International Journal of

Molecular Sciences

Review
Tryptophan Metabolism in Depression: A Narrative Review
with a Focus on Serotonin and Kynurenine Pathways
Ana Salomé Correia 1,2,3 and Nuno Vale 1,3,4, *

1 OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS),
Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal; anncorr07@gmail.com
2 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228,
4050-313 Porto, Portugal
3 CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Hernâni Monteiro,
4200-319 Porto, Portugal
4 Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine,
University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
* Correspondence: nunovale@med.up.pt; Tel.: +351-220426537

Abstract: Depression is a common and serious disorder, characterized by symptoms like anhedonia,
lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and
not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as
neuroinflammation. There is a high need for the development of new therapies and gaining new
insights into this disease is urgent. One important player in depression is the amino acid tryptophan.
This amino acid can be metabolized in two important pathways in the context of depression: the
serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several
processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and
kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review
aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in
Citation: Correia, A.S.; Vale, N.
depression, starting with a global overview about these topics and ending with the focus on these
Tryptophan Metabolism in pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation
Depression: A Narrative Review with in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in
a Focus on Serotonin and Kynurenine depression, particularly the serotonin and kynurenine pathways.
Pathways. Int. J. Mol. Sci. 2022, 23,
8493. https://doi.org/10.3390/ Keywords: Trp metabolism; serotonin pathway; kynurenine pathway; depression; inflammation;
ijms23158493 brain-derived neurotrophic factor; stress; microbiota
Academic Editor: Yong-Ku Kim

Received: 20 July 2022

Accepted: 28 July 2022 1. Introduction
Published: 31 July 2022
Depression is a disease that affects millions of people around the world. It is a very
Publisher’s Note: MDPI stays neutral complicated disease, difficult to study and fully understand, being one of the biggest chal-
with regard to jurisdictional claims in lenges in medicine and neurosciences. Currently, there are several therapeutic modalities
published maps and institutional affil- for this disease, particularly antidepressant therapy and psychotherapy. However, despite
iations. being quite effective, there is still a lot of failure in this therapy, and, above all, relapse of
depression is a common reality. Thus, the deepening of the molecular knowledge inherent
to this disease to fill the existing gaps in the therapy is a major focus of neuroscience. In
fact, several factors are associated with the development of depression, such as exposure to
Copyright: © 2022 by the authors.
high levels of permanent stress; neuroinflammation; and general dysregulation of neuro-
Licensee MDPI, Basel, Switzerland.
transmitters, such as serotonin (5-HT), dopamine, and noradrenaline [1,2]. The metabolism
This article is an open access article
distributed under the terms and
of the amino acid tryptophan (Trp) has a high participation in all of these processes. This
conditions of the Creative Commons
amino acid is obtained exclusively from the diet and plays a fundamental role in several
Attribution (CC BY) license (https:// physiological reactions. Its metabolism into 5-HT and kynurenine (Kyn) plays a key role in
creativecommons.org/licenses/by/ depression [3], as will be explained in detail throughout this manuscript. Thus, all of the
4.0/). processes associated with the metabolism of Trp into 5-HT/Kyn must be strictly regulated

Int. J. Mol. Sci. 2022, 23, 8493. https://doi.org/10.3390/ijms23158493 https://www.mdpi.com/journal/ijms

 Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW

detail throughout this manuscript. Thus, all of the processes associated wit
Int. J. Mol. Sci. 2022, 23, 8493 metabolism of Trp into 5-HT/Kyn must be strictly regulated to not disturb 2 of 17its homeo
balance. The Kyn pathway is important for several physiological processes includi
generation of cell energy, inflammation, immune response, and neurotransm
However, overactivation of this pathway is generally associated with a lower acti
to not disturb its homeostatic balance. The Kyn pathway is important for several physio-
of the 5-HT pathway, promoting the development of mechanisms associated
logical processes including the generation of cell energy, inflammation, immune response,
depression. Furthermore, it is important to note that this pathway is divided int
and neurotransmission. However, overactivation of this pathway is generally associated
major branches: neurotoxic and neuroprotective branches. In depression, there is
with a lower activation of the 5-HT pathway, promoting the development of mechanisms
greater activation of the neurotoxic branch of this pathway [4,5]. Regarding the
associated with depression. Furthermore, it is important to note that this pathway is di-
pathway, it also assumes vital functions throughout the body, involving v
vided into two major branches: neurotoxic and neuroprotective branches. In depression,
physiological processes such as mood, motor control, regulation of circadian rhythm
there is much greater activation of the neurotoxic branch of this pathway [4,5]. Regarding
gastrointestinal regulation. In depression, this pathway is widely studied, and in ge
the 5-HT pathway, it also assumes vital functions throughout the body, involving various
it is known that increased levels of 5-HT and disruptions to its receptors and path
physiological processes such as mood, motor control, regulation of circadian rhythm, and
gastrointestinalare also widely
regulation. associated with
In depression, this disease
this pathway [6,7]. Thus,
is widely theand
studied, study of Trp metabol
in general,
Kyn and 5-HT takes a central importance in the investigation
it is known that increased levels of 5-HT and disruptions to its receptors and pathways of depression. Ther
this narrative review will focus on these pathways
are also widely associated with this disease [6,7]. Thus, the study of Trp metabolism in in processes suc
neuroinflammation, stress, microbiota, and brain-derived
Kyn and 5-HT takes a central importance in the investigation of depression. Therefore, this neurotrophic
narrative reviewdysregulation
will focus on in these
depression.
pathways The inmain goal is such
processes to clarify these processes, which ma
as neuroinflammation,
in the development of new therapies or biomarkers and
stress, microbiota, and brain-derived neurotrophic factor dysregulation in depression. help to improveThe the quality
of patients who suffer from this condition that is so disturbing
main goal is to clarify these processes, which may help in the development of new ther- and challenging to
daily lives. For the research, collection of papers was carried
apies or biomarkers and help to improve the quality of life of patients who suffer from out through a search
this condition PubMed
that is sodatabase,
disturbing considering mainlyto
and challenging literature published
their daily in the
lives. For thelast 5 years and foc
research,
on the
collection of papers wasmost relevant
carried papers for
out through the topic.
a search Figure
on the PubMed1 summarizes the information pres
database, considering
in published
mainly literature this review. in the last 5 years and focusing on the most relevant papers for
the topic. Figure 1 summarizes the information presented in this review.

Figure 1. Schematic abstract

Figure of the information
1. Schematic presented
abstract of the in thispresented
information review. Briefly,
in this the Trp metabolism
review. Briefly, the Trp meta
is important in several processes
is important connected
in several with depression,
processes particularly
connected with neuroinflammation,
depression, stress
particularly neuroinflammation
response, gut microbiota
response,dysregulation,
gut microbiotaand brain-derived
dysregulation, andneurotrophic
brain-derivedfactor activity. Illustration
neurotrophic factor activity. Illus
created with BioRender [8]. TPH2:
created with tryptophan
BioRender hydroxylase
[8]. TPH2: 2; 5-HT1A:
tryptophan serotonin
hydroxylase 1A receptor;
2; 5-HT1A: serotoninIDO:
1A recepto
indoleamine 2-3-dioxygenase
indoleamine 2-3-dioxygenase 1; TDO: tryptophan1; TDO: tryptophan 2,3-dioxygenase;
2,3-dioxygenase; SERT: serotonin transpo
SERT: serotonin transporter.

2. Depression—A Brief Contextualization

Depression is a globally prevalent disease. About 280 million people in the world have
depression [9]. This is a very debilitating illness, characterized by anhedonia, sad mood,
disrupted circadian cycle, changes in appetite or weight, lack of energy, and cognitive
 2. Depression—A Brief Contextualization
Depression is a globally prevalent disease. About 280 million people in the world
have depression [9]. This is a very debilitating illness, characterized by anhedonia, sad
Int. J. Mol. Sci. 2022, 23, 8493 3 of 17
mood, disrupted circadian cycle, changes in appetite or weight, lack of energy, and
cognitive abnormalities. In severe cases, this disease can even lead to death by suicide
[9,10]. One of the major problems associated with depression is the high rate of recurrence,
abnormalities.
therapy failure,Inandsevere
lackcases, this disease can evenespecially
of diagnosis/treatment, lead to death by suicide
in low- [9,10]. One of
and middle-income
the major problems associated with depression is the high rate of recurrence,
countries [1,9,2]. However, there are effective treatment modalities, particularly therapy failure,
and lack of diagnosis/treatment, especially in low- and middle-income
psychotherapy and/or antidepressant medication [2]. Despite all of the recent advances countries [1,2,9].
in
However, there are effective treatment modalities, particularly psychotherapy
neurosciences, there is still no explanation for all of the molecular aspects of depression. and/or
antidepressant medication
However, it is known that [2]. Despite
biogenic all ofdeficiency
amine the recent (particularly
advances in neurosciences,
5-HT, dopamine, thereandis
still no explanation for all of the molecular aspects of depression. However,
noradrenaline), neurotrophic factors such as brain-derived neurotrophic factor (BDNF), it is known that
biogenic amine deficiency (particularly 5-HT, dopamine, and noradrenaline), neurotrophic
gut microbiota deregulation, genetic, immunologic, endocrine, environmental factors,
factors such as brain-derived neurotrophic factor (BDNF), gut microbiota deregulation,
and neurogenic problems are underlying the origin of depression [11]. The role of
genetic, immunologic, endocrine, environmental factors, and neurogenic problems are
monoamines in depression is widely studied. Particularly, 5-HT is highly connected with
underlying the origin of depression [11]. The role of monoamines in depression is widely
depression. This monoamine is produced from the amino acid Trp, and the disrupted
studied. Particularly, 5-HT is highly connected with depression. This monoamine is
activity of 5-HT pathways is related to the pathophysiology of depression [6]. Indeed,
produced from the amino acid Trp, and the disrupted activity of 5-HT pathways is related
nowadays, antidepressants based on 5-HT reuptake to the synaptic cleft (SSRIs—selective
to the pathophysiology of depression [6]. Indeed, nowadays, antidepressants based on 5-HT
5-HT reuptake inhibitors) and are effective and one of the most prescribed worldwide,
reuptake to the synaptic cleft (SSRIs—selective 5-HT reuptake inhibitors) and are effective
highlighting the role of 5-HT in depression. Nevertheless, it is important to keep in mind
and one of the most prescribed worldwide, highlighting the role of 5-HT in depression.
that this disease is extraordinarily complex, and impaired 5-HT activity can cause
Nevertheless, it is important to keep in mind that this disease is extraordinarily complex,
depression, but is neither necessary nor sufficient, with the presence of other factors being
and impaired 5-HT activity can cause depression, but is neither necessary nor sufficient,
important
with [6], as referred
the presence of otherabove
factors(Figure 2).
being important [6], as referred above (Figure 2).

Figure 2.2.Depression
Figure Depression is a complex disease. disease.
is a complex Hypothalamic–pituitary–adrenal (HPA) axis (HPA)
Hypothalamic–pituitary–adrenal dysfunction,
axis
low levels of neurotransmitters (such as 5-HT, noradrenaline, and dopamine) and
dysfunction, low levels of neurotransmitters (such as 5-HT, noradrenaline, and dopamine) neurotrophic factors
and
(such as BDNF),
neurotrophic brain(such
factors atrophy of regions
as BDNF), such
brain as the hippocampus,
atrophy of regions suchincreased levels of inflammation
as the hippocampus, increased
levels
and of inflammation
oxidative and oxidative
stress, and decreased levels stress, and decreased
of neurogenesis are somelevels of neurogenesis
underlying are some
features of depression.
underlying created
Illustration featureswith
of depression.
BioRenderIllustration
[8]. created with BioRender [8].

3. Trp Metabolism
3. Trp Metabolism
Trp
Trp isisananamino
aminoacid obtained
acid exclusively
obtained through
exclusively the diet.
through theThis amino
diet. This acid is essential
amino acid is
for several human processes, including gastrointestinal and nervous functions,
essential for several human processes, including gastrointestinal and nervous functions, being used
for protein synthesis and metabolized essentially by two pathways: the Kyn
being used for protein synthesis and metabolized essentially by two pathways: the Kyn and the 5-HT
pathways.
and the 5-HT Additionally,
pathways.in the gut, the microbiota
Additionally, in the gut, metabolizes
the microbiotaTrpmetabolizes
by the indole pathway.
Trp by the
Figure 3 summarizes the Trp metabolism by the Kyn and 5-HT pathway, which are the
focus of this article.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 18

Int. J. Mol. Sci. 2022, 23, 8493 4 of 17

indole pathway. Figure 3 summarizes the Trp metabolism by the Kyn and 5-HT pathway,
which are the focus of this article.

3. Summary of the two major metabolic pathways of the amino acid Trp:
Figure 3. Trp: 5-HT and Kyn
Kyn
pathways. All of the abbreviations
pathways. abbreviations are
are described
described in
in text.
text. Illustration
Illustration created
created with
with BioRender
BioRender [8].
[8].

The Kyn is the major Trp Trp metabolism

metabolism pathway (about 95% of free Trp is is aa substrate
substrate
for this
this pathway)
pathway) [12].[12]. This pathway is important
important for for physiological
physiological processes
processes including
including
the generation of cell energy,
energy, inflammation,
inflammation, immune response, and neurotransmission.
neurotransmission.
Indeed, this metabolic pathway influences physical exercise responses and mental health,
being linked to diseases such as depression, schizophrenia,schizophrenia, cancer,
cancer, and diabetes
diabetes [4,5,12].
[4,5,12].
This pathway exists in several cells/tissues, such as the liver, brain, and immune
cells/tissues, such as the liver, brain, and immune cells [4]. cells [4].
The rate-limiting and
The rate-limiting and first
firststep
stepininthe
theKyn
Kynpathway
pathway is is
thethe conversion
conversion of Trp
of Trp to Kyn
to Kyn by
by the
the enzymes
enzymes indoleamine
indoleamine 2-3-dioxygenase
2-3-dioxygenase 1 and1 2and
(IDO12 (IDO1 and IDO2)
and IDO2) and tryptophan
and tryptophan 2,3-di-
2,3-dioxygenase
oxygenase (TDO). (TDO).
Then, Then,
Kyn isKyn
mainlyis mainly
convertedconverted to 3-hydroxykyn
to 3-hydroxykyn (3-HK) by (3-HK) by the
the enzyme
enzyme kynurenine 3-monooxygenase (KMO). 3-HK is then converted
kynurenine 3-monooxygenase (KMO). 3-HK is then converted to xanthurenic acid (XA) to xanthurenic acid
(XA) by the enzyme kynurenine aminotransferase (KAT) and to 3-hydroxyanthranilic
by the enzyme kynurenine aminotransferase (KAT) and to 3-hydroxyanthranilic acid (3- acid
(3-HAA)
HAA) byby thethe enzyme
enzyme kynureninase(Kynu).
kynureninase (Kynu).Then,
Then,3-HAA
3-HAAisismetabolized
metabolized in in picolinic
picolinic acid
acid
(PA) by aminocarboxymuconate-semialdehyde decarboxylase
(PA) by aminocarboxymuconate-semialdehyde decarboxylase (ACMSD) and (ACMSD) and in quinolinic
in quino-
acid
linic (QA) by non-enzymatic
acid (QA) by non-enzymatic conversion.
conversion.AfterAfter
that,that,
QA is QAmetabolized
is metabolizedto NAD+
to NAD+by theby
action of quinolinate phosphoribosyl transferase (QPRT). Additionally,
the action of quinolinate phosphoribosyl transferase (QPRT). Additionally, to a lesser ex- to a lesser extent,
Kyn
tent, is
Kynmetabolized into into
is metabolized kynurenic acidacid
kynurenic (Kyna) by the
(Kyna) enzymatic
by the enzymaticaction of KAT
action of KATandandin
anthranilic acid (AA) by Kynu’s action
in anthranilic acid (AA) by Kynu’s action [4,13]. [4,13].
The 5-HT pathway is also extremely important to human physiology. Serotonergic
The 5-HT pathway is also extremely important to human physiology. Serotonergic
networks are crucial in behavioral aspects (such as mood, sexuality, memory, appetite, stress
networks are crucial in behavioral aspects (such as mood, sexuality, memory, appetite,
response, and anger), as well as other central nervous system effects (like motor control,
stress response, and anger), as well as other central nervous system effects (like motor
regulation of circadian rhythm, and body temperature) and effects outside of the central
control, regulation of circadian rhythm, and body temperature) and effects outside of the
nervous system, such as gastrointestinal regulation, nociception, mammary gland devel-
central nervous system, such as gastrointestinal regulation, nociception, mammary gland
opment, vasoconstriction/dilation, regulation of heart rate, and platelet aggregation [7].
development, vasoconstriction/dilation, regulation of heart rate, and platelet aggregation
This pathway’s first and rate-limiting step is the conversion of Trp to 5-hydroxytryptophan
[7]. This pathway’s first and rate-limiting step is the conversion of Trp to 5-hydroxytryp-
(5-HTP) by the enzymes tryptophan hydroxylase 1 or 2 (TPH1 or 2, mostly expressed in
tophan (5-HTP) by the enzymes tryptophan hydroxylase 1 or 2 (TPH1 or 2, mostly ex-
peripheral and in the central nervous tissues, respectively). Then, 5-HTP is decarboxylated
pressed in peripheral and in the central nervous tissues, respectively). Then, 5-HTP is de-
by the aromatic acid decarboxylase (AADC) to form 5-HT, which can be metabolized to
carboxylated by the aromatic acid decarboxylase (AADC) to form 5-HT, which can be me-
form N-acetylserotonin (NAS) by arylalkylamine N-acetyltransferase (AANAT), and then
tabolized
by to form N-acetylserotonin
N-acetylserotonin O-methyltransferase (NAS)
(ASMT) by to arylalkylamine
form melatonin. N-acetyltransferase
5-HT can also be
metabolized by the enzyme monoamine oxidase (MAO) to form 5-hydroxyindoleacetic
acid (5-HIAA), the major 5-HT metabolite [3,13,14].
Lastly, the indole pathway is conducted by the gut microbiota. Briefly, this pathway
generates several metabolites (like indole and tryptamine) that are important to the host
Int. J. Mol. Sci. 2022, 23, 8493 5 of 17

physiology. Indeed, these metabolites participate in processes such as immune system

regulation, gastrointestinal motility, inflammation, and anti-oxidative effects [13,15].

4. Trp Metabolism in Depression—An Overlook

The Trp metabolism is widely involved in depression and other neuropsychiatric
disorders, mainly by being responsible for the synthesis of both 5-HT and Kyn, which are
important neuroactive compounds [3]. Indeed, a study focused on the effect of dietary Trp
on affective disorders highlighted that a diet enriched in Trp may result in less depressive
symptoms and better mood states of individuals. Additionally, a diet with low levels of
Trp resulted in irritability and anxiety in comparison with when the same individuals had
a Trp-rich diet [16].
Particularly, the role of 5-HT in this disease is deeply studied. Focusing on the
metabolism of Trp to 5-HT/melatonin/5-HIAA, several aspects are intimately connected
with depression’s etiology and pathophysiology. The enzyme TPH has an essential role
in many mental disorders, including depression. Studies demonstrate that stress inhibits
the expression of this enzyme, reducing the levels of 5-HT [17]. Indeed, studies also cor-
relate the expression of TPH1 enzyme with depression and responses to antidepressant
medication. A solid hypothesis is that the periphery cells that produce 5-HT have a TPH1
dysfunction, leading to deficient brain 5-HT levels. This leads to a homeostatic response to
low 5-HT levels by the TPH2 enzyme, which was overexpressed in individuals that have
committed suicide [18,19]. Additionally, both 5-HTP and 5-HT play important roles in
depression. 5-HTP may help increase 5-HT levels, reducing the symptoms of depression.
Evidence points out that the transport of 5-HTP across to the brain is deficient in depres-
sion [20,21]. Another study showed that the combination of 5-HTP with nialamide (an
antidepressant, MAO inhibitor) was beneficial when compared with the administration
of nialamide alone [20,22]. The same happened with the combination of L-deprenil (an-
other MAO inhibitor) with 5-HTP [20,23]. Decreased levels of 5-HT and disruptions in its
receptors and pathways are also widely associated with this pathology. Indeed, deficits
in serotonergic transmission, including reductions in 5-HT neurons and their projections,
are associated with this disease and failure of antidepressant responses. Additionally, the
most commonly prescribed antidepressants are based on the blockade of 5-HT transporter
(5-HTT or SERT), increasing the levels of 5-HT on the synaptic cleft, promoting antidepres-
sant responses [6,24]. MAO enzyme imbalances are also associated with the pathology
of depression. Indeed, monoamine oxidase inhibitors (MAOIs) have proven efficacy in
treating depression [25]. MAO-A is more involved in the pathophysiology of depression,
as elevated MAO-A activity and expression are observed in depressed individuals and in
animal models of depression [26]. Nevertheless, MAO-B activity is also altered in depres-
sion. Indeed, a study revealed that elevated MAO-B levels were found in the prefrontal
cortex of patients with major depressive episodes [27]. Other important metabolites in the
5-HT pathway are 5-HIAA and melatonin. Starting with 5-HIAA, a study reported that
low levels of this metabolite in cerebrospinal fluid were associated with suicidal attempts
in depressed individuals [28], being linked with low levels of 5-HT. Lastly, low levels of
melatonin were also observed in depressed patients [29], despite some literature inconsis-
tencies. For example, there are studies that correlate lower nocturnal serum/saliva levels
of melatonin to depression, whereas others found no differences or even elevated levels
(versus non depressed individuals) [30,31]. Nevertheless, studies in animals demonstrated
that melatonin reduced neuroinflammation induced by lipopolysaccharide (LPS), as well
as NF-κB expression in the cortex and the hippocampus of these animals, leading to the
attenuation of autophagy impairment and improvement of depressive symptoms [32].
The Kyn pathway is also implicated in depression. Indeed, this pathway is strongly
activated in depression, and may contribute to the progression of the disease [33]. Both
IDO and TDO enzymes are overactivated during depression, highlighting the use of IDO
and TDO inhibitors as potential drugs to treat depressive disorder [33]. Additionally, it
is important to remember that the metabolite Kyna is considered a neuroprotective com-
Int. J. Mol. Sci. 2022, 23, 8493 6 of 17

pound, whereas 3HK is neurotoxic. In depression, there is an imbalance between these

compounds. Indeed, astrocytes mainly produce Kyna because they lack the enzyme KMO,
whereas microglia and macrophages produce essentially the neurotoxin QA from the 3HK
pathway [19,34,35]. In depression, it is stated that there is a loss of astrocytes, contribut-
ing to the overactivation of 3HK pathway. In turn, the overactivation of this pathway
induces even more astrocyte and neuronal apoptosis, lowering the levels of important
neuroprotective factors produced by these cells, such as glial-derived neurotrophic factor
(GDNF) [19]. Thus, KMO activation relates to depression. Additionally, it was observed
that increases in the levels of QA contribute to reduced levels of dopamine, choline, and
γ-aminobutyric acid (GABA) [36], as well as disturbances in glutamatergic pathways, also
known to be dysfunctional in depression [19,37]. Furthermore, in depression, hippocampal
atrophy is described. This hippocampal atrophy may also be linked with imbalances in
neurotoxic/neuroprotective compounds such as QA/Kyna [38]. Evidence also suggests
that the overproduced proinflammatory cytokines in depression induce the IDO enzyme,
promoting the Kyn pathway, and thus decreasing the activation of the 5-HT pathway and
reducing 5-HT production [38]. In mice exposed to chronic unpredictable mild stress,
a Trp-rich diet shifted the Trp metabolism more toward the 5-HT pathway than to the
Kyn pathway, which was enhanced in these mice previously to Trp supplementation [39].
Thus, several pieces of evidence indicate that the Kyn pathway is an important player in
depression, being a potential therapeutic target. In this review, we will focus on processes
such as inflammation and neurotrophic factor expression in depression, associated with
Trp metabolism in the Kyn and 5-HT pathways.

4.1. Trp Metabolism and Depression’s Associated Neuroinflammation

Neuroinflammation is a hallmark widely associated with several neurological and
neuropsychiatric diseases, such as depression and Alzheimer’s disease. By regulating the
production of immune factors and immune cell activation, neuroinflammation assumes an
important role in depression [40]. There is a positive relationship between antidepressant
therapy/psychotherapy and the reduction of inflammatory signs, highlighting the con-
nection between depression and inflammatory processes [41]. Proinflammatory cytokines
are substances produced essentially by activated macrophages, involved in the overacti-
vation of inflammatory reactions. Some examples are IL-1β, IL-6, and TNF-α [42]. These
cytokines are involved in HPA–axis overactivation, leading to an increase in cortisol con-
centration and glucocorticoid receptor resistance, mechanisms linked to the pathogenesis
of depression [41,43].
Alteration of Trp metabolism by proinflammatory cytokines is also an important
process that links inflammation to depression. Indeed, these cytokines induce the IDO
enzyme, promoting the activation of the Kyn pathway and consequently reducing the
activation of 5-HT pathway of Trp, leading to an overall decrease in 5-HT synthesis [38].
Additionally, as referred above, the overactivation of Kyn pathway leads to an imbalance
in neurotoxic/neuroprotective compounds, particularly 3-HK/QA/Kyna. Studies revealed
that patients treated with IFN-α have reduced levels of Trp, increased levels of Kyn and
Kyn/Trp ratio activity, and increases in depressive symptoms [44]. Other evidence that
highlights the importance of Kyn pathway in inflammatory processes associated with
depression is the efficacy of ketamine as an antidepressant agent. Indeed, this drug appears
to induce anti-inflammatory effects. Animal studies and clinical evidence revealed that this
drug decreased pro-inflammatory cytokines levels (such as IL-6 and TNF-α), decreased
levels of IDO enzyme, and reduced the activation of the neurotoxic pathway of the Kyn
pathway [45–49]. Furthermore, COVID-19-associated depression is widely reported [50]. A
recent study also indicated that, in COVID-19 patients, there was a major urinary increase
in Kyn, which was associated with disease severity and systemic inflammation [51] and
may be associated with the high levels of depressive symptoms in COVID-19 patients.
Indeed, inflammatory cytokines released in the process of COVID-19 inflammation activate
both the HPA–axis and the IDO enzyme, increasing the levels of toxic metabolites of the
Int. J. Mol. Sci. 2022, 23, 8493 7 of 17

Kyn pathway, which increases overall neuroinflammation and neuronal death, promoting
depressive conditions [52]. Additionally, antidepressants with anti-inflammatory prop-
erties inhibit IDO induction by decreasing the levels of proinflammatory cytokines in
immune-activated individuals, contributing to attenuation of depressive symptoms [53].
The role of the immune system in depression is also supported by the homeostasis of gluta-
matergic neurotransmission, which can be regulated by the QA/Kyna ratio, synthetized
by microglia and astrocytes, respectively [54]. Overactivation of the neurotoxic arm of
Kyn pathway was also observed in suicide attempters, coupled to increased inflammatory
responses. By raising the levels of QA (agonist of NMDA-receptor—N-methyl-D-aspartate
receptor, a glutamate receptor), NMDA-receptor was overactivated, supporting the use of
NMDA-receptor antagonists such as ketamine and dextromethorphan in the treatment of
this disease [55]. Another recent study also supported the role of Kyn in depression’s asso-
ciated neuroinflammation. Saffron administration in mice attenuated inflammation-related
metabolic pathways and modulated the expression of Kyn-related neurotoxicity, attenu-
ating depressive-like behaviors in these animals [56]. Furthermore, the administration of
the anti-inflammatory herb Radix Polygalae to mice exposed to chronic restraint stress
led to modulation of inflammation, microbiota, and Trp/Kyn metabolism. Indeed, Radix
Polygalae reversed the 5-HIAA decrease and the Trp, Kyna, and 3-HK increase induced by
the stress exposure. This herb increased the 5-HT/Kyn ratio, which was decreased under
the stress exposure, revealing an interaction between the anti-inflammatory mechanism
of action and Trp metabolism [57]. Another study that evaluated the link between Trp
metabolism and depressive symptoms in obesity reported that elevated levels of C-reactive
protein (that reflects inflammation) correlated with low levels of Trp and Trp indole path-
way metabolites such as indole-3-carboxaldehyde, observed in the more severe cases of
depressive behavior [58]. In post-partum women with severe depression, dysregulation
of the immune response and Kyn pathway, as well as a reduction in 5-HT levels, was
also observed. Indeed, Trp was directed more towards the Kyn pathway than to the 5-HT
pathway, and had high levels of inflammatory markers, such as IL-6 and IL-8 [59].
Inflammation is also connected to disturbances in the 5-HT pathway of Trp metabolism,
not only by the overactivation of Kyn pathway (explained above), but also by other mech-
anisms. There is a large amount of evidence showing that, in patients with depression,
proinflammatory cytokines originated by the microglia (TNF-α for example) reduce the
presence of 5-HT [60]. Indeed, modulation of 5-HT levels by the administration of SSRIs
reduced the Th17/Treg ratio, supporting an anti-inflammatory action of these drugs [61].
Other studies also demonstrated this connection between 5-HT and inflammatory pro-
cesses. Mice treated with rapamycin (blocks activation of immune T and B cells) showed
increased levels of 5-HT (compared with healthy controls) [62]. Another depressogenic
action of cytokines is the increased expression of the 5-HT transporter, SERT [63]. This
transporter was reported to be upregulated in neurons by the cytokines IL-1β and TNFα.
Indeed, it was found that p38 mitogen-activated protein kinase induced activation of SERT
by inflammatory cytokines [64]. Additionally, SERT expression in immune cells was also
observed in response to IFNα [65]. Other studies also support this evidence of SERT
overexpression by the action of cytokines. After cytokine-induced LPS administration in
mice, SERT activity was stimulated, triggering depressive-like behavior in these animals.
In cultured serotonergic cells and nerve terminal preparations in vitro, SERT activity was
also upregulated by inflammatory cytokines [66]. Cytokines are also reported to affect
the synthesis of monoamines such as 5-HT through disruption of tetrahydrobiopterin, an
important enzyme co-factor to Trp hydroxylase [67,68]. Additionally, high stress levels can
also lead to increased levels of pro-inflammatory cytokine production, leading to changes
in serotonergic pathways, involved in the development of depression [67]. Paroxetine, an
SSRI, has also been demonstrated to be an effective treatment for minimizing depression
induced by IFNα, in patients with melanoma and hepatitis C [69,70]. These studies support
the interplay between neuroinflammation and Kyn/5-HT pathways in depressive disorder.
Int. J. Mol. Sci. 2022, 23, 8493 8 of 17

4.2. Trp Metabolism and Depression’s Associated Chronic Stress

Uncontrolled stress induces changes in the central nervous system, promoting the
development of neuropsychiatric disorders such as depression [41]. The human stress
response is strictly regulated by the HPA–axis, which, when activated, is responsible for the
increase in glucocorticoid levels, particularly cortisol, an important player in depression
and other neurological disorders [71].
As discussed above, proinflammatory cytokines promote an imbalance in neuro-
toxic/neuroprotective metabolites by the overactivation of the neurotoxic arm of the Kyn
pathway. Besides that, these proinflammatory cytokines also activate the HPA–axis, leading
to stress responses that underlie depressive states, such as the observed hippocampal
atrophy [38]. Particularly, by activating NMDA receptors, QA stimulates the production
of interleukins such as IL-6, promoting the overactivity of this axis [72]. Elevated levels
of cortisol correlate with lower levels of Trp in the plasma and a higher Kyn/Trp ratio,
observed in patients who tried to commit suicide [73]. Indeed, cortisol is known to activate
TDO, increasing Kyn production and shifting Trp metabolism from 5-HT to Kyn produc-
tion [74]. Thus, the conversion of Trp in Kyn is promoted by chronic stress levels, mainly
by elevations in cortisol and pro-inflammatory cytokines, which in turn activate IDO/TDO
enzymes [75]. Indeed, treatment with allopurinol (TDO inhibitor) prevented stress-related
reduction in brain 5-HT concentrations by blocking TDO activity. This treatment led to a
reduction in the Kyn pathway activation ratio [76,77]. Additionally, the administration of
1-methyl-Trp (an inhibitor of IDO enzyme) alleviated depressive-like behavior in rodents
exposed to LPS-induced stress [78]. Indeed, LPS exposure increased brains’ IDO mRNA
expression in rodents, resulting in overactivation of the Kyn pathway [79]. Physical exercise
also supports the effects of Kyn pathway in depression’s associated stress. The skeletal mus-
cle PGC-1α1 enzyme’s activity is induced by physical exercise, inducing kat expression and
the conversion of Kyn into Kyna, a neuroprotective metabolite of the Kyn pathway. This
conversion of Kyn into Kyna controls the Kyn/Kyna balance, reducing the levels of free
Kyn and protecting the brain against stress-induced depressive behaviors [80]. PGC-1α1
activity is known to reduce with age and with pathologies such as diabetes. Thus, this lack
of activity may contribute to the depression associated with other pathologies/age [76].
Serotonergic networks are deeply influenced by stress responses. Indeed, some ex-
periments demonstrate this connection. For example, a study carried out in cynomolgus
monkeys revealed that the animals that were more sensitive to stress underexpressed genes
such as TPH2 and 5-HT 1A receptor, important genes in the normal functioning of 5-HT
pathways [81]. Additionally, as referred above, it was revealed that rats exposed to stress
presented lower levels of 5-HT compared with healthy or treated rats. TPH1 and TPH2 were
also less expressed in the rats exposed to high stress levels [17]. Other studies support the
connection of cortisol to serotonergic pathways. For example, the administration of crocin
decreased cortisol levels and increased the levels of 5-HT, ameliorating depressive-like
behavior in mice [82]. The same profile of response was also obtained with the administra-
tion of gossypetin [83], aqueous extracts of miswak, and date palm [84]. Lower levels of
HPA–axis hormones and increased levels of 5-HT and brain-derived neurotrophic factor
were also obtained with Trp oligopeptide diets, promoting positive effects on anxious
depression in mice [85]. Taken together, all of this information highlights the relationship
between Trp metabolism and the stress response present in depression.

4.3. Trp Metabolism and Microbiota in Depression

A lot of studies support the role of gut microbiota in the pathogenesis of disorders
such as depression. Indeed, the changes in the gut microbiota observed in depression
affect the HPA–axis, neurotransmitter levels, and inflammatory processes [86]. The use of
germ-free models to study the relationship between depression and the microbiome has
revealed the crucial role of these microorganisms in normal brain functioning. For example,
exaggerated levels of corticosterone and adrenocorticotropin (HPA–axis hormones) were
observed in germ-free mice exposed to elevated levels of stress [87]. Furthermore, the
Int. J. Mol. Sci. 2022, 23, 8493 9 of 17

administration of Lactobacillus sp. normalized the elevated corticosterone levels present in

rats after maternal separation [88].
A study that involved a murine model of chronic restraint stress revealed that these
animals had depressive-like behavior, as well as strong activation of the Kyn pathway.
Indeed, IDO was overactivated in the brain and the gut. In these animals, the microbiome
profile was altered, and the treatment with Parabacteroides elevated the 5-HT concentra-
tion, supporting the connection between 5-HT/Kyn pathways and the microbiome [89].
Another study revealed that, in stressed mice, there were reduced levels of Lactobacillus and
high levels of Kyn, reflected in behavioral alterations. In these mice, when the Lactobacillus
population was restored, Kyn metabolism was suppressed by IDO1 inhibition in the intes-
tine, particularly by the reactive oxygen species produced by these microorganisms [90].
The evaluation of the antidepressant activity of probiotics such as Bifidobacteria infantis in
rats also revealed that, compared with controls, these rats had a marked increase in plasma
concentrations of Trp and Kyna, as well as reduced 5-HIAA levels, especially in the frontal
cortex [91]. In depressive mice, a Trp-rich diet restructured the gut microbiome, increasing
the number of Lachnospiracea, Lactobacillus, and Bifidobacterium [39].
The direct influence of gut microbiota in serotonergic networks is known. A study
showed that oral administration of S. boulardii attenuated the LPS-induced depressive
behaviors, increasing the levels of brain-derived neurotrophic factor and 5-HT in the
serum [92]. Another study involved rats also exposed to stress, particularly chronic un-
predictable mild stress. These rats developed depressive-like behavior and their fecal
microbiota were evaluated by 16S rRNA sequence analysis. The results revealed that the
microbiota of these rats differed significantly from healthy controls, which may contribute
to depressive-like behavior by interfering with Trp metabolism. Indeed, the levels of 5-HT
and TPH2 were low in the brain, contrasting with high levels of IDO expression [93]. The
comparison of germ-free and conventional animals also indicated that the plasma levels
of 5-HT in conventional animals were 2.8-fold higher than in germ-free animals, support-
ing the role of microorganisms in 5-HT production [94]. In another study, L. lactis strain
WHH2078 increased 5-HTP levels and the expression of TPH1 in cells. In mice exposed
to chronic unpredictable mild stress, these bacteria also alleviated the depressive-like be-
haviors, restoring central 5-HT and 5-HTP levels [95]. Another study evaluated the effect
of a mung bean protein diet in undernourished rats. This diet led to the reproduction of
probiotics, particularly Bifidobacteria and Lactobacillus, as well as increased levels of Trp and
5-HTP in the serum, compared with rats treated with low levels of mung bean protein,
revealing low levels of cognitive dysfunction [96]. The administration of the probiotic
strain L. rhamnosus IMC 501 to zebrafish also led to increased expression levels of bdnf
and genes involved in the brain’s 5-HT signaling metabolism, particularly h1a, tph1b,
tph2, htr1aa, slc6a4a, and mao. Indeed, this was correlated with the behavior of the fishes,
particularly the shoaling behavior. Additionally, a significant increase in Firmicutes was
also observed [97]. These studies support the role of the gut microbiota in Trp metabolism
associated with depressive disorder.

4.4. Trp Metabolism and Brain-Derived Neurotrophic Factor Expression in Depression

Different neurotrophic factors are highly connected to depression, notably BDNF.
These factors are important to neuronal plasticity, a process defined by the adaptation of
the nervous system in response to different stimuli. Depressed individuals have decreased
levels of BDNF in the blood and brain structures connected with depression, such as the hip-
pocampus. Additionally, antidepressants such as SSRIs increase BDNF expression [98,99].
Trp metabolism is implicated in BDNF function. Indeed, a study reported that the depletion
of Trp in healthy patients led to a compensatory increase in serum BDNF levels. This
response was not observed in depressed individuals, in which BDNF levels, as well as
plasma Trp levels, remained low [100]. In another study in depressive mice exposed to
chronic unpredictable chronic stress, Trp supplementation also improved the expression of
BDNF [39].
Int. J. Mol. Sci. 2022, 23, 8493 10 of 17

Kyn pathway and BDNF expression are also connected in the context of depression.
By interacting with the NMDA receptor, QA induces signaling pathways that reduce BDNF
expression [45]. Other Kyn neurotoxic metabolites besides QA also weaken glial-neuronal
networks important to neurotrophic factor synthesis, particularly BDNF [19]. Indeed,
studies demonstrate that BDNF may modulate the Kyn pathway. After exposure to stress
conditions, heterozygous mice (BDNF+/−, about 50% reduction of BDNF expression)
showed increased activation in the neurotoxic arm of the Kyn pathway, increasing the
level of neurotoxic metabolites such as 3-HK, in contrast with the wild-type animals [101].
In another study, the Kyn pathway was altered in mice displaying BDNF Val66Met poly-
morphism. This polymorphism relates to increased predisposition to develop psychiatric
disorders. In this study, these mice showed overactivation of the Kyn pathway [102].
Another study evaluated the effect of the acute examination stress in healthy students,
revealing that the elevation of BDNF levels present in these students limited the neuroin-
flammatory arm of the Kyn pathway, supporting an interplay between BDNF and the Kyn
pathway [103]. This interplay was also supported by a study that revealed that blockade of
IDO1 attenuated depressive-like behavior in mice exposed to chronic unpredictable mild
stress, with a concomitant increase in hippocampal BDNF expression and neurogenesis in
the hippocampus [104].
Impaired expression of BDNF alters 5-HT pathways. For example, it is known that
BDNF stimulates the plasticity of 5-HTergic neurons [105]. This neurotrophic factor reduces
SERT and 5-HT1A receptor function mainly in the hippocampus, and reduces 5-HT2A
receptor function in other brain areas such as the prefrontal cortex [106]. Indeed, studies
in a rat model of acute psychological stress revealed that agonists of 5-HT1A and 5-HT2A
receptors increased BDNF protein expression in diverse brain regions, opposing the effects
of 5-HT1A and 5-HT2A receptor antagonists, supporting the connection between BDNF
and the 5-HT system [107]. In raphe neurons, BDNF promoted the expression of TPH and
upregulated the uptake of 5-HT. This neurotrophic factor also promoted the development
and function of serotonergic neurons [108]. Indeed, the connection of BDNF to serotonergic
pathways is supported by the interaction of this factor with serotonergic receptors such
as 5-HT1A and 5-HT2A, which were impaired in conditions when the BDNF gene was
deleted [108–110]. Another piece of evidence that supports this connection is that the
increased levels of 5-HT may increase BDNF levels, as observed upon administration of
SSRI antidepressants. Indeed, the block of SERT enhances 5-HT pathways through the in-
teraction with different 5-HT receptors that, in turn, increase CREB phosphorylation, which
leads to increased levels of BDNF transcription [108]. Another interesting study evaluated
the effects of gardening in elderly people. In the gardening group, Trp metabolism was
increased, correlated with increased levels of BDNF [111]. Another recent study highlights
the relationship between TPH2 expression and BDNF levels. The administration of a
pargyline (MAO inhibitor) in zebrafish treated with an irreversible inhibitor of TPH2 (p-
chlorophenylalanine) led to reduced BDNF levels, revealing an interdependence between
5-HT and BDNF systems in the antidepressant response [112]. The interaction between
5-HT neurotransmission and the BDNF-related pathways was also supported by another
study. In this study, enhanced Trp intake led to increased activation of 5-HT pathways
that, in turn, modulated the BDNF system, protecting against cognitive decline in aged
rats [113]. Physical exercise is also known to upregulate the BDNF–5-HT system. Indeed,
5-HT participates in BDNF-mediated neuroplasticity, stimulated by aerobic physical exer-
cise in rats [114]. Altogether, these studies support the interplay between BDNF and Trp
metabolism in the 5-HT and Kyn pathways.

4.5. Pharmacological Modulation of Trp Metabolism in Depression—An Overlook

As described throughout this manuscript, Trp metabolism is crucial in the pathophysi-
ology of depression, with great emphasis on the 5-HT pathway. Thus, the pharmacological
modulation of the effects of this pathway plays a major role in the therapy of this disease.
Nevertheless, it is important to refer that, in the management of depression, psychotherapy
Int. J. Mol. Sci. 2022, 23, 8493 11 of 17

also assumes a heavy role. Table 1 summarizes the main drug classes related to 5-HT in the
treatment of depression. These drugs act mainly downstream the production of 5-HT.

Table 1. Principal drug classes related to 5-HT in the treatment of depression.

Drug Class Brief Description Examples

Inhibit SERT at the
SSRIs—Selective 5-HT presynaptic axon terminal, Fluoxetine, sertraline,
Reuptake Inhibitors increasing the amount of 5-HT escitalopram, paroxetine [115]
in the synaptic cleft [115]
Block MAO enzyme,
inhibiting the breakdown of Moclobemide,
MAOIs—Monoamine
5-HT and other tranylcypromine, phenelzine,
Oxidase Inhibitors
neurotransmitters, increasing isocarboxazid [116]
their levels [116]
Inhibit the reuptake of both
5-HT and norepinephrine, by
SNRIs—Serotonin–
blocking reuptake Venlafaxine, duloxetine,
Noradrenaline
transporters, increasing their desvenlafaxine [118]
Reuptake Inhibitors
amount in the synaptic
cleft [117]
Block the reuptake of 5-HT
and norepinephrine, act as
antagonists on post-synaptic
Amitriptyline, imipramine,
TCAs—Tricyclic cholinergic (alpha1 and
desipramine,
Antidepressants alpha2), muscarinic, and
clomipramine [118]
histaminergic receptors (H1),
enhancing
neurotransmission [119]
Antagonism of 5-HT2
NaSSAs—Noradrenergic and (5-HT2A and 5-HT2C) and
Specific Serotonergic 5-HT3 receptors, block α2 Mirtazapine [120]
Antidepressants receptors, enhancing
neurotransmission [120]

Therapies regarding the direct manipulation of Kyn pathways are still not available in
the common medical practice for depression. However, future and intensive research may
generate novel insight into this pathway and the way to manipulate it. Nevertheless, ad-
ministration of 4-chlorokynurenine (an investigational antidepressant drug) enhanced the
neuroprotective arm of the Kyn pathway, decreasing the neurotoxic arm [121]. Additionally,
the administration of escitalopram revealed a 50% decrease in plasma QA, suggesting that
these drugs reduce the neurotoxic arm of the Kyn pathway [122]. Chronic administration
of antidepressants (amitriptyline, imipramine, fluoxetine, and citalopram) in rats also
revealed an increase in Kyna production in the hippocampus and cortex, increasing the
neuroprotective arm of the Kyn pathway [123]. Ketamine also led to increased levels of
Kyna in the serum, associated with a reduction in depression severity [49]. IDO1, TDO,
KMO, and KAT inhibitors are also under investigation, mainly for cancer and not depres-
sion purposes [124]. Indeed, investigations focusing on Trp metabolism may generate a
next step on the treatment of depression.

5. Conclusions
It is extremely important to deeply study depression’s molecular mechanisms, aiming
to understand this extremely complex disease that is very prevalent worldwide. New
therapies urgently need to be developed, and are only possible when research efforts
are present. The study of Trp metabolism in the context of depression may provide new
knowledge and therapeutic possibilities. This amino acid, by being metabolized into the
Int. J. Mol. Sci. 2022, 23, 8493 12 of 17

5-HT or Kyn pathway, assumes a crucial role in several aspects profoundly connected to
depression’s physiopathology, such as neuroinflammation, chronic stress, dysregulation
in the gut microbiota, and BDNF expression levels. The maintenance of the Trp-Kyn/Trp-
5-HT balance is critical for physiological homeostasis, being important to prevent the
development of neuropsychiatric diseases such as depression.

Author Contributions: Conceptualization, N.V.; formal analysis, A.S.C. and N.V.; writing—original
draft preparation, A.S.C.; writing—review and editing, A.S.C. and N.V.; supervision, N.V.; project
administration, N.V.; funding acquisition, N.V. All authors have read and agreed to the published
version of the manuscript.
Funding: This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional through
the COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI),
Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia, in
a framework of the projects in CINTESIS, R&D Unit (reference UIDB/4255/2020) and within the
scope of the project “RISE—LA/P/0053/2020. Nuno Vale also thanks support from FCT and FEDER
(European Union), award number IF/00092/2014/CP1255/CT0004 and CHAIR in Onco-Innovation
at FMUP.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Ana Salomé Correia also acknowledges FCT for funding her PhD grant (SFRH/
BD/146093/2019).
Conflicts of Interest: The authors declare no conflict of interest.

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