended dietary amount (1.50 μg/100 kcal) outlined by the Food and Agriculture Organization of the United Nations/World Health Organization (FAO/WHO). Thus, infants who consume the ketone formula are expected to suffer from biotin deficiency. Therefore, this study was conducted to evaluate the effects of the ketogenic diet on biotin status in mice.