BAOJ Pediatrics

Manuel Moya, BAOJ Pediat 2016, 2: 5 2: 027 Review Low Tryptophan (TRP) Chronic Intake Present Consequences Manuel Moya1* 1University Miguel Hernandez. Campus S. Juan. Alicante, Spain

Abstract TRP protracted deficiency led to a delayed growth among other consequences [1]. Again as in other micronutrient deficiencies Essential amino acids (EEA) deficiency will have important unethically induced in humans the inherited diseases of amino consequences for health upkeep, especially in Low- and Middle- acid metabolism give us the possibility to analyze some of the income Countries (LMIC). By mixing different plant derived consequences of TRP deficiency. This is the case of Hartnup disease, products complete proteins can be obtained but this is not achieved an autosomal recessive defect affecting the transport of mono at present. amino-mono carboxylic, ie all ten neutral amino acids, across the Tryptophan (TRP) has three main metabolic routes leading to intestinal mucosa and renal tubules. It is not a severe disease but the synthesis of proteins, serotonin and nicotinic acid (niacin or has red and rough skin after sun exposure, ataxia (wide-base gait), vitamin Bȝ). Its deficiency will lead to micronutrient undernutrition short stature, glossitis, diarrhea and important emotional instability especially in LMIC. The specific requirements throughout the although no mental deficiency. This picture is very close to that lifespan are now well known due to new techniques such as of niacin deficient classical pellagra. We should remember at this indicator amino acid oxidation. Also, the EAA role in food intake point that 60 mg of TRP are equivalent to 1 mg of niacin and how (amount and quality) regulation through the protein kinases is a nicotinic acid and nicotinamide form part of the coenzymes NAD recent discovery action. The consequences of the TRP lack have and NADP. The first has a prime redox function (NAD+/NADH), been evident since pellagra times. Knowledge of undernutrition non-redox functions (DNA repair, telomere maintenance) and also has improved since accurate body measurements, the new unified extracellular functions. NADP has very similar functions but it is growth standards and metabolomics that allow us to measure not used in lipid synthesis and in the elongation of free fatty acids. It only the micronutrients but also the intermediate compounds would not be exaggerated to assume that even a modest deficit of along their metabolic pathways. these coenzymes present in all body cells would carry a growth Nutrition in the first 1000 days of life in some LMIC is the and development impairment. The mitochondrial oxidation cornerstone period which can be extended up to the 5th anniversary. of NADH which is coupled with ATP synthesis is metabolic Hopefully evidence based study conclusions could be applied to all evidence supporting the energetic component of micronutrient young children of the world. New agricultural technologies allow undernutrition. to enrich different cereals with the deficient amino acids, the best Tryptophan is also a precursor of serotonin (TRP-> 5-OH TRP-> results come from lysine enriched maize, but unfortunately this has 5-OH tryptamine), a neurotransmitter located in the gastrointestinal not been attempted in chickpeas. Until this moment arrives little tract, platelets and central nervous system. The serotonin functions changes in crops allowing mixing flours that can produce basic in the CNS have contributed to the wide workforce towards the foods containing complete proteins is a possibility that without end of the last century applied to its mechanisms and eventual doubt will contribute to decrease the figure of 6 million of under- applications to different human alterations of sleep, food intake five who die every year all over the world. or depression [2]. In 1980’s studies showed the administration of Abbreviations: EAA, Essential Amino Acids; FAO, UN Food Agri- TRP to varied neurological conditions such as depression, autism, cultural Organization; HIC, High –Income Countries; 5-HT, Sero- La Tourette syndrome, sexual dysfunctions, Down syndrome, tonin; LMIC, Low- Middle-Income Countries; TRP, Tryptophan; Epilepsy…that overuse moved the FDA to prevent the tryptophan IAAO, Indicator Amino Acid Oxidation importation. Research from this period was very valuable ie

Keywords: Essential Amino Acids; Tryptophan; Complete Proteins; *Corresponding author: Manuel Moya, University Miguel Hernández. Micronutrients Undernutrition. Campus S. Juan. Alicante, Spain E-mail: [email protected] Introduction Rec Date: November 23, 2016, Acc Date: November 29, 2016, Pub Date: Tryptophan (TRP) is an essential amino acid (humans cannot November 29, 2016. synthesize it) belonging to the neutral amino acid group that once Citation: Manuel Moya (2016) Low Tryptophan (TRP) Chronic Intake Pres- absorbed may follow three routes: protein synthesis, serotonin (or 5- ent Consequences. BAOJ Pediat 2: 027. hydroxytriptamine) synthesis and nicotinic acid (niacin or vitamin Copyright: © 2016 Manuel Moya. This is an open-access article distribut- Bȝ) synthesis. This proves its importance not only in nutrition but ed under the terms of the Creative Commons Attribution License, which also in human health. As is frequent in nutrition the first induced permits unrestricted use, distribution, and reproduction in any medium, deficiency came from the animal experience, demonstrating that provided the original author and source are credited.

BAOJ Pediat, an open access journal Volume 2; Issue 4; 027 Citation: Manuel Moya (2016) Low Tryptophan (TRP) Chronic Intake Present Consequences. BAOJ Pediat 2: 027. Page 2 of 5

ESSENTIAL COMPLETE PROTEIN CHICKPEA FLOUR SOYBEAN FLOUR SORGHUM GRAIN MAIZE WHOLE AMINO ACIDS mg/g prot mg/g prot mg/g prot mg/g prot mg/g prot Trp 7 1.1 14 10,2 9 Thr 27 38 42 31,2 37 Ile 25 47 50 42,1 38 Leu 55 76 85 140,8 133 Lys 51 60 70 20,2 27 Met + Cys 25 29 28 16,6 41 Phe + Tyr 47 91 88 53,3 92 Val 32 56 53 52,2 46 His 18 29 28 20,6 27 Prot g/100g 22 36 10,4 8 TABLE. Essential amino acids and protein content in chickpea flour and different cereal products in comparison to the complete protein pattern. tryptophan transport across the blood-brain barrier [3,4] or kinase CGN2 gene [10] which has a central role maintaining amino on clinical grounds [5,6]. Nowadays this enthusiasm has been acid homeostasis in yeast and animals. If the essential amino replaced by more accurate results but some information on food acids uncharged tRNAreaches the anterior piriform cortex of the intake regulation will be considered below. rats, then the animal restricts the intake of diets lacking essential amino acids. Animals on tryptophan deficient diet also showed an Nutritional Aspects aversive response [11]. Similar regulating mechanisms are related Amino acid metabolism as the building blocks of proteins is to the protein kinase mTOR (mechanistic TOR) of mammals when influenced by the amount, quality of food proteins and the sources nutrient availability is variable [12] with a therapeutic prospect of preformed α-amino nitrogen. The classical division into three that is that mTOR activity can be modified by rapamycine. These groups: essential, conditionally essential and non-essential amino induced modifications can explain better some of the long-term acids are valid. The conditional group being those with a rate effects of obesity- insulin resistance, but they also play a role in of synthesis that is not able to meet the cellular needs in certain undernutrition (low levels of EAA) as we will see below. These new physiological conditions, such as cysteine in the newborn period breakthroughs affecting the biological response, in this case by the or first year of life [7]. TRP is an essential amino acid (EAA) and its essential amino acids require further research [13]. age requirements after the initial Estimated Average Requirements Nutritional consequences of tryptophan deficiency have been (EAR), followed by Recommended Daily Allowances (RDA) are approached from the beginning of the micronutrient undernutrition finally settled by the widely accepted norm of the Dietary Reference measurements. In a healthy adult the synthesis of protein is around Intakes DRIs [8], these can be summarized as follows (mg/kg/day): 300 g per day, that implies an uptake and release of 150 g of essential 0-6 months 25; 7-12 months 10; > 1year 7; and adult 4. These figures amino acids, if dietary supply is roughly of 6 g per day, a recycling varied a little according to the mentioned sources of Requirements amino acid from protein breakdown is probably the major source and were not far from those obtained by the Indicator Amino Acid for maintaining the dynamic essential pool. In pediatric ages with Oxidation (IAAO) a most reliable technique. Incomplete proteins steady and peak growth periods the balance must be positive are those that one (or more) essential amino acids are in insufficient although its timing and the extent is unknown accurately. From quantity for growth, development and repair of body tissues. the animal experience it is well known that plasma tryptophan Unfortunately in wide areas of the world plant proteins do not increases when the intake exceeds normal requirements and contain all essential amino acids and they are the main food base for when there is a high carbohydrate content in the diet, in this last children and adolescents. The role of tryptophan in undernutrition situation due to the increased TRP bound to albumin [14]. Another has been studied through its metabolites of indicant, 5-HT, and important issue is that undernutrition has not a specific pattern of nicotinic acid…since long ago specially in countries where plasma essential amino acids. In a study on severe undernourished ‘protein-energy malnutrition’ were common [9]. It was the era end children [15] the levels of tyrosine, tryptophan and leucine were of triple D, dermatitis, diarrhea and dementia. Most recently the lower than in the control group. This pattern is heavily affected by new approach comes when more precise clinical (somatometry) the protein intake amount and quality (ratio of EAA closer to that and biochemical (metabolomics and mass spectrometry) methods of egg protein). The plant quality protein is very varied as has been are widely used, even in large epidemiological studies. It was demonstrated after the study through stable isotopes in 116 LMIC possible to ascribe the micronutrient alterations to the clinical [16,17]. Furthermore the habitual and accessible plasmatic window findings. One of the most representative paradigms is the protein is also affected by the fact that amino acids cannot be stored and

BAOJ Pediat, an open access journal Volume 2; Issue 4; 027 Citation: Manuel Moya (2016) Low Tryptophan (TRP) Chronic Intake Present Consequences. BAOJ Pediat 2: 027. Page 3 of 5 must be incorporated to proteins or oxidized. importance of adequate nutrition of infant and young children, Undernutrition is more precisely assessed nowadays when even the expanded concept of first 1000 days of child existence the classic definitions are giving way to not only an accurate and subsequent health status , has started the ’B-24 Project’. The somatometry but also uniform references (Cole, CDC, WHO) conundrum of references existence for nutrition in this period will have been established and made comparable different samples. be sieved through a systematic review procedure in the first path Conceptually it is important to determine first the context of steps. Undernutrition and make clear that Malnutrition (bad nutrition) In these aspects of nutritional effects of TRP its relation to obesity includes both Undernutrition and Obesity [18]. Undernutrition should be mentioned. It is accepted that high brain levels of serotonin can be defined as inadequate nutrition resulting from lack of food contribute to satiety and this was the origin of the now retired drugs (plus other factors) or failure of the body to absorb or assimilate that activate postsynaptic 5-HT receptors. Furthermore it has been nutrients properly. At present it is evaluated through the widely described [30] how obese individuals have low levels of TRP that recognized Z-score system [19], being undernutrition and could originate serotonin deficiency in the brain thus diminishing underweight respectively when Zs is <-2 SD and between <-1SD the satiety response to food intake. The balance hunger/ satiety as to <-2 SD. These limits are important due to the vast majority of a primarily survival function is widely preserved and regulated underweights being frequently overlooked. Other terms such as (more than 10 peptides) in hypothalamic nuclei of mammals. To stunting (<-2SD from median height) are less informative if the consider only an isolated factor will probably lead to picturesque target height is not known. Classical terms are less used probably diets doomed to failure. because they are largely arbitrary. Due to the advances in the Nutritional and Food Resources in Low- and Middle-- In biochemical measurements, the undernutrition concept includes come Countries the micronutrient deficiencies also known as Hidden hunger and it is pertinent to say that the classical ‘big four’ (vitamin A, zinc, Good nutrition is not evenly adequate in the world because iodine and iron) have been expanded although not evenly. Also malnutrition is increasing at the expense of overweight and obesity the concept of Food security (access to food for all) although and although its other component undernutrition is receding it is with a more epidemiological background has proved quite useful a quanti and qualitatively reality still too important in Low- and because its application has allowed us to discover populations with Middle-Income Countries (LMIC). The absolute figures and trends moderate undernutrition even in high income countries. are a matter of concern at individual, national and international level. In this frame it is difficult to identify the specific clinical consequences of TRP deficiency, whether by deprivation or by a kynure- Another relevant aspect is the specific prevalence of undernutrition nine pathway block, the development of a weak pellagra syndrome in children under-five years, a period of special health relevance [20,21] points out the relation to inadequate nutrition. Another according to the WHO Global Health Observatory in which aspect derived from TRP deficiency came from the mouse chronic infections are a real threat with a higher mortality rate especially granulomatous disease. When this condition appears in young chil- in LMIC. The good news is that this pediatric health problem is dren it is serious due to the incapacity to cope with bacterial infec- receding all over the world: In 1960 there were 300 million that tions, granulomas and eventual death is not infrequent despite the in 2015 had gone down to 113 million (-33%), but the problem adequate antimicrobial therapy. The cause lies in the incapacity of is still important especially in South Asia with 28.7 million and phagocytes to produce NADPH and consequently reactive oxygen Sub-Saharan Africa (> 50 countries) with 51.3 million [31]. These species so lethal for bacteria [22]. Finally the nutritional studies on worrying figures will continue because the world population will the Autism spectrum disorders showed that the prevalence of low be of 9.1 billion by 2050, whereas the developed countries will levels of tryptophan (and tyrosine) was related to the frequent un- increase by 6%, South Asia will do so by 48% and Sub-Saharan dernutrition and not as a possible cause of the disease [23]. A wider Africa by 130%. Consequently malnutrition as the present double involvement of all lower circulating essential amino acids has re- burden that is the coexistence of underweight and overweight will cently been approached as coexistent with stunting (24). Even this go on according to the United Nations Population Division [32]. group has raised a suggestive hypothesis [25] according to which As mentioned essential amino acids are not completely present in the mentioned mechanistic TORC1 pathway, which is exquisitely plants or crops that are important if not the only food available sensitive to EAA availability, will repress protein and lipid synthesis for people living in certain wide areas such as Sub-Saharan Africa and consequently growth velocity. All this should be considered in or South-Central Asia. Basic genetic and genetic engineering the context of other macro and micronutrients and further adverse technologies initiated in the middle of the past century have evolved conditions frequent in LMIC. at a fast rate allowing the improvement of this lacking problem. Tryptophan fortified foods have been used for improving clinical Genetic modification has been successful in maize and increasing conditions of undernourished children using hydrolyzed collagen lysine content is possible in sorghum but no transformation has [26] and egg white [27] with acceptable results, although not been settled at large scale. In the case of chickpeas the only genetic generalized. Conversely more recent mixtures of available cereals transformation has been related to agronomic traits (resistance and legumes still have tryptophan as limiting amino acid [28]. The to pests, drought…) but not for increasing TRP content [33], this Dietary Guidelines for Americans [29] have taken into account the despite the high concern of the Indian Council of Agriculture

BAOJ Pediat, an open access journal Volume 2; Issue 4; 027 Citation: Manuel Moya (2016) Low Tryptophan (TRP) Chronic Intake Present Consequences. BAOJ Pediat 2: 027. Page 4 of 5

This could be the solution at mid or long term but in the meantime 7. Reeds PJ, Burrin DG, Davis TA(2000) Protein nutrition of the neonate. mixes of plant foods adapted to local climate arid conditions can Proc Nutr Soc 59: 87-97. be a feasible solution. 8. Otten, JP Hellwig, LD Meyers (2006) Institute of Medicine. DRI values Chickpea seeds [34] or flours [35,36] are a reasonable food resource for indispensable amino acids by life stage and gender group. In Di- etary reference intakes (DRI): The essential guide to nutrient require- but their low content in the essential amino acid tryptophan (Table) ments. is a nutritional risk especially for weaned infants and under-fives [37]. Preformed nicotinic acid is widely present in foods derived 9. Metwalli OM, Shukkry AS, Ghali I, Shukri I, Ismail S, et al. (1997) Stud- from plants or animals. The last one, meat, meat products, dairy ies on tryptophan metabolism in protein-energy malnutrition (PEM). 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