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How important is tryptophan in human health?

Article  in  Critical Reviews in Food Science and Nutrition · February 2019

DOI: 10.1080/10408398.2017.1357534

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How important is tryptophan in human health?

Joanna Ka»u_zna-Czapli�nskaa, Paulina Gatareka, Salvatore Chirumbolo b, Max Stanley Chartrandc,and Geir Bjørklund d

aDepartment of Chemistry, Institute of General and Ecological Chemistry, Lodz University of Technology, Lodz, Poland; bDepartment of Neurologicaland Movement Sciences, University of Verona, Italy; cDigiCare Behavioral Research, Casa Grande, AZ, USA; dCouncil for Nutritional and EnvironmentalMedicine, Mo i Rana, Norway

ABSTRACTTryptophan (Trp) is an amino acid and an essential component of the human diet. It plays a crucial role inmany metabolic functions. Clinicians can use Trp levels in the course of diagnosing various metabolicdisorders and the symptoms associated with those diseases. Furthermore, supplementation with thisamino acid is considered in the treatment of depression and sleep disorders, mainly due to the Trprelationship with the synthesis of serotonin (5-HT) and melatonin. It is also used in helping to resolvecognitive disorders, anxiety, or neurodegenerative diseases. Reduced secretion of serotonin is associatedwith autism spectrum disorder, obesity, anorexia and bulimia nervosa, and other diseases presentingperipherals symptoms. The literature strongly suggests that Trp has a significant role in the correctfunctionality of the brain-gut axis and immunology. This information leads to the consideration of Trp asan essential dietary component due to its role in the serotonin pathway. A reduced availability of Trp indiet and nutraceutical supplementation should be considered with greater concern than one mightexpect. This paper constitutes a review of the more salient aspects gleaned from the current knowledgebase about the role of Trp in diseases, associated nutritional disorders, and food science, in general.

KEYWORDSTryptophan; serotonin;metabolic disorder;neurodegenerative disease;food technology; human diet

Introduction

The role of the essential amino acid tryptophan (Trp) is gainingin interest relative to dietary and nutritional sciences. Recentresearch has demonstrated that this amino acid exerts a protec-tive action in the intestine, as it contributes to the enhancedexpression of the tight junction proteins claudin-3 and zonulaoccludens (ZO-1) in the jejunum of experimental animals (Liuet al., 2017). Its fundamental importance appears mostly in itsrelationship with serotonin, which is important in food-to-nutrition synthesis. Past research has suggested a direct connec-tion between serotonin production and the available circulatingTrp, recently proposed as a hallmark as a possible marker ofpsychiatric serotonin-related disorders (Comai et al., 2016).From a food technology viewpoint, the importance of Trp inhuman physiology would suggest recommendations and guide-lines by worldwide experts to supplement or enrich foods withTrp. Due to the complexity of the relationship of serotonin andmelatonin and circadian rhythms, it’s hard to ascertain or attri-bute the needed levels of Trp in a given diet (Hulsken et al.,2013; Silva et al., 2017).

However, several researchers have suggested that Trp sup-plementation in a daily diet might improve pharmacotherapyin some diseases (Figure 1). Because of the tryptophan hascomparatively low tissue storage and their concentration in thebody is low, compared to other amino acids, for healthy nutri-tion are needed only small amounts (Richard et al., 2009).Some food products containing tryptophan are presented in

Table 1(Rambali et al., 2002; Richard et al., 2009; USDA FoodComposition Databases, 2017). The recommended daily dosefor adults is estimated to be between 250 mg and 425 mg, whichresults in a dietary intake of 3.5 to 6.0 mg/kg of body weight perday (Richard et al., 2009).

Tryptophan is an essential component of the diet. It plays akey role in protein synthesis, and is a precursor of biologicallyactive compounds such as serotonin, melatonin, quinolinicacid, kynurenic acid, tryptamine, and also coenzymes impor-tant for electron transfer reaction (redox balance of metabo-lism), such as nicotinamide adenine dinucleotide (NADC).This compound, which are final product tryptophan metabo-lism, might be produced from ingested tryptophan but alsovitamin B3 (niacin) (Richard et al., 2009; de Figueiredo et al.,2011; Palego et al., 2016). To people health is detrimental bothdeficiency and excessive intake. Tryptophan has been used totreat variety disorders, but in most countries has been with-drawn. During the treatment of tryptophan preparations havebeen observed undesirable symptoms including a variety ofpulmonary, cutaneous, and neurologic symptoms, and alsoeosinophilia-myalgia syndrome, and disease associated withmuscle pain. Many different diseases and disorders have beenlinked with tryptophan and its metabolites (Table 2). Anincreased metabolism of Trp, or adverse effects of low Trp suchas decreased absorption or intake, have been observed in differ-ent types of pathology. It should be mention disease and disor-ders such as premenstrual syndrome (PMS) (tryptophan plays

CONTACT Joanna Ka»u_zna-Czapli�nska joanna.kaluzna-czaplinska@p.lodz.pl Department of Chemistry, Institute of General and Ecological Chemistry, Lodz Uni-versity of Technology, Zeromskiego 116, 90–924 Lodz, Poland.© 2017 Taylor & Francis Group, LLC

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a role in increased activation of Trp catabolism), pellagra(caused by a deficiency of niacin which precursor is Trp),chronic kidney disease (is observed alterations in Trp metabo-lism in the case of kynurenine pathway) (Karu et al., 2016), coe-liac disease (availability of Trp to the brain is low, especially insubjects with depression), Parkinson’s disease (large neutralamino acid compete with Trp), mental disorders (reducedavailability of Trp what is consequence is low level of serotonin)(Sainio, Pulkki, and Young, 1996; Russo et al., 2009), sleep dis-orders (abnormal level of melatonin, which is synthesize fromserotonin) (Kaczor and Skalski, 2016), schizophrenia (dysfunc-tional serotonin transmission), bulimia and anorexia (depletionof Trp) (Sainio, Pulkki, and Young, 1996; Russo et al., 2009).

It is well known that Trp is only available through the die-tary process, as its precursors allow gut microflora to synthesizethe essential amino acid in humans. Tryptophan can be metab-olized through the methoxyindole and kynurenine pathways.The kynurenine pathway, which takes up about 95% of the bio-logically available Trp, is controlled by the rate-limitingenzymes indoleamine 2,3-dioxygenase (IDO) and Trp 2,3-diox-ygenase (TDO).

Stress hormones and Trp induce TDO synthesis and activa-tion, while IDO can be induced by pro-inflammatory, inter-feron-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a),and Th-1 type cytokines, i.e. during an innate response of theimmune system. IDO suppresses the activity causing the induc-tion of TDO, and vice versa, while the ratio of kynurenine

(products) to Trp (substrate) gives information about IDOactivity. Upregulation of the IDO activity caused by chronicinflammation of the immune system could be a major factor inthe initiation and propagation of obesity and associated meta-bolic syndrome (Mangge et al., 2014).

Tryptophan supplementation could promote synthesis andneurotransmission of serotonin. Moreover, it may be effectivein treating disorders of serotonin deficiency by increasing theprecursor for 5-HT synthesis and normalizing its release(Haleem, 2012). Levels of Trp, and hence its circulating bio-availability, does not seem to be directly linked to cognitionand mood improvements, as recent reports suggest that excessof Trp impairs cognition, rather than improving it (Hulskenet al., 2013). On the other side, a deficiency in Trp, caused bymalnutrition, may affect the central and peripheral serotoniner-gic pathways, although further nutrition-derived hormonalmolecules may rescue some of this deficiency (Patrick andAmes, 2014).

With serotonergic dysfunction have been associated withsymptoms of panic, depression, aggression and suicidality.Because the serotonin system is involved in the various psychi-atric disorders, but not only, serotonin system is also involvedin the regulation of satiety, it can be concluded that the activityof serotonin can be important in the pathophysiology of eatingdisorders such as anorexia nervosa. A fundamental concern fornutritionists and food technologists is to focus on the role ofTrp in neurological and immune disorders, to achieve a deepawareness and knowledge of the risks and potentials associatedwith the supplementation use of this amino acid. The aim ofthis paper is based on the currently existing and very recent lit-erature to present a more focused viewpoint relative to the roleof Trp in diseases associated with human nutritional disorders.

1. Tryptophan and irritable bowel syndrome

One of the most common alimentary tract illnesses in humansis irritable bowel syndrome (IBS). This disease also constitutesa significant social problem. IBS is a bowel function disorder.Pain associated with defecation and defecation frequency orstool consistency characterizes this disease. Still unclear is etio-pathology of the illness. Pathological factors include, amongothers, disturbances in the functions of serotonin at this level of

Figure 1. Tryptophan and different diseases.

Table 1. Tryptophan amount per 100 g in common foods.

Tryptophan (mg)

milk 42eggs 165wheat flour 110sausage 93potato 28chees 325beef 230banana 10soybeans 160bread, oat bran, toasted 140chia seeds, dried 440chicken, breast, skinless, boneless, meat only 400cocoa 290

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the digestive process ( _Zelowski et al., 2013). IBS is a functionalgastrointestinal disease, because these disorders arise from dys-function of the organ, excluding morphological changes withinit (Fitzgerald et al., 2008).

There are four clinical forms of this syndrome: IBS withconstipation (IBS-C), IBS with diarrhea (IBS-D), mixed IBS(IBS-M) and unsubtyped IBS (Longstreth et al., 2006).Throughout the world, about 10–20% of adolescents and adultsexhibit symptoms associated with IBS (Fitzgerald et al., 2008).Irritable bowel syndrome is more common in women than inmen. The disease develops most often in the third decade of life(Drossman et al., 2002). The factors causing this diseaseinclude, among others, environmental, genetic, depression,inflammatory predispositions, and chronic stress (Fitzgeraldet al., 2008; _Zelowski et al., 2013).

Fitzgerald et al. (2008) examined patients with IBS andhealthy, of comparable age and body mass index (BMI) andsex-matched controls. They observed the higher concentrationof kynurenine in the blood of patients with IBS in comparisonwith the control group and positive correlation between thekynurenine/tryptophan (Kyn/Trp) ratio and IBS symptomseverity (Fitzgerald et al., 2008).

Keszthelyi et al. (2012) demonstrated a relationship betweenthe amount of serotonin, synthesized in the brain, and theamount of Trp supplied to the body with diet. Their random-ized placebo-controlled study suggested that the sudden short-age of the precursor of serotonin obtained by administering anamino acid-enriched beverage lacking Trp to patients resultedin the dramatic reduction of the concentration of serotonin inthe blood, as well as, a decrease in the level of 5-hydroxyindole-acetic acid in urine. In contrast, there was no change in the con-centration of these compounds in the intestinal mucosa. Theresearchers concluded that 5-HT synthesis in the brain is highlydependent on the availability of Trp in plasma, which is influ-enced by the competitive uptake of other large neutral aminoacids (LNAAs) and Trp across the blood-brain barrier(Keszthelyi, 2012).

Other scientists measured serum serotonin concentration inindividuals with irritable bowel syndrome, compared with con-trol group, and also evaluated the urine concentration of 5-hydroxyindole acetic acid (5-HIAA), which is a metabolite ofserotonin. They examined participants aged 19–50 years,including healthy subjects, patients with predominant constipa-tion (IBS-C) and patients with predominant diarrhea (IBS-D).The results pointed to a reduction of serotonin concentrationin patients with IBS-C and IBS-D. In all patients with IBS, adecrease in urinary excretion of 5-hydroxyindole acetic acidwas observed. These results indicate that disturbed metabolismof serotonin could play a role in the pathogenesis of functionalbowel diseases (Moskwa et al., 2007).

Studies conducted by Atkinson et al. (2006), showed thatpatients with IBS-D (aged 19–52 years) have a higher concen-tration of serotonin in the blood than healthy patients, both inthe fasting and during the postprandial time. However, the dif-ferences were not detected as IBS with constipation (IBS-C,aged 19–52 years). Food intake significantly increased levels ofserotonin in the blood of patients with IBS with diarrhea, withrespect to healthy subjects (n D 35, aged 18–46 years). Theresults assessed the concept that an impaired release might

characterize IBS-C, whereas IBS-D is characterized by reducedserotonin reuptake (Atkinson et al., 2006).

Reports by Dunlop et al. (2005) indicated an increase in thepostprandial levels of serotonin in the blood of patients with adiarrhea form of IBS (IBS-D) and a significant reduction inpatients with constipation-predominant IBS (IBS-C), comparedto healthy controls (Dunlop et al., 2005). Dunlop et al. (2005)examined 15 patients with IBS-D, 15 patients with IBS-C and15 healthy control participants. This study compared postpran-dial serotonin release and mucosal serotonin metabolism invarious types of IBS. The results demonstrated that patientswith IBS-C showed impaired postprandial serotonin release.

Houghton et al. (2003) examined 39 female patients withIBS-D aged 19–52 years, and 20 healthy females aged 20–46 years. Obtained data suggested that postprandial symptom-atology could be connected with increased plasma serotoninconcentration in IBS-D patients (Houghton et al., 2003; Dunlopet al., 2005). Furthermore, sleep disorders are frequently associ-ated with women affected by IBS. In this circumstance, it hasbeen observed that a reduction in the early nighttime ratio ofmelatonin: Trp may be related to the altered sleep status in IBScases (Heitkemper et al., 2016).

Current therapy of IBS should involve Trp biology andmetabolism, either by improving diet panels, herbal therapyand/or using pharmacotherapeutic drugs able to prevent orreduce Trp catabolism and chemical degradation (Grundmann,Yoon and Moshiree, 2010; Catanzaro et al., 2014; Shi et al.,2015). At the same time, the controversial role of the excess ofTrp that has been reported in past studies on gut mucosa can-not yet be dismissed (Madara and Carlsso, 1991).

2. Obesity, overweight and tryptophan metabolism

In the last four decades, obesity has increased dramaticallythroughout the world. In 1980 the number of obese and over-weight people were 857 million, whereas by 2013 this numberhad increased to 2.1 billion (Youssef, 2015). Obesity is a verycomplex, multifactorial metabolic disorder, which is oftenrelated to an immune-mediated systemic inflammation of theadipose tissue and to insulin resistance and hyperlipoproteine-mia, where a major role is exerted by NF-kB (Catrysse and VanLoo, 2017). The basic determinants of obesity can be bothover-nutrition and lack of physical exercise. Simple reasoningon a diet should suggest that the excessive intake of food mighteven lead to an excess intake of Trp precursors and of food-derived Trp.

Furthermore, Trp is responsible for the calorie intake regula-tion (Mangge et al., 2014). Recent data suggests that obesity isassociated with altered Trp and tyrosine (Tyr) metabolism(Strasser, Berger, and Fuchs, 2015). As previously reported,these compounds also play a role in neuropsychiatric symp-toms (Andr�e et al., 2014). As the primary pathway of Trpmetabolism is the kynurenine pathway, and indoleamine-2,3-dioxygenase (IDO) is the first enzyme of the pathway, theseproinflammatory molecules that stimulate IDO may cause orexacerbate obesity (Andr�e et al., 2014; Mangge et al., 2014;Strasser, Berger, and Fuchs, 2015). Yet, apparently contradic-tory issues do exist, particularly regarding activity of Trp basedon its circulating levels in obese subjects, or in those

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circumstances where metabolic syndrome may have conse-quences in other anatomic regions of the human body (Oxenk-rug, 2013; Mangge et al., 2014; Oxenkrug, 2015; Yu et al., 2017).

In overweight adults, Strasser, Berger, and Fuchs, 2015)investigated the effect of a two-week caloric restriction weightloss diet (CRWLD) on the circulating levels of leptin, on furtherinflammatory biomarkers and assessing the short-term dietaryeffects of Trp and inflammatory biomarkers in overweightadults (Strasser, Berger, and Fuchs, 2015), researchers found animpairment in the biosynthesis of serotonin from its naturalprecursor. This may be related to the increased susceptibilityfor mood disorders and carbohydrate craving observed in thestudy. Leptin is a hormonal peptide, produced by adipocytes,which is correlated to body fat homeostasis and satiety, as itcontributes in regulating food intake and energy balance butthe functionality of which is also strongly associated with theneurological activity (Zhou et al., 1997; Van Doorn et al.,2017). High levels of leptin characterize most of the patientswith obesity (L€onnqvist et al., 1995; Hundal et al., 2000; Savinoet al., 2013), suggesting the involvement of a peripheral andcentral resistance. Recent papers showed that a reduction ofbody weight has a dramatic impact on the circulating levels ofleptin (Klempel and Varady, 2011; Musil et al., 2015). In theresearch carried on by Strasser, Berger, and Fuchs (2015), thereduction of leptin concentrations in the circulation canimprove insulin sensitivity, blood pressure, and blood lipid lev-els. Concentrations of Trp and Kyn decreased significantly by15 and 17% for the low caloric diet (LCD) group and by 21 and16% for the very low-calorie diet (VLCD) group, while leptinwas reduced by 46% (Strasser, Berger, and Fuchs, 2015).

Reducing body weight by increasing metabolic activity andaccelerating the onset of satiety may involve a serotoninergic-driven mechanism. For this reason, it might be very useful inthe treatment of obesity to consider the supplementation ofTrp during caloric restriction diet (Yu et al., 2017). Also,increased availability of Trp can increase the production ofserotonin and reduce the symptoms of depression in peoplestruggling with overweight (Oh, Park, and Kim, 2016). Thus,Trp supplementation could prove very useful in the treatmentof uncontrolled weight gain or prevent neuropsychiatric symp-toms (Strasser, Berger, and Fuchs, 2015).

Despite the fact that weight loss in obese patients showed animprovement or prevention of changes in the ratio of theintake/bioavailable Trp and other signals related to obesity thatactivates the immune system and inflammation, in obesepatients with bariatric surgical intervention a reduction in thisratio or of immune markers was not found (Brandacher et al.,2007). Current literature reports several studies dealing withobesity and Trp metabolism, which are often related toimmune-mediated inflammation, with notorious differencesbetween juveniles and adults (Mangge et al., 2014; Reininghauset al., 2014; Raheya et al., 2015).

In a study from a group with Mangee et al. (2014), 527 par-ticipants aged between 10–65 years were analyzed. Resultsshowed that Kyn serum levels and Kyn/Trp ratio to over-weight/obese adults (age from 18, to 65 years), significantlyincreased in comparison to controls. Data for ow/ob juvenilemales (age �18 years) showed decreased Kyn/Trp ratio valuescompared to controls. Furthermore, juveniles fulfilling the

criteria of the metabolic syndrome exhibited constant Kyn/Trpratio and Kyn, whereas adults with MetS had significantlyincreased Kyn and Kyn/Trp ratio. Trp serum levels decreasedin adult ow/ob females but were not markedly different fromnormal weighted patients in the ow/ob groups or between ow/ob group with or without MetS (Mangge et al., 2014).

The results from these researchers suggested that Trpmetabolism and obesity vary significantly between juvenilesand adults. This indicates that early onset low-grade inflamma-tion, which can be found in obese adolescents, is different fromadults, and that juveniles are more likely to suffer from a pro-cess driven by a Th2-mediated response, contrarily to obeseadults, where a Th1 immune mechanism is prevalent. Thesefacts have potential clinical significance, because, first, conser-vative treatment of obesity through lifestyle changes includemore prevalent physical activity during childhood and adoles-cence, and can prevent the critical transition to more aggressiveimmunology before there is irreversible clinical damage. Sec-ond, a simple analytical determination of the concentration ofKyn/Trp may provide more reliable diagnostic evidence of thepresence of Th-1 proinflammatory markers regardless of age,particularly in obese patients (Mangge et al., 2014).

Furthermore, scientists have indicated that potential patho-genic links do exist between serotonin levels, chronic immuneactivation and in decreased IDO-mediated Trp in obesity (Ritzeet al., 2015; Ritze et al., 2016). Immune activation and systemicinflammation are associated with obesity comorbidity, while atthe same time it is connected with synthesized and releasedproinflammatory cytokines (like TNF-a, INF-g, hormones-leptin and others) in adipose tissue. IDO is inducible by IFN-g;and is also involved in the regulation of immune responses anddegraded Trp to form N-formyl kynurenine, which subse-quently can convert to niacin. Furthermore, IDO can reduceTrp plasma levels in morbidly obese patients. Serotonin pro-duction may be reduced by Trp metabolic changes, and thiscan in turn contribute to depression, mood disturbances, andimpaired satiety leading to increased caloric uptake and finallyobesity.

Obesity has shown to be associated with a reduced concen-tration of Trp in the plasma, independently from dietary intakeor weight reduction (Namkung et al., 2015; Zhang et al., 2015).As stated earlier, Trp is a precursor for the biosynthesis of 5-hydroxytryptamine (5HT, serotonin). Serotonin is a neuro-transmitter and biochemical regulator, which contributes tosatiety and hunger balance. Gustatory information during theact of eating is transmitted to the nucleus accumbent, which istypically considered the reward center. This leads to the releaseor the up-regulation of serotonin and opiates, which are calledthe “reward mediators”. Likewise, appetite-controlling neuronsare connected to specialized brain regions (Halford and Blun-dell, 2000).

Overeating and obesity are the results of diet including pal-atable food, where the time spent eating will be prolonged dueto suppressed satiety (Brandacher et al., 2007). In this context,serotonin as neurotransmitter may be involved in the controlof food intake, which is a satiety signal (Halford and Blundell,2000). Moreover, this process is responsible for the inhibitionof the expression of neuropeptides Y, which occur in the hypo-thalamus, through depressing hunger and control of body

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Table2.

Summaryofstud

iesregardingam

ount

oftryptoph

anandits

metabolitesinbody

fluids

invario

usdiseases

ordisorders.

No.

Disease

ordisorder

Metabolites

Stud

ypopu

latio

nSex

Sample

Relatio

nto

disease

Levelofm

etabolite

Methods

Reference

1IrritableBowel

Synd

rome(IBS)

kynu

renine

(Kyn)

tryptoph

an(Trp)

IFN-g

41IBS33

controls

female

plasma

Increase

ofTrpalongtheKyncatabolic

pathway

caused

increasedsensivity

ofthe

IDOto

IFN-g

andassociationbetweenIFN-

gandKyn/Trpratio

contrib

uteto

serotonergicdysfun

ction,viadeficit5

-HT,

which

may

explaingeneratio

ngastrointestinalsymptom

andincrease

incidenceofanxietyanddepression.

Kyn"T

rp$

Kyn/Trp"

IFN-g

$Trp,Kyn-

HPLCIFN-g-

electrochemiluminesc

ence

multip

lexsystem

Fitzgerald

etal.2008

2IrritableBowel

Synd

rome(IBS)

kynu

renicacid(KYN

A)qu

inolinicacid(QA)

37IBS20

controls

both

serum

Controlofthe

gutm

otilityandenteric

neurnalexcitabilityisinvolved

balance

betweenqu

inolinicandkynu

renicacid.

KYNA#Q

A"

HPLC

Wollnyetal.

2006

3IrritableBowel

Synd

rome(IBS)

tryptoph

an(Trp)

serotonin(5-HT)5-

hydroxyind

oloacetic

acid(5-HIAA)

14IBS14

controls

both

plasma

Serotonergicmodulationby

ATDaaffects

visceralperceptio

nandcogn

ition

inIBS

andcontrol.

Trp#5

-HIAA#

HPLC

Kilkensetal.

2004

4IrritableBowel

Synd

rome(IBS)

serotonin(5-HT)5-

hydroxyind

oloacetic

acid(5-HIAA)

23IBS-C23

IBS-D25

controls

both

serum

urine

Metabolismof5-HTandsecretionmay

bedisturbedinirritablebowelsynd

rome

(IBS).D

isturbed

metabolismofserotonin

probablyplay

aroleinpathogenesisof

functio

nalbow

eldiseases.

5-HT"5

-HIAA#

ELISA

Moskw

aetal.

2007

5IrritableBowel

Synd

rome(IBS)

tryptoph

an(Trp)

8IBS-C10

IBS-D11

control

both

plasma

Rise

leveloftryptophanaffectson

gastrointestinalsymptom

sinIBSandalso

decreasesanxietysymptom

s.

ATDa :Trp#A

TIb:Trp

#HPLC

Shufflebotham

etal.2006

6IrritableBowel

Synd

rome(IBS)

serotonin(5-HT)

29IBS-C55

IBS-D35

controls

both

plasma

Modulatingofdifferent

5-HTreceptorsare

involvinginIBS.Redu

ced5-HTreup

take

connectedwith

IBS-D,impairedrelease

may

belinkedwith

IBS-C.

IBS:C:5-HT#I

BS-D:5-HT

"HPLC

Atkinson

etal.

2006

7IBS-D

serotonin(5-HT)

39IBS-D20

controls

female

plasma

Symptom

exacerbatio

nfollowingmeal

ingestioninpatientswith

IBS-Dis

conn

ectedwith

increasedlevelsofplasma

5-HT,togetherwith

aredu

ctionin5-HT

turnover.

5-HT"

HPLC

Hough

ton

etal.2003

8IrritableBowel

Synd

rome(IBS)

serotonin(5-HT)5-

hydroxyind

oloacetic

acid(5-HIAA)

15IBS-C15

IBS-D15

controls

both

plasma

IBS-Cpatientsshow

impairedpostprandial5-

HTrelease.

IBS-C:5-HT"5

-HIAA#

HPLC

Dunlopetal.

2005

9Ch

ronicKidn

eyDisease

(CKD

)tryptoph

an(Trp)10

metabolitesofTrpc

27both

serum

Declineinkidn

eyfunctio

nisassociated

with

metabolismof

tryptoph

anviathe

kynu

renine

pathway,w

ithoutevident

eliminationoftryptoph

anmetabolismvia

the5-HTpathway.

KYNA"w

ereassociated

with

#cognitive

functio

nIAA"w

ascorrelated

with

anxietyand

depression

LC-M

S/MS

Karu

etal.

2016

10Obesity

tryptoph

an(Trp)Trp

/LNAA

dratio

9obese8controls

both

plasma

BrainTrpup

take

iscorrelated

with

the

plasmaTrp/LN

AAratio

.Thisdeterm

ine

brainserotoninsynthesis.Serotonin-

mediatedregu

latio

nof

food

intake

may

contrib

uteto

bluntedTrp/LN

AA,w

hich

response

tocarbohydrateintake

inthe

obese.

Trp#

HPLC

Caballero

etal.1988

(Continuedon

nextpage)

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Table2.

(Continued)

No.

Disease

ordisorder

Metabolites

Stud

ypopu

latio

nSex

Sample

Relatio

nto

disease

Levelofm

etabolite

Methods

Reference

11Obesity

tryptoph

an(Trp)

kynu

renine

(Kyn)

Kyn/Trpratio

359ow

/obe

212

controls

both

serum

Indu

ctionof

theTrp-Kynpathway

are

associated

todevelopm

ento

fthe

metabolicsynd

romeinobesity.O

besity

andTrpmetabolismdiffersbetween

juvenilesandadults.

adult:Trp#

HPLC

Mangg

eetal.

2014

Kyn"

Kyn/Trp"

juvenile:Trp

"Kyn#

Kyn/Trp#

12Obesity

tryptoph

an(Trp)

kynu

renine

(Kyn)

Kyn/Trpratio

27overweigh

t11

obese

both

serum

Disturbed

metabolism

ofTrpinfluentson

biosynthesisofserotoninandmight

beassociated

with

increasedcarbohydrate

cravingandsusceptib

ilityform

ood

disturbances.

VLCD

fLCDg

HPLC

Strasseretal.

2015

Trp

##

Kyn

##

Kyn/Trp

$$

13Obesity/Depressiontryptoph

an(Trp)

973individu

als

both

plasma

LowerTrplevelsinoverweigh

t/obesewom

ansugg

eststhatlowTrp(lowserotonin

synthesis)may

contrib

uteto

either

vulnerabilityto

depression

inobese

wom

enor

vulnerabilityto

obesity

indepressedwom

en.

ow/obe

wom

enmen

HPLC

Rahejaet

al.

2015

Trp

#"

14Type

2Diabetes

(T2D

)tryptoph

an(Trp)

kynu

renine

(Kyn)

kynu

renicacid

(KYN

A)

30T2D24

controls

both

plasma

IncreasedplasmalevelsofKynandKYNAof

T2Dpatientsmight

confirm

“kynurenine

hypothesis”ofinsulin

resistance

andits

progressionto

T2D.

Trp"K

yn"K

YNA"

GC-MS

Oxenkrug,

2015

15BipolarD

isorder

(BD)

kynu

renine

(Kyn)K

yn/

Trpratio

78BD

(54overweigh

t,24

norm

alweigh

t),

156controls(76

overweigh

t,80

norm

alweigh

t)

both

serum

IncreasedlevelofkynurenineandKyn/Trp

ratio

intheoverweigh

tpatientswith

BDcouldbe

connectedbetweenshort

perio

dsof

euthym

iaandworsening

ofillnesscourse

inoverweigh

tpatientswith

BD.

Overweigh

tpatients

with

BD:Kyn

"Kyn/

Trp"

HPLC

Reiningh

aus

etal.2014

16An

orexiaNervosa

(AN)

tryptoph

an(Trp)

32acAN

h32

recANi32

controls

female

plasma

InacAN

hpatientsobserved

lowerTrplevels,

which

also

influenceindiminished5-HT.

Redu

cedavailabilityofthe5-HTmay

accountfor

thepoor

response

totreatm

entA

Npatients.

acAN

hrecANi

HPLC

Ehrlich

etal.

2009

Trp

##

17An

orexiaNervosa

(AN)

5-hydroxyind

oloacetic

acid(5-HIAA)

14AN

10controls

female

cerebrospinal

fluid(CSF)

Centralnervous

system

serotoninergic

metabolismisassociated

with

weigh

tloss

andmalnutrition

inAN

.

5-HIAA#

GC-MS

Kaye

etal.

1988

18An

orexiaNervosa

(AN)

tryptoph

an(Trp)

serotonin(5-HT)

LNAA

dTrp/LN

AAratio

42AN

42controls

both

plasma

Decreaseindepressive

symptom

sand

anxiety,which

encoun

teredinthecourse

ofre-fe

edinginAN

may

bebio-availability

oftryptoph

an.

Trp#5

-HT#L

NAA

d#

Trp/LN

AA#

HPLC

Gauthieretal.

2014

19An

orexiaNervosa

(AN)

tryptoph

an(Trp)LNAA

d

Trp/LN

AAratio

13AN

21controls

female

plasma

Mooddisturbances

have

been

connected

with

redu

ceserotonergicfunctio

n.InAN

individu

alsobserved

redu

cedcentral

serotoninmetabolism(braintryptoph

anavailabilitydecreased).

Trp:afterp

roteinmeal"

aftercarbohydrate

meal#

Trp/LN

AA:

afterp

roteinmeal#

aftercarbohydrates

meal"

HPLC

Schw

eiger

etal.1986

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20Bu

limia(BN)and

Anorexia

Nervosa

(AN)

tryptoph

an(Trp)LNAA

d

Trp/LN

AAratio

13BN

10AN

15controls

female

plasma

Decreased

Trp/LN

AAratio

may

cause

consequences

such

asdisturbances

ofmoodandneuroend

ocrin

eregu

latio

nin

ANindividu

als.

AN:Trp/LNAA

#vs

control

HPLC

Schreiber

etal.1991

BN:Trp/LNAA

ratio

$vs

controls

21An

orexiaNervosa

(AN)

tryptoph

an(Trp)

serotonin(5-HT)Trp/

LNAA

ratio

19AN

12controls

both

blood

Inpathologycouldbe

involved

allm

easured

biologicalindicesexcept

5-HT.AN

isassociated

with

impu

lsivity

andanxiety.

5-HT"t

otalTrp#f

ree

Trp#t

otalTrp/LN

AA#

HPLC

Askenazy

etal.

1998

22An

orexiaNervosa

(AN)

tryptoph

an(Trp)

serotonin(5-HT)5-

hydroxytryptophan

(5-HTP)

16AN

25controls

female

serum

Basedon

thesestud

iescanbe

distingu

ished

twodifferent

subg

roup

sofAN

patients.

One

ofgroupcharacterized

byamarkedly

lowerTrpleveland

high

erlevelsof

5-HTP

and5-HT.

Trp#5

-HT#

HPLC

Comaiet

al.

2010

5-HTP

"

23An

orexiaNervosa

(AN)

tryptoph

an(Trp)

20AN

20controls

—serum

HighlevelofTrp

may

triggerA

NbecauseTrp

isaprecursoro

f5-HT.Serotoninis

responsibleform

oodregu

latio

n,andit

high

levelm

aycausedepression

and

decreasedeatin

gwhich

leadsto

AN.

Trp"

HPLC

Naureen

etal.

2014

24Bu

limiaNervosa

(BN)

tryptoph

an(Trp)Trp/

LNAA

ratio

22BN

16controls

female

plasma

Participantswith

BNcanbe

morevulnerable

tothemoodloweringeffectsofATDa .

Acutechangesin5-HTactivity

arelinked

with

moodBN

subjects.

Trp"

fluorometric

methodof

DenklaandDew

eyKaye

etal.

2000

25Au

tism(ASD

)tryptoph

an(Trp)

37ASD28

controls

adults

—plasma

Abnorm

alTrp-serotoninmetabolisminthe

brainmight

beresponsibleforthe

clinical

manifestations

andbehavioral

abnorm

alities

ofautism.H

ighfree

Trp

levelisresponsibleforlow

ermental

developm

entand

hyperactivity.

totalTrp

$free

Trp"

fluorometric

methodof

DenklaandDew

eyHoshino

etal.

1986

12controlschild

26Au

tism(ASD

)tryptoph

an(Trp)

20ASDadults

both

plasma

Changesinbehavior

(increasing

whirling

,bang

ing,hittingself,rocking,andtoe

walking

)aretriggeredby

depletingTrpin

adultp

atientswith

ASD.

—HPLC

McDougle

etal.1996

27Au

tism(ASD

)tryptoph

an(Trp)

55ASDchildren44

controls

both

plasma

DecreaselevelofTrp

inASDcouldimpair

serotoninsynthesis,andthislead

toa

worsening

inbehavior

inASDsubjects.

LowerlevelofTrp

might

bedu

eto

redu

cedproteinintake

and/or

dysfunction

insynthesizing

proteininto

aminoacidsin

thedigestivetract.

Trp#

HPLC-MS/MS

Adam

setal.

2011

28Au

tism(ASD

)tryptoph

an(Trp)

138ASDchildren138

controls

both

plasma

LowerlevelofTrp

may

deterio

ratio

ninthe

behavior

ofautistic

children.Trpandother

LNAA

dcompeteforb

rainserotonin

synthesisandwhenislowlevelofTrp

then

islowbrainserotoninsynthesis.

Trp#

HPLC

Naushad

etal.

2013

29Au

tism(ASD

)tryptoph

an(Trp)

33ASDchildren21

controls

both

urine

Abnorm

alTrp-serotoninmetabolisminthe

brainmight

beresponsibleforthe

worsening

ofautistic

symptom

s.Redu

celevelofTrp

may

causeincreasedirritability

andmild

depression.

Trp#

GC-MS

Ka»u_ zna-

Czapli� nska

etal.2010

30Au

tism(ASD

)tryptoph

an(Trp)

14ASDchildren10

controls

both

urine

LowerlevelofTrp

may

lead

totheworsening

ofautistic

symptom

s(increasedirritability

andmild

depression).

Trp#

GC-MS

Ka»u_ zna-

Czapli� nska

etal.2014

(Continuedon

nextpage)

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Table2.

(Continued)

No.

Disease

ordisorder

Metabolites

Stud

ypopu

latio

nSex

Sample

Relatio

nto

disease

Levelofm

etabolite

Methods

Reference

31Au

tism(ASD

)tryptoph

an(Trp)

48ASD53

controls

both

urine

Abnorm

alam

inoacidmetabolism(includ

ing

Trpmetabolism),increasedoxidative

stress,and

alteredgu

tmicrobiom

esin

ASD.

Trp#

UPLC/MS/MSGC-MS

Mingetal.

2012

32Parkinson’sDisease

(PD)

tryptoph

an(Trp)

kynu

renine

(Kyn)

Kyn/Trpratio

22PD

11controls

both

serum,cerebrospinal

fluid(CSF)

IncreasedTrpdegradationinperip

heral

bloodinPD

patientssubstantiatesthatin

thisdiseaseparticipateimmunological

abnorm

alities.Interferon-mediatedIDO

activity

isresponsibleforthe

increasedTrp

degradationrateas

isevidentb

ythe

increasedKyn/Trpratio

s.

Trp#K

yn#K

yn/Trp

"HPLC

Widneretal.

2002

33Parkinson’sDisease

(PD)

tryptoph

an(Trp)

20PD

20controls

both

cerebrospinalfluid

(CSF)

Degradatio

nofTrpcanlead

tothegeneratio

nof

3-HKA

,acompoun

dleadingto

increasedoxidativestressinpreclinicalPD

stud

ies.

Trp#

GC-TO

FMS

Trup

petal.

2014

34Parkinson’sDisease

(PD)

3-hydroxykynurenine(3-

HK)

48PD

57controls

—cerebrospinalfluid

(CSF)

3-HKlinkedwith

potent

excitotoxicity

properties.Blockproductio

nof3-HK

(through

Trpcatabolism)allows

neuroprotectivestrategy

andtherapeutic

interventio

nagainst3

-HKform

ation.

3-HK"

UHPLC-MS/MSGC-MS

Lewitt

etal.

2013

35Parkinson’sDisease

(PD)

tryptoph

an(Trp)

92PD

65controls

both

urine

Degradatio

nofTrpmay

beconnectedwith

theactivated

cell-mediatedimmune

response

typicalofP

D.

Trp#

GC-MSLC-M

SLuan

etal.

2015

36Alzheimer’sDisease

(AD)

tryptoph

an(Trp)

kynu

renine

(Kyn)

Kyn/Trpratio

21AD

20controls

—serum

IncreasedTrpdegradationinAD

patientsis

associated

with

sign

sofachronicimmune

activation,whileincreasedKyn/Trpwas

associated

with

redu

cedcogn

itive

performance.

Trp#K

yn"K

yn/Trp

"HPLC

Widneretal.

1999

37Alzheimer’sDisease

(AD),

Hun

tington’s

disease(HD)

tryptoph

an(Trp)

kynu

renine

(Kyn)

Kyn/Trpratio

24AD

12HD

—serum

System

icchronicimmun

eactivationin

patientswith

ADandHDisassociated

with

sign

ificant

degradationofTrp,which

ismostlikelydu

eto

activationof

IDOby

immunologicstimuli.

Trp#K

yn#K

yn/Trp

"HPLC

Widneretal.

2000

38Alzheimer’sDisease

(AD)

tryptoph

an(Trp)

kynu

renine

(Kyn)

Kyn/Trpratio

43AD

both

serum

Increasedbloodconcentrationof

Kyn/Trpis

associated

with

immuneactivationand

inflam

mationrepresentcriticalfactorsin

thepathogenesisofAD

.

Trp#K

yn"K

yn/Trp

"HPLC

Wissm

ann

etal.2013

39Alzheimer’sDisease

(AD)

tryptoph

an(Trp)

16AD

17controls

both

plasma

AcuteTrpdepletionhadno

effecton

cortisol

secretionforsub

jectswith

ADandhealthy

controls.

Trp#

HPLC

Porter Marshall,

and

O’Brien

2002

40Alzheimer’sDisease

(AD)

kynu

renicacid(KYN

A)19

AD20

controls

both

cerebrospinalfluid

(CSF)

Nosign

ificant

alteratio

nsinCSFKYNAlevels

inAD

patientscomparedto

controls.In

ADtheinconsistencyofKYNAalteratio

nscouldbe

becauseof

theheterogeneity

ofthedisease.

KYNA$

KYNA"f

emale

ADvs

maleAD

HPLC

Wennstr€ om

etal.2014

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41SleepDisorders

(SD)

melatonin

94individu

als

male

saliva

Thecombinedinterventio

non

breakfast,

morning

sunlight

andevening-lighting

seem

sto

beeffectiveto

keep

high

ermelatoninsecretionatnigh

t.Higherlevel

ofmelatoninisresponsiblefore

asyonset

ofthenigh

tsleep

andhigh

erqu

ality

ofsleep.

melatonin"i

nG3vs

G1

andG2j

ELISA

Wadaet

al.

2013

42Delayed

Sleep

Phase

Synd

rome

(DSPS)

melatonin

56individu

als

both

saliva

Exam

inationof

themelatoninsecretion

profilecanrevealseveralkey

differences

betweenindividu

alswith

andwith

out

circadianrhythm

disrup

tions.

Thetim

eofmelatonin

secretionare

sign

ificantlydelayed

inDSPSpatients.

ELISA

Rahm

anetal.

2009

43SleepDeprivation

tryptoph

an(Trp)

serotonin(5-HT)

109individu

als

—plasma

Theincreasedlevelsof

5-HTandTrpmay

explaintheantid

epressiveeffectofacute

sleepdeprivation.

Trp"5

-HT"

LC-M

SDaviesetal.

2014

$no

differences

inlevelsmetabolite

betweensubjectswith

disease/disorder

andcontrols

"increaselevelofm

etabolite

insubjectswith

disease/disordercomparedto

controls

#decreaselevelofm

etabolite

insubjectswith

disease/disordercomparedto

controls

a ATD

-AcuteTryptoph

anDepletio

nbATI-AcuterTryptoph

anIncrease,sub

jectsconsum

edan

aminoaciddrinkthateithercontaining

2.3gTrp

c 10metabolitesofTrp:

serotonin(5-HT)

5-hydroxy-3-indoleaceticacid(5-OHIAA)

kynu

renine

(Kyn)

kynu

renicacid(KYN

A)qu

inolinicacid

xanthurenicacid

quinaldicacid

3-OHanthranilic

acid

indoxylsulfate

indole-3-acetic

acid(IA

A)dLN

AA-Large

NeutralAm

inoAcids

e ow/ob-

overweigh

t/obesesubjects

f VLCD-V

eryLowCaloric

Diet

gLCD-Low

Caloric

Diet

h acAN-p

articipantswith

acuteanorexianervosa(AN)

i recAN-p

articipantswerepreviouslytreatedforanorexianervosa(AN)

j G1-no

interventio

nG2-have

protein-richfoodsandvitaminB-6-richfoodsatbreakfastand

sunlight

exposureafterb

reakfast

G3-thesamecontentasG2andincand

escent

light

exposureatnigh

t

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adiposity (Wurtman and Wurtman, 1995; Manousopoulouet al., 2016). Also, it has been found that serotonin specificallyregulates fat and/or carbohydrate intake (Blundell and Lawton,1995; Bray, 2001).

3. Anorexia nervosa and bulimia nervosa

Eating disorders (EDs) are widespread and serious diseasesthroughout the world, with a chronic course and potentiallyfatal outcome (Winkler et al., 2016). Genetic and environmen-tal factors contribute to the development of many complex eat-ing disorders (Haleem, 2012). The most common eatingdisorders may include anorexia nervosa (AN) and bulimianervosa (BN). Both diseases are disorders of considered to arisefrom unknown etiology. They usually begin during adolescencein women, but may also be seen in men (Becker et al., 2003;Kaye et al., 2005, 2008; Haleem, 2012).

A study conducted by Haleem (2012) suggested that femalesare more vulnerable to food restriction, which may start with achronic deficiency in Trp levels and bioavailability. Monoamin-ergic neurotransmitters such as serotonin (5-HT), noradrena-line (NA) and dopamine (DA) contribute to the regulationfeeding behavior, while the accessibility of precursor aminoacids in the blood powerfully influences the synthesis of thosemonoamines in the brain (Ehrlich et al., 2009).

The most common symptoms of eating disorders arerestricted eating, body image distortions, and denial of emacia-tion, binge-purge behaviors, and resistance to treatment. Theyare also characterized by aberrant patterns of weight regulationand feeding behavior, but also by different perceptions towardsshape and body weight, dysphoric mood exhibit behaviors,such as perfectionism and obsessive–compulsiveness. AN andBN are relapsing and often are chronic disorders, whereas ANhas the highest death rate compared to other psychiatricdisorders.

Patients with AN accompanied an obsession with bodyweight and inexplicable fear of weight gain, even in the face ofthe increasing destruction of the body, characteristically exhibitmotor restlessness and excessive exercise (Kaye, Gendall, andStrober, 2001). The main role in behavioral changes observedin a patient with anorexia nervosa presents anomalies occurringin the serotoninergic pathway. In AN an individual’s serotoninlevel is involved in almost all the behavioral changes. Patientswith AN show higher frequency of compulsive exercising rela-tive to those with BN patients (Haleem, 2012). After a period offood restriction, the sufferer usually emerges with BN. Theymay or may not have been linked with weight loss. After surfeitfollowed by self-induced vomiting or different way compensa-tion of surfeit, people suffering from BN also have a fear ofweight gain and distorted view of their body shape. Individualswith BN are impulsive, and often sensation seeking, whereasindividuals with AN tend toward emotional expressiveness andconstriction of affect, and may exhibit great constraint.

The above-described characteristics of anorexia nervosa andbulimia nervosa often begin in childhood, are premorbid andoften persist even after recovery. This would suggest that suchbehavior caused by underfeeding is not secondary. Dysregula-tion of impulse control and appetite or mood in AN and BNcontributes modified brain serotonin function. The occurrence

of AN precedes the disturbance of neuronal serotonin modula-tion, which contributes to premorbid symptoms of inhibition,anxiety, and obsessionality. In patients with BN, it has beenobserved that dietary depletion of Trp is associated with Trp-associated mood irritability and increased food intake, which iscaused by dysfunction of serotonergic tone (Kaye et al., 2005,2008). Because Trp is the precursor to serotonin, Trp deficitcould significantly alter serotoninergic neurotransmission. Inthe refeeding, the Trp/LNAA ratio increases, as it associatedwith a decrease in depressive symptoms. This fact provides anargument for a possible impact of the AN mood symptomswith the serotoninergic pathway through a normalization ofthe biological markers. The increase in the Trp/LNAA ratio ispossible by the intake of related essential amino acids. Thetransport of Trp is predictive through the blood-brain barriertowards the cerebrospinal fluid (CSF) in the evaluation of theTrp/LNAA ratio. Then, Trp can be used for the synthesis ofcerebral serotonin. In these particular ways, the serotoninergictransfer, which leads to a decrease in depressive symptoms, isrestored (Gauthier et al., 2014). For all patients with EDs, com-mon features include dysfunctional cognizance relating toshape and weight and result in restrained eating behaviors.

In the literature, there is lots of evidence of anxiety, appe-tite dysregulation, extremes of impulse control and obses-sional behaviors, caused by disturbances 5-HT in thosesuffering from EDs. Enhancement of the brain serotoninrelease, which can affect appetite regulation, can determinemeal consumption, depending on the amount of protein andcarbohydrate in the meal. Carbohydrate consumption causesdepletion of the large neutral amino acids valine, leucine,isoleucine, phenylalanine and tyrosine. This LNAA competeswith Trp for uptake into the brain. Such elevates the plasmaTrp/LNAA ratio, thereby the amount of Trp in the brain,causing rapid synthesis and release of 5-HT. In contrast, adiet rich in proteins can block those effects, resulting in thelarge amounts of LNAA in the blood (Fernstrom et al., 1979;Kaye et al., 2005, 2008). The results of many studies indicatea decrease in plasma of the Trp/LNAA ratio and Trp levelsin patients with acute underweight (Schreiber et al., 1991;Askenazy et al., 1998; Ehrlich et al., 2009; Comai et al., 2010;Gauthier et al., 2014).

A broader viewpoint is shown by Gauthier et al. (2014),where they show links between serotonin biomarkers, nutri-tional status and psychological states in anorexia nervosa con-jointly. For the first time, they were able to highlight the role ofthe low level of Trp in plasma, blood serotonin, and LNAA andTrp/LNAA ratio with malnutrition (Gauthier et al., 2014).They also found a positive correlation between anxiety, depres-sion score, and total blood serotonin levels in a group of ANindividuals classified as an impulsive. These results are consis-tent with the results obtained by other teams. Acute Trp deple-tion in AN patients was found to lead to an increase in anxiety.Through the restrictive dietary behaviors, individuals maydecrease cerebral serotonin synthesis. Additionally, reduced 5-HT concentrations in hypothalamic causes hyperactivity, whichintensifies behaviors leading to weight loss. The emergence ofBN symptoms and amplified impulsivity appear to be related tolow serotonin levels. This may explain the frequent overlapbetween the restrictive forms of AN and the bulimic state, and

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behaviors are alternating between these eating disorders(Gauthier et al., 2014).

4. Autism spectrum disorder

Autism spectrum disorder (ASD) is a developmental, multi-factorial disorder, characterized by symptoms that evolvewith age adversely affecting the development of the child(Bara, Bucciarelli, and Colle, 2001). The incidence of ASDhas grown worldwide by 600% since the 1970s. In the US,currently at least one of 68 children has ASD (Zablotskyet al., 2015; Christensen et al., 2016). Patients with ASDdemonstrate the problem with interacting and exhibit littleinterest in others and lack of social awareness (Ka»u _zna-Czapli�nska and B»aszczyk, 2012). Etiology and pathogenesisof ASD are not still fully known. However, evidence pointsto nutritional deficiencies or overloads, complex geneticinteractions, maternal age and health state, exposure tochemicals or viruses, heavy metal toxicity, immunologicaloverload from early vaccinations, certain food additives,and dysfunctional immune systems or allergies. Deficienciesin the levels of amino acids occur for many children withdevelopmental disorders.

In recent years, observations relative to metabolic bio-markers have shed light on the influence of amino acids on var-ious developmental disorders. In some cases, the neurologicalfunction could be specified just by studies of amino acids. Someresearchers have suggested that a pivotal role in ASD might befound with Trp metabolism. A metabolite of Trp is the neuro-transmitter serotonin (5-HT), which is, among other things,responsible for regulating humor and behavior, and also facili-tating calmness, feeling of well-being, relaxation, personal secu-rity, concentration, and self-confidence. Hence, reducedserotonin levels have been demonstrated to influence manydevelopmental disorders. For this reason, it is reasonable toposit a connection between escalation of autistic symptoms andabnormal levels of serotonin (Adams and Holloway, 2004).Likewise, a dysfunctional serotonergic system could be involvedwith ASD. As stated above, Trp is converted into serotonin inthe brain, where it competes for transport with nine other large,neutral amino acids (LNAA) (Beretich, 2009).

Many children with ASD exhibit a deficiency in Trp due tosignificant food selectivity and self-imposed diet restriction.This often leads to reduced levels of serotonin and a worseningof autistic behaviors. The literature mentions that urinaryexcretion of Trp might be caused by a low concentration of die-tary proteins. In 1986, research suggested a link between someproblems in children with ASD and abnormal Trp metabolism.The results indicated that free plasma Trp levels were evaluatedin ASD children compared to healthy children and adult con-trols (Hoshino et al., 1986). Therefore, biochemical abnormali-ties were associated with a significantly lower level of Trp inurine.

More recently, researchers examined 54 children aged4–10 years, 33 ASD children (4 female and 29 males) and 21normal children as healthy controls (8 females and 13 males)—the gender ratios in the subjects under study, incidentally, wereabout the same as found in other studies. The ASD childrenwere divided into a group of 10 children with ASD on the

restricted diet low casein and gluten, and 23 ASD childrenwithout restricted diet. The highest values of Trp in urine wereobserved in control group. Significantly lower concentrationlevels of Trp were reported in the samples from 23 ASD chil-dren that were on the restricted diet. Low levels of Trp mightalso cause intensification of the symptoms of ASD, such asincreased irritability and mild depression (Ka»u_zna-Czapli�nska,Michalska, and Rynkowski, 2010). McDougle et al. (1993) havereceived similar results about low diet in Trp. The researchersalso suggested that by depleting Trp in an adult with ASD theymight induce significant changes in behavior, which were notseen in that control group such as increasing whirling, banging,hitting self, rocking, and toe walking (McDougle et al., 1996).

Other scientists focused on the relationship between devel-opmental disorders and metabolic disturbances. Researchersexamined 55 children ages 5–16 years with ASD and 44 healthycontrols of similar age, gender, and geographical distribution.The study was aimed at comparing the metabolic and nutri-tional status of ASD children with that of control children andinvestigated autism severity to the Trp-related biomarkers.Results showed significantly decreased Trp in the children withASD. This might be due to reduced protein intake, and dys-function in synthesizing protein into amino acids in the diges-tive tract. Decreased Trp could further impair serotoninsynthesis. A deficiency of Trp and thus serotonin lead to a sig-nificant worsening in behavior in ASD participants (Adamset al., 2011).

Similar results were also found in other studies. For exam-ple, Naushad et al. (2013) examined 138 autistic children, 120males and 18 females, and 138 non-autistic controls, 120 malesand 18 females. Children were matched for age, gender, ethnic-ity and geographical area. Researchers observed markedly lowerlevels of Trp in the ASD children (Trp levels decreased by anaverage of 48%), compared to healthy controls (Naushad et al.,2013).

5. Parkinson and alzheimer diseases

The pathogenesis of neurodegenerative disorders such as Par-kinson’s (PD) and Alzheimer’s diseases (AD) are not entirelyknown. However, it is believed that in this pathogenic processare involved immunologic mechanisms. In the developmentand progression of PD and AD, a cause has been ascribed tostimulate immunocompetent cells and a significant number of(proinflammatory) cytokines (Widner et al., 2002). Parkinson’sdisease categorically belongs to chronic, progressive, and irre-versible neurodegenerative diseases, which are caused mainlyby the progressive degeneration of the dopaminergic pathway.The second most common neurodegenerative disease amongolder adults is PD. So far, the disease has long been considereda disease of old age (over 60 years of age), but it also occursincreasingly in younger people. When the damage of dopami-nergic neurons reaches 50–60%, and the striatum does notreach adequate dopaminergic input, there arise characteristicmotor symptoms and behaviors (Andersen et al., 2017).

Symptoms and signs of PD are resting tremor, curved pos-ture, bradykinesia, rigidity, depression, and postural instability,shuffling gait. For severe disability progressively lead to long–term complications of dopaminergic treatment, which focuses

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on minimizing the symptoms like motor blocks and dyskinesia.The close relationship might observe between neurodegenera-tive diseases and nutritional status (Barichella, Cereda, and Pez-zoli, 2009). PD is very difficult, if not impossible, to diagnosebefore motor symptoms have begun developing. Other symp-toms associated with early stage disease are very unspecificincluding obstipation, olfactory deficiency, depression, andsleep disorders (Andersen et al., 2017).

Increased risk of PD can relate to many factors, such asconsumption of (processed) dairy products, past traumaticbrain injury, heavy metal toxicity, certain food additives,polypharmacy, certain parasites, and exposure to pesticidesand even history of melanoma (although this latter factorappears strictly correlational). In contrast, the factors thatreduce the risk of occurring PD are associated with caffeineconsumption, smoking, physical activity, and higher serumurate concentrations of NSAIDs. Caffeine, nicotine, andurate may be neuroprotective and give benefits in patientswith early PD. Whether this mild evidence is offset by theother more serious detriments implicated by caffeine, nico-tine, and NSAIDs is another matter. Researchers are lookingfor possible ways to identify this disease in its early stagesand possibly using (healthy) neuroprotective interventionsbefore the presentation of motor symptoms (Ascherio andSchwarzschild, 2016).

Tryptophan is the precursor not only of serotonin, but alsois degraded to the kynurenic acid, 3-hydroxykynurenine, andquinolinic acid. Kynurenine pathway that regulates the synthe-sis of these neuroactive metabolites. The human immune sys-tem controls the kynurenine pathway. Hyperfunction orhypofunction of neuroactive metabolites is caused by dysregu-lation of the kynurenine pathway, which relates closely to neu-rological and neurodegenerative disorders. The concentrationof 3-hydroxykynurenine (3-HK) is increased in the basal gan-glia of PD patients, whereas kynurenic acid (KYNA) andkynurenine levels are slightly reduced (Ogawa et al., 1992;Schwarcz et al., 2012). The strongest quinolinic acid (QUIN) isfound in glial cells. This fact suggests that QUIN might partici-pate in the pathogenic process in Alzheimer’s disease (Guille-min et al., 2005; Schwarcz et al., 2012). Interferon g (INF- g)product large amounts of neopterin, wherein IFN-g inducesindoleamine 2,3-dioxygenase (IDO), which causes degradationL-tryptophan to kynurenine.

In the literature, there are reports on high concentrations ofneopterin, Trp, and kynurenine found in serum and CSF sam-ples. Widner,Leblhuber, and Fuchs (2002) examined 22patients with PD (15 females and seven males) and 11 age-matched controls group, without obvious neuropsychiatricsymptoms (6 females and five males). From eight patients withPD were collected cerebrospinal fluid specimens. The resultsshowed significantly higher concentrations of neopterin andkynurenine/Trp ratio (kyn/trp ratio) and lower Trp concentra-tions in serum samples of PD patients compared to healthycontrols. Similar relationships were found in CSF from eightPD patients. Comparing the two body fluids, serum neopterinconcentrations were higher than in CSF. It can be assumed thatreduced dietary intake of Trp could significantly contribute toTrp depletion in PD patients (Widner et al., 2002). Similarresults were obtained by Ogawa et al. (1992) who observed in

PD patients increased the level of 3-hydroxykynurenine (3-HA), while the level of KYNA decreased.

The search for new biomarkers is always scientific interest.Lewitt et al. (2013) employed targeted metabolomics, usingCSF from PD patients and controls. They observed changes inthe ratio of 3-hydroxykynurenine (3-HK)/kynurenic acid(KYNA). This variation in the ratio 3-HK/KYNA is significantbecause 3-HK is a precursor of the quinolinic acid and by gen-eral hydroxyl radicals might cause oxidative damage. WhereasKYNA has neuroprotective potential. Promote neurodegenera-tion in the brain might cause an increased ratio of 3-HK/KYNA (Lewitt et al., 2013). In another study, Mollenhauer andZhang (2013) tried to unveil the candidate metabolic pathwayrelated to PD. They examined 35 patients with PD withoutdementia, and as a control group, 15 healthy age-matched par-ticipants without PD. The results showed that metabolomicprofiles of patients with PD were substantially different fromcontrol groups. PD profiles had significantly lower levels ofTrp. Decreased serum Trp levels appear to be significantlyrelated to psychiatric problems in patients with PD (Mollenha-uer and Zhang, 2013).

Alzheimer’s disease was first described more than a centuryago. This disease affects approximately 35.6 million peopleworldwide in 2010 and by the year 2050 estimated 115 millionpeople (Van Wijngaarden et al., 2017). One of the major causesof dementia is AD. So far, the pathogenesis of this disease isnot completely understood. It is, however, well known that thekynurenine pathway is the principal route for the metabolismof the Trp. Among other metabolic pathways, Trp is the kynur-enine pathway involved in AD pathogenesis (Kincses, Toldi,and V�ecsei, 2010). Hence, changes in AD behaviors have beenobserved in the kynurenine pathway. These changes are basedon a reduction in the serum concentration of KYNA and Trpand in increased concentrations of 3- hydroxykynurenine (3-HA) and kynurenine (O’Farrell and Harkin, 2017).

The mechanism of AD is similar to other neurodegenerativediseases such PD. Mechanisms of AD are associated with thekynurenine pathway (KP). Many proinflammatory cytokinesactivate kynurenine pathway, and then they create metabolitesassociated with the pathogenesis of AD. For limiting kynure-nine pathway responsible is indoleamine-2-3 dioxygenase(IDO). The expression of IDO is markedly increased with theproliferation of proinflammatory cytokines INF-g. Overexpres-sion of IDO is induced by INF-g in the presence of amyloidplaques, which leads to dysregulation of KP. In dysregulationof KP is also involved interleukin-18 (IL-18), which inducesstrong inflammatory reactions. IL-18 appears to be responsiblefor the production of neurotoxic QUIN, wherein is promotedneurodegeneration. Furthermore, QUIN may cause anincreased level of lipid peroxidation in oxidative stress and mayprovoke neuronal death by cytotoxicity. In AD patients,unchanged levels of QUIN in cerebral and CSF have beenobserved, whereas the level of KYNA was increased in the stria-tum, but in CSF and plasma, the level of KYNA was decreased.At this time, there is still no clear explanation concerning tohow decrease KYNA levels that contribute to Alzheimer’s dis-ease (Tan, Yu, and Tan, 2012).

(Kincses, Toldi, and V�ecsei, 2010) presented evidence ofthe participation of the kynurenine pathway in the

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pathogenesis of AD. They measured the kynurenine, Trpand KYN/Trp ratio in the plasma. Examined were tenpatients with AD (six females and four males) and 15healthy controls (11 females and four males). The resultsshowed that Trp concentration was significantly lower inAD patients than controls, while KYN showed no signifi-cant differences between AD patients compared to controls,and the KYN/Trp ratio was considerably higher in patientswith AD (Kincses, Toldi, and V�ecsei, 2010).

In the pathogenesis of AD, inflammation and immune acti-vation are factors related to increased blood concentration ofcertain biomarkers, such as the kynurenine to Trp ratio (KYN/Trp) and neopterin. Wissmann et al. (2013) examined 43 ADpatients (26 females and 17 males, range aged 57–99 years),they measured neopterin, Trp, and kynurenine concentration.They observed lower Trp levels, higher kynurenine levels, and ahigher KYN/Trp ratio, which is correlated with the higher con-centration of neopterin. (Wissmann et al., 2013). Similar resultswere obtained by Widner et al. (1999), which examined 24patients with AD and observed lower Trp levels, higher kynure-nine levels, and KYN/Trp ratio.

Other scientists examined the concentrations of the com-pound in CSF of patients with AD. They explored correlationsbetween KYNA levels, well-established AD, cognitive declineand proinflammatory markers. Then they measured KYNA lev-els in 19 AD patients, aged 72–79 years, and 20 healthy con-trols, age matched. The results showed that AD patients havesignificantly KYNA levels versus the healthy controls. Addi-tionally, they observed that female AD patients had signifi-cantly higher KYNA levels compared to male AD patients,wherein this result was not observed in the healthy controlgroup (Wennstr€om et al., 2014).

6. Tryptophan and sleep disorders

Sleep disorders are a serious problem in industrialized soci-eties and concerns not only adults but also children andyoung people. It is estimated that sleep disorders affect atleast 20–40% of adults, and half of them consider it to beimportant. Likewise, various types of sleep difficulties con-cern 25–62% of the population of children, depending ontheir stage of development (Blader et al., 1997; Kaczor andSkalski, 2016).

In recent years, experts were interested in the relation-ship between sleep and diet. The basis for the discussion ofthe problem is the enzyme pathway of melatonin synthesis,which precursor for melatonin is serotonin. This, in turn, issynthesized by enzymatic transformation of Trp (Kaczorand Skalski, 2016).

Hormones produced in the brain, such as serotonin andmelatonin, control sleep and circadian rhythms in humans.Melatonin is an active biological compound that is respon-sible for regulating diurnal rhythms and influences theimmune and reproductive system, and gastrointestinalmotility and other digestive processes. The pineal glandsecretes melatonin during periods of darkness. Its task is toregulate circadian rhythms and sleep patterns (Richardet al., 2009; Szczepanik, 2007). Tryptophan is often used forthe treatment of sleep disorders. In the diet Trp produces

therapeutic effects through melatonin. A crucial feature ofTrp treatment is that it does not directly reduce cognitiveability (Richard et al., 2009).

One hypothesis is that sunlight accelerates serotonin synthe-sis. Studies in Japan suggest that combined intervention of abreakfast rich in Trp, regular morning sun exposure, and even-ing lighting combine to improve higher melatonin secretion atnight. Associated with this was found improved sleep qualityand reduced time required to fall asleep (Nakade et al., 2012;Wada et al., 2013).

Infant sleep problems constitute a serious disorder andmight affect brain development (and be implicated in othermore serious health problems, as well). In the literature, thereis a report about the impact of diet on improving the conditionsof sleep. Cubero et al. (2009) examined 30 children with sleepproblems, aged 8–16 months old. In the evening meal, theyadministrated to infants were cereals with varying content ofTrp over a five-week period. Feeding of enriched cereals led tothe maintenance of calmer children and restored sleep. Theyconcluded that regulation of circadian cycle can be influencedby diet (Cubero et al., 2009).

One of many sleep disorders is night terrors. Sharp wakingfrom sleep characterizes night terrors, accompanied by persis-tent terror and fear or increased heart rate, sweating, andscreaming. Promising results have been demonstrated that Trpsupplementation for night terrors. Bruni et al. (2004) examinedthe influence L-5-hydroxytryptophan on sleep terrors. Theystudied 45 children (34 males and 11 females, aged 3.2–10.6 years) safer from sleep terrors. The studied group was sup-plementation by L-5-hydroxytryptophan. Within a month,they observed a reduction of more than half night terror epi-sodes in over 93% of children. These results confirm thatarousal level might be positively influenced by treatment withL-5-hydroxytryptophan, resulting in reduced sleep terrorbehaviors in children (Bruni et al., 2004).

7. Conclusion

The interest in Trp is growing throughout research and healthcommunity worldwide (Figure 2). The role of Trp in the

Figure 2. Diagram of the frequency of scientific reports on the use of tryptophansupplementation in the study of different diseases in 2007–2016. The literaturereview was based on PubMed sources, sorted by best match, for the phrase: tryp-tophan supplementation or Trp supplementation and diseases.

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relationship serotonin-Trp uptake with diet is particularlyintriguing and deserves much more insightful data to achieve aforthright and clearer conclusion. Certainly, research in thenutritional fields must be further investigated and implemented,to elucidate the role of supplemented Trp in foods and mealsthat improve human health and prevent many serotonin-relatedpathologies. We believe that an optimized and personalized dietcan help to minimize the symptoms of illness, which will resultin improved health.

ORCID

Salvatore Chirumbolo http://orcid.org/0000-0003-1789-8307Geir Bjørklund http://orcid.org/0000-0003-2632-3935

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