nutrients Review Histidine: A Systematic Review on Metabolism and Physiological Effects in Human and Different Animal Species Joanna Moro 1, Daniel Tomé 1, Philippe Schmidely 2, Tristan-Chalvon Demersay 3 and Dalila Azzout-Marniche 1,* 1 AgroParisTech, Université Paris-Saclay, INRAE, UMR PNCA, 75005 Paris, France; [email protected] (J.M.); [email protected] (D.T.) 2 AgroParisTech, Université Paris-Saclay, INRAE, UMR0791 Mosar, 75005 Paris, France; [email protected] 3 Ajinomoto Animal Nutrition Europe, 75017 Paris, France; [email protected] * Correspondence: [email protected]; Tel.: +33-1-44087244 Received: 1 April 2020; Accepted: 8 May 2020; Published: 14 May 2020 Abstract: Histidine is an essential amino acid (EAA) in mammals, fish, and poultry. We aim to give an overview of the metabolism and physiological effects of histidine in humans and different animal species through a systematic review following the guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). In humans, dietary histidine may be associated with factors that improve metabolic syndrome and has an effect on ion absorption. In rats, histidine supplementation increases food intake. It also provides neuroprotection at an early stage and could protect against epileptic seizures. In chickens, histidine is particularly important as a limiting factor for carnosine synthesis, which has strong anti-oxidant effects. In fish, dietary histidine may be one of the most important factors in preventing cataracts. In ruminants, histidine is a limiting factor for milk protein synthesis and could be the first limiting AA for growth. In excess, histidine supplementation can be responsible for eating and memory disorders in humans and can induce growth retardation and metabolic dysfunction in most species. To conclude, the requirements for histidine, like for other EAA, have been derived from growth and AA composition in tissues and also have specific metabolic roles depending on species and dietary levels. Keywords: histidine; metabolism; physiological effects; human; animal species 1. Introduction Histidine is an essential amino acid in mammals, fish and poultry because it is not de novo synthesized and must be obtained through the diet [1,2]. In these organisms, histidine deficiency induces a decrease in body weight. Moreover, nitrogen balances cannot be maintained with a histidine-devoid diet. In the study by Kriengsinyos et al. [3], it has been shown that histidine deficiency may not affect nitrogen balance if the total protein intake is higher than the current recommendation (0.75 g/kg). However, histidine deficiency induces a decrease in AA oxidation and a decrease in protein turnover. Taking into account these other parameters of protein metabolism, histidine is considered as an indispensable AA in healthy adults. Some studies have also reported the indispensability of histidine for ruminants [4]. Histidine is abundant in red meat and fish, but its content varies among fish species, from histidine-rich fish (dark muscle fish) to histidine-poor fish (white muscle fish). Histidine is present in the body of different species in different forms, including free L-histidine, N (alpha)-acetylhistidine (NAH), histidine-containing protein, and histidine-containing dipeptides such as carnosine and anserine (HRC). Nutrients 2020, 12, 1414; doi:10.3390/nu12051414 www.mdpi.com/journal/nutrients Nutrients 2020, 12, 1414 2 of 20 Depending on the species, the requirements and toxicity of histidine differ, as does its effect on metabolism. Therefore, our aim is to present a systematic review following the guidelines of PRISMA [5] (methodology in Supplementary Material, Table S1) of the metabolic and physiological effects of histidine in humans and different animal species. The scope of this review is to compare histidine supplementation on different species, the effect of histidine supplementation on the metabolism, and to analyze the requirement and toxicity for each species. Firstly, common physiological roles of histidine in different species are described, and then, a species-by-species description is made for humans, rodents, pigs, chickens, fish, and ruminants. 2. Common Physiological Roles of Histidine in Different Species 2.1. Histidine Requirements and Metabolism Histidine requirements are expressed differently among species. For humans, histidine requirements are expressed as daily intake per kilogram body weight. For other species, lysine is frequently used as the reference AA, being known as the first limiting AA. Hence, the requirement patterns for other AAs, including histidine, are expressed in ratio to lysine requirements. According to the Food and Agriculture Organization of the United Nations (FAO), the histidine ratio (percent histidine/lysine) varies: 36 for pigs (20 to 50 kg), 32 for chicks (0 to 3 wk), 36 for rats, 33 for salmonids, 39 for trout, 37 for common carp and 34 for tilapia. Histidine undergoes different metabolic pathways (Figure1). It can be methylated to either 1-methyl or 3-methyl histidine, or converted to imidazole-pyruvic acid by transaminase, which produces imidazole-lactic acid by reduction. Transaminase activity is elevated in fetal rat livers and decreases after birth. Its activity can be modulated by diet: it increases when diet protein content is above 25%, whereas it is not modified below 25%. Histidine can be condensed with β-alanine to form carnosine and anserine, which are involved in protection against oxidative stress [6]. It can also be condensed with decarboxylation to form histamine, or it can undergo irreversible degradation. An irreversible, non-oxidative deamination leads to the formation of trans-urocanic acid and ammonia by the histidine ammonia-lyase, also called histidase, which is a cytoplasmic enzyme [6]. To do this, the α-amino group of L-histidine is removed [7]. This is the primary step in histidine degradation that has been studied in mammals and bacteria. Urocanic acid has a protective role against harmful effects of ultraviolet rays on the skin. It is metabolized in the liver to 4, 5-dihydri-4-oxo-5-imidazolepropanoic acid by urocanate hydratase, and is then converted to formimino-glutamate (FIGLU) and N5-formimino-tetrahydro-folate. In epiderma, urocanate hydratase is not present, and urocanic acid is the last compound of histidine catabolism. This compound accumulates in the epidermis and acts as a natural sunscreen that protects the skin from the effects of UV light [8,9]. Histidase, located only in the liver and epidermis, is the rate-limiting enzyme of histidine degradation [10]. Its activity is very low in the fetal liver and increases progressively during the first three weeks after birth [11]. Some cases of histidase deficiency have been described. In this context, the main step in histidine catabolism is transamination with the accumulation of imidazole-pyruvate, imidazole-lactate and imidazole-acetate [11]. Gene expression of histidase can be modulated by diet. High protein diets or amino acid-imbalanced diets stimulate its expression [12]. Histidase activity increases proportionally to the increase of protein content in the diet. Rats fed histidine-imbalanced diets have shown a lower food intake and weight gain with a higher histidase gene expression [12]. In the case of undernutrition, there is a decrease in histidase activity and histidase mRNA abundance in the liver. This decrease seems to prevent histidine catabolism [13]. It was also shown that in rats on a low protein diet, a load of histidine induced a lower histidine oxidation compared to rats on an adequate diet [14]. Lastly, some studies have shown that histidase can be controlled by estrogen. In female rats, the activity of this enzyme is down-regulated upon ovariectomy [15]. Nutrients 2020Nutrients, 12, 1414 2020, 12, x FOR PEER REVIEW 3 of 20 3 of 20 regulated upon ovariectomy [15]. Figure 1. Catabolic pathways of histidine [11]. Figure 1. Catabolic pathways of histidine [11]. 2.2. Physiological Role of Histidine is Common for All Species 2.2. Physiological Role of Histidine is Common for all Species Incorporation into protein: Borsook and Wolf reported that the main region for histidine retention was the viscera.Incorporation This was determined into protein: by theBorsook injection and of labeledWolf reported AAs into that rodents the andmain the region subsequent for histidine analysisretention of the rate was of the incorporation viscera. This intowas proteindetermined tissue by [the16,17 injection]. The of maximum labeled AAs rate into of histidine rodents and the incorporationsubsequent into proteins analysis is of slower the rate (max of atincorporation 30 min after into injection protein of labeledtissue [16,17]. AAs) than The formaximum leucine rate of and lysinehistidine (max at incorporation 10 min for lysine into proteins and 20 min is slower for leucine). (max at In 30 guinea min after pigs, injection 30 min after of labeled intravenous AAs) than for injectionleucine of 16 mg and/kg lysine of histidine, (max at the10 ratemin offor incorporation lysine and 20 of min histidine for leucine). is 0.9 µ InM guinea in small pigs, intestine 30 min after and 1.7 µintravenousM in liver per injection g of protein of 16 mg/kg per hour. of histidine, The highest the incorporationrate of incorporation was measured of histidine in microsome is 0.9 µM in small fractionsintestine [16]. and 1.7 µM in liver per g of protein per hour. The highest incorporation was measured